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1
Roy, Monideepa, Zhigang Li, and David B. Sacks. "IQGAP1 Is a Scaffold for Mitogen-Activated Protein Kinase Signaling." Molecular and Cellular Biology 25, no. 18 (September 15, 2005): 7940–52. http://dx.doi.org/10.1128/mcb.25.18.7940-7952.2005.
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ABSTRACT IQGAP1 modulates many cellular functions such as cell-cell adhesion, transcription, cytoskeletal architecture, and selected signaling pathways. We previously documented that IQGAP1 binds extracellular signal-regulated kinase (ERK) 2 and regulates growth factor-stimulated ERK activity. Here we show that MEK, the molecule immediately upstream of ERK in the Ras/mitogen-activated protein (MAP) kinase signaling cascade, also interacts directly with IQGAP1. Both MEK1 and MEK2 bound IQGAP1 in vitro and coimmunoprecipitated with IQGAP1. The addition of ERK2 enhanced by fourfold the in vitro interaction of MEK2 with IQGAP1 without altering binding of MEK1. Similarly, ERK1 promoted MEK binding to IQGAP1, but either MEK protein altered the association between IQGAP1 and ERK. Epidermal growth factor (EGF) differentially regulated binding, enhancing MEK1 interaction while reducing MEK2 binding to IQGAP1. In addition, both knockdown and overexpression of IQGAP1 reduced EGF-stimulated activation of MEK and ERK. Analyses with selective IQGAP1 mutant constructs indicated that MEK binding is crucial for IQGAP1 to modulate EGF activation of ERK. Our data strongly suggest that IQGAP1 functions as a molecular scaffold in the Ras/MAP kinase pathway.
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Eblen, Scott T., Jill K. Slack, Michael J. Weber, and Andrew D. Catling. "Rac-PAK Signaling Stimulates Extracellular Signal-Regulated Kinase (ERK) Activation by Regulating Formation of MEK1-ERK Complexes." Molecular and Cellular Biology 22, no. 17 (September 1, 2002): 6023–33. http://dx.doi.org/10.1128/mcb.22.17.6023-6033.2002.
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ABSTRACT Utilizing mutants of extracellular signal-regulated kinase 2 (ERK2) that are defective for intrinsic mitogen-activated protein kinase or ERK kinase (MEK) binding, we have identified a convergent signaling pathway that facilitates regulated MEK-ERK association and ERK activation. ERK2-Δ19-25 mutants defective in MEK binding could be phosphorylated in response to mitogens; however, signaling from the Raf-MEK pathway alone was insufficient to stimulate their phosphorylation in COS-1 cells. Phosphorylation of ERK2-Δ19-25 but not of wild-type ERK2 in response to Ras V12 was greatly inhibited by dominant-negative Rac. Activated forms of Rac and Cdc42 could enhance the association of wild-type ERK2 with MEK1 but not with MEK2 in serum-starved adherent cells. This effect was p21-activated kinase (PAK) dependent and required the putative PAK phosphorylation sites T292 and S298 of MEK1. In detached cells placed in suspension, ERK2 was complexed with MEK2 but not with MEK1. However, upon replating of cells onto a fibronectin matrix, there was a substantial induction of MEK1-ERK2 association and ERK activation, both of which could be inhibited by dominant-negative PAK1. These data show that Rac facilitates the assembly of a mitogen-activated protein kinase signaling complex required for ERK activation and that this facilitative signaling pathway is active during adhesion to the extracellular matrix. These findings reveal a novel mechanism by which adhesion and growth factor signals are integrated during ERK activation.
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Yuan, Jimin, Wan Hwa Ng, Zizi Tian, Jiajun Yap, Manuela Baccarini, Zhongzhou Chen, and Jiancheng Hu. "Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis." Science Signaling 11, no. 554 (October 30, 2018): eaar6795. http://dx.doi.org/10.1126/scisignal.aar6795.
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RAS-RAF-MEK-ERK signaling has a well-defined role in cancer biology. Although aberrant pathway activation occurs mostly upstream of the kinase MEK, mutations in MEK are prevalent in some cancer subsets. Here, we found that cancer-related, activating mutations in MEK can be classified into two groups: those that relieve inhibitory interactions with the helix A region and those that are in-frame deletions of the β3-αC loop, which enhance MEK1 homodimerization. The former, helix A–associated mutants, are inhibited by traditional MEK inhibitors. However, we found that the increased homodimerization associated with the loop-deletion mutants promoted intradimer cross-phosphorylation of the activation loop and conferred differential resistance to MEK inhibitors both in vitro and in vivo. MEK1 dimerization was required both for its activation by the kinase RAF and for its catalytic activity toward the kinase ERK. Our findings not only identify a previously unknown group of MEK mutants and provide insight into some key steps in RAF-MEK-ERK activation but also have implications for the design of therapies targeting RAS-ERK signaling in cancers.
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Geest, Christian R., Miranda Buitenhuis, Marian J. A. Groot Koerkamp, Frank C. P. Holstege, Edo Vellenga, and Paul J. Coffer. "Tight control of MEK-ERK activation is essential in regulating proliferation, survival, and cytokine production of CD34+-derived neutrophil progenitors." Blood 114, no. 16 (October 15, 2009): 3402–12. http://dx.doi.org/10.1182/blood-2008-08-175141.
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AbstractA plethora of extracellular stimuli regulate growth, survival, and differentiation responses through activation of the MEK-ERK MAPK signaling module. Using CD34+ hematopoietic progenitor cells, we describe a novel role for the MEK-ERK signaling module in the regulation of proliferation, survival, and cytokine production during neutrophil differentiation. Addition of the specific MEK1/2 inhibitor U0126 resulted in decreased proliferation of neutrophil progenitors. Conversely, transient activation of a conditionally active MEK1 mutant resulted in the expansion of progenitor cells, which thereafter differentiated normally into mature neutrophils. In contrast, chronic MEK1 activation was found to induce cell death of CD34+ neutrophil progenitors. Microarray analysis of CD34+ progenitor cells showed that activation of MEK1 resulted in changes in expression of a variety of cell-cycle modulating genes. Furthermore, conditional activation of MEK1 resulted in a dramatic increase in the expression of mRNA transcripts encoding a large number of hematopoietic cytokines, chemokines, and growth factors. These findings identify a novel role for MEK-ERK signaling in regulating the balance between proliferation and apoptosis during neutrophil differentiation, and they suggest the need for tight control of MEK-ERK activation to prevent the development of bone marrow failure.
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Du, Lili, and Jesse D. Roberts. "Transforming growth factor-β downregulates sGC subunit expression in pulmonary artery smooth muscle cells via MEK and ERK signaling." American Journal of Physiology-Lung Cellular and Molecular Physiology 316, no. 1 (January 1, 2019): L20—L34. http://dx.doi.org/10.1152/ajplung.00319.2018.
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TGFβ activation during newborn lung injury decreases the expression of pulmonary artery smooth muscle cell (PASMC)-soluble guanylate cyclase (sGC), a critical mediator of nitric oxide signaling. Using a rat PASMC line (CS54 cells), we determined how TGFβ downregulates sGC expression. We found that TGFβ decreases sGC expression through stimulating its type I receptor; TGFβ type I receptor (TGFβR1) inhibitors prevented TGFβ-1-mediated decrease in sGCα1 subunit mRNA levels in the cells. However, TGFβR1-Smad mechanisms do not regulate sGC; effective knockdown of Smad2 and Smad3 expression and function did not protect sGCα1 mRNA levels during TGFβ-1 exposure. A targeted small-molecule kinase inhibitor screen suggested that MEK signaling regulates sGC expression in TGFβ-stimulated PASMC. TGFβ activates PASMC MEK/ERK signaling; CS54 cell treatment with TGFβ-1 increased MEK and ERK phosphorylation in a biphasic, time- and dose-dependent manner. Moreover, MEK/ERK activity appears to be required for TGFβ-mediated sGC expression inhibition in PASMC; MEK and ERK inhibitors protected sGCα1 mRNA expression in TGFβ-1-treated CS54 cells. Nuclear ERK activity is sufficient for sGC regulation; heterologous expression of a nucleus-retained, constitutively active ERK2-MEK1 fusion protein decreased CS54 cell sGCα1 mRNA levels. The in vivo relevance of this TGFβ-MEK/ERK-sGC downregulation pathway is suggested by the detection of ERK activation and sGCα1 protein expression downregulation in TGFβ-associated mouse pup hyperoxic lung injury, and the determination that ERK decreases sGCα1 protein expression in TGFβ-1-treated primary PASMC obtained from mouse pups. These studies identify MEK/ERK signaling as an important pathway by which TGFβ regulates sGC expression in PASMC.
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Hu, Wen-Yang, Parivash Afradiasbagharani, Ranli Lu, Lifeng Liu, Lynn A. Birch, and Gail S. Prins. "Morphometric Analysis of Rat Prostate Development: Roles of MEK/ERK and Rho Signaling Pathways in Prostatic Morphogenesis." Biomolecules 11, no. 12 (December 4, 2021): 1829. http://dx.doi.org/10.3390/biom11121829.
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The molecular mechanisms underlying prostate development can provide clues for prostate cancer research. It has been demonstrated that MEK/ERK signaling downstream of androgen-targeted FGF10 signaling directly induces prostatic branching during development, while Rho/Rho-kinase can regulate prostate cell proliferation. MEK/ERK and Rho/Rho kinase regulate myosin light chain kinase (MLCK), and MLCK regulates myosin light chain phosphorylation (MLC-P), which is critical for cell fate, including cell proliferation, differentiation, and apoptosis. However, the roles and crosstalk of the MEK/ERK and Rho/Rho kinase signaling pathways in prostatic morphogenesis have not been examined. In the present study, we used numerical and image analysis to characterize lobe-specific rat prostatic branching during postnatal organ culture and investigated the roles of FGF10-MEK/ERK and Rho/Rho kinase signaling pathways in prostatic morphogenesis. Prostates exhibited distinctive lobe-specific growth and branching patterns in the ventral (VP) and lateral (LP) lobes, while exogenous FGF10 treatment shifted LP branching towards a VP branching pattern. Treatment with inhibitors of MEK1/2, Rho, Rho kinase, or MLCK significantly inhibited VP growth and blocked branching morphogenesis, further supporting critical roles for MEK/ERK and Rho/Rho kinase signaling pathways in prostatic growth and branching during development. We propose that MLCK-regulated MLC-P may be a central downstream target of both signaling pathways in regulating prostate morphogenesis.
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Chen, Haixia, Renpeng Guo, Qian Zhang, Hongchao Guo, Meng Yang, Zhenfeng Wu, Shan Gao, Lin Liu, and Lingyi Chen. "Erk signaling is indispensable for genomic stability and self-renewal of mouse embryonic stem cells." Proceedings of the National Academy of Sciences 112, no. 44 (October 19, 2015): E5936—E5943. http://dx.doi.org/10.1073/pnas.1516319112.
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Inhibition of Mek/Erk signaling by pharmacological Mek inhibitors promotes self-renewal and pluripotency of mouse embryonic stem cells (ESCs). Intriguingly, Erk signaling is essential for human ESC self-renewal. Here we demonstrate that Erk signaling is critical for mouse ESC self-renewal and genomic stability. Erk-depleted ESCs cannot be maintained. Lack of Erk leads to rapid telomere shortening and genomic instability, in association with misregulated expression of pluripotency genes, reduced cell proliferation, G1 cell-cycle arrest, and increased apoptosis. Erk signaling is also required for the activation of differentiation genes but not for the repression of pluripotency genes during ESC differentiation. Furthermore, we find an Erk-independent function of Mek, which may explain the diverse effects of Mek inhibition and Erk knockout on ESC self-renewal. Together, in contrast to the prevailing view, Erk signaling is required for telomere maintenance, genomic stability, and self-renewal of mouse ESCs.
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Eblen, Scott T., Jill K. Slack-Davis, Adel Tarcsafalvi, J. Thomas Parsons, Michael J. Weber, and Andrew D. Catling. "Mitogen-Activated Protein Kinase Feedback Phosphorylation Regulates MEK1 Complex Formation and Activation during Cellular Adhesion." Molecular and Cellular Biology 24, no. 6 (March 15, 2004): 2308–17. http://dx.doi.org/10.1128/mcb.24.6.2308-2317.2004.
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ABSTRACT Cell adhesion and spreading depend on activation of mitogen-activated kinase, which in turn is regulated both by growth factor and integrin signaling. Growth factors, such as epidermal growth factor, are capable of activating Ras and Raf, but integrin signaling is required to couple Raf to MEK and MEK to extracellular signal-regulated protein kinase (ERK). It was previously shown that Rac-p21-activated kinase (PAK) signaling regulated the physical association of MEK1 with ERK2 through phosphorylation sites in the proline-rich sequence (PRS) of MEK1. It was also shown that activation of MEK1 and ERK by integrins depends on PAK phosphorylation of S298 in the PRS. Here we report a novel MEK1-specific regulatory feedback mechanism that provides a means by which activated ERK can terminate continued PAK phosphorylation of MEK1. Activated ERK can phosphorylate T292 in the PRS, and this blocks the ability of PAK to phosphorylate S298 and of Rac-PAK signaling to enhance MEK1-ERK complex formation. Preventing ERK feedback phosphorylation on T292 during cellular adhesion prolonged phosphorylation of S298 by PAK and phosphorylation of S218 and S222, the MEK1 activating sites. We propose that activation of ERK during adhesion creates a feedback system in which ERK phosphorylates MEK1 on T292, and this in turn blocks additional S298 phosphorylation in response to integrin signaling.
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Zhan, Fenghuang, Lei Shi, Siqing Wang, Hongwei Xu, Thai M. Cao, Chunjiao Xu, Yong Wu, Maurizio Zangari, Guiyuan Li, and Guido J. Tricot. "CKS1B Mediates SKP2/p27Kip1-Independent Myeloma Cell Survival and Disease Progression through Activation of MEK/ERK and JAK/STAT3 Signaling Pathways." Blood 114, no. 22 (November 20, 2009): 126. http://dx.doi.org/10.1182/blood.v114.22.126.126.
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Abstract Abstract 126 We previously reported that CKS1B may influence myeloma (MM) cell growth and survival through SKP2/p27Kip1-dependent and -independent mechanisms. However, there is still no direct evidence to prove that CKS1B has a role in MM cell proliferation and disease progression. The present study was performed to establish its functional role and define CKS1B-mediated SKP2/p27Kip1-independent down-stream signaling pathways. CKS1B was over-expressed in OCI-MY5 and XG1 MM cell lines by lentivirus. Western blots confirmed CKS1B over-expression. Cells were cultured in medium containing 1% fetal bovine serum for 7 days. CKS1B-transfection resulted in increased cell proliferation compared to empty-vector (EV)-transfected controls. We also examined the role of CKS1B in myeloma resistance to the general used chemotherapeutic drugs, such as bortezomib (5nM), doxorubicin (100nM) and etoposide (100nM). Untreated cells and empty-vector (EV)-transfected cells with or without drug treatments served as controls. Significant less inhibition of cell growth and cell death was observed after drug treatment in CKS1B-transfected cells compared with controls (P < .05). To screen down-stream signaling pathways associated with cell growth and survival in OCI-MY5, MS28PE and XG-1 cells were transfected with specific CKS1B-shRNA, which resulted in decreased phosphorylation of MEK1/2, ERK1/2, STAT3, MCL1 and BCL2 compared to wild-type and control cells, transfected with scrambled CKS1B-shRNA. To confirm these results, we examined the alteration of STAT3, MEK/ERK and BCL2 signaling pathways in OCI-MY5 and XG1 cells after forced over-expression of CKS1B. Increased levels of p-MEK1/2, p-ERK1/2, p-STAT3, MCL1 and p-BCL2 were observed compared to the EV-transfected controls, confirming that CKS1B activates STAT3, MEK/ERK and BCL2 signaling pathways. In Contrast, SKP2 over-expression or p27Kip1 inhibition resulted in inhibition of STAT3 and MEK/ERK pathways with no remarkable changes inBCL2. Further investigation showed that BCL2 is a downstream target of MEK/ERK signaling. Stimulation of STAT3, MEK/ERK and BCL2 signaling pathways only partially abrogated MM cell death and growth inhibition induced by CKS1B knockdown. Targeting either the STAT3, MEK/ERK or BCL2 signaling pathway with specific inhibitors induced significant MM cell death and growth inhibition in CKS1B-over-expressing MM cells; their combination had a synergistic effect on cell death and growth inhibition. Our findings provide a rationale for targeting STAT3 and MEK/ERK/BCL2 signaling in the therapy of aggressive CKS1B-overexpressing MM, which shows increased proliferation and drug-resistance Disclosures: No relevant conflicts of interest to declare.
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Popik, Waldemar, and Paula M. Pitha. "Inhibition of CD3/CD28-Mediated Activation of the MEK/ERK Signaling Pathway Represses Replication of X4 but Not R5 Human Immunodeficiency Virus Type 1 in Peripheral Blood CD4+T Lymphocytes." Journal of Virology 74, no. 6 (March 15, 2000): 2558–66. http://dx.doi.org/10.1128/jvi.74.6.2558-2566.2000.
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ABSTRACT Binding of human immunodeficiency virus type 1 (HIV-1) to CD4 receptors induces multiple cellular signaling pathways, including the MEK/ERK cascade. While the interaction of X4 HIV-1 with CXCR4 does not seem to activate this pathway, viruses using CCR5 for entry efficiently activate MEK/ERK kinases (W. Popik, J. E. Hesselgesser, and P. M. Pitha, J. Virol. 72:6406–6413, 1998; W. Popik and P. M. Pitha, Virology 252:210–217, 1998). Since the importance of MEK/ERK in the initial steps of viral replication is poorly understood, we have examined the role of MEK/ERK signaling in the CD3- and CD28 (CD3/CD28)-mediated activation of HIV-1 replication in resting peripheral blood CD4+ T lymphocytes infected with X4 or R5 HIV-1. We have found that the MEK/ERK inhibitor U0126 selectively inhibited CD3/CD28-stimulated replication of X4 HIV-1, while it did not affect the replication of R5 HIV-1. Inhibition of the CD3/CD28-stimulated MEK/ERK pathway did not affect the formation of the early proviral transcripts in cells infected with either X4 or R5 HIV-1, indicating that virus reverse transcription is not affected in the absence of MEK/ERK signaling. In contrast, the levels of nuclear provirus in cells infected with X4 HIV-1, detected by the formation of circular proviral DNA, was significantly lower in cells stimulated in the presence of MEK/ERK inhibitor than in the absence of the inhibitor. However, in cells infected with R5 HIV-1, the inhibition of the MEK/ERK pathway did not affect nuclear localization of the proviral DNA. These data suggest that the nuclear import of X4, but not R5, HIV-1 is dependent on a CD3/CD28-stimulated MEK/ERK pathway.
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Burgermeister, Elke, and Rony Seger. "PPARγand MEK Interactions in Cancer." PPAR Research 2008 (2008): 1–16. http://dx.doi.org/10.1155/2008/309469.
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Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts multiple functions in determination of cell fate, tissue metabolism, and host immunity. Two synthetic PPARγligands (rosiglitazone and pioglitazone) were approved for the therapy of type-2 diabetes mellitus and are expected to serve as novel cures for inflammatory diseases and cancer. However, PPARγand its ligands exhibit a janus-face behaviour as tumor modulators in various systems, resulting in either tumor suppression or tumor promotion. This may be in part due to signaling crosstalk to the mitogen-activated protein kinase (MAPK) cascades. The genomic activity of PPARγis modulated, in addition to ligand binding, by phosphorylation of a serine residue by MAPKs, such as extracellular signal-regulated protein kinases-1/2 (ERK-1/2), or by nucleocytoplasmic compartmentalization through the ERK activators MAPK kinases-1/2 (MEK-1/2). PPARγligands themselves activate the ERK cascade through nongenomic and often PPARγ-independent signaling. In the current review, we discuss the molecular mechanisms and physiological implications of the crosstalk of PPARγwith MEK-ERK signaling and its potential as a novel drug target for cancer therapy in patients.
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Patel, Aleena L., Eyan Yeung, Sarah E. McGuire, Andrew Y. Wu, Jared E. Toettcher, Rebecca D. Burdine, and Stanislav Y. Shvartsman. "Optimizing photoswitchable MEK." Proceedings of the National Academy of Sciences 116, no. 51 (December 3, 2019): 25756–63. http://dx.doi.org/10.1073/pnas.1912320116.
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Optogenetic approaches are transforming quantitative studies of cell-signaling systems. A recently developed photoswitchable mitogen-activated protein kinase kinase 1 (MEK1) enzyme (psMEK) short-circuits the highly conserved Extracellular Signal-Regulated Kinase (ERK)-signaling cascade at the most proximal step of effector kinase activation. However, since this optogenetic tool relies on phosphorylation-mimicking substitutions in the activation loop of MEK, its catalytic activity is predicted to be substantially lower than that of wild-type MEK that has been phosphorylated at these residues. Here, we present evidence that psMEK indeed has suboptimal functionality in vivo and propose a strategy to circumvent this limitation by harnessing gain-of-function, destabilizing mutations in MEK. Specifically, we demonstrate that combining phosphomimetic mutations with additional mutations in MEK, chosen for their activating potential, restores maximal kinase activity in vitro. We establish that this modification can be tuned by the choice of the destabilizing mutation and does not interfere with reversible activation of psMEK in vivo in bothDrosophilaand zebrafish. To illustrate the types of perturbations enabled by optimized psMEK, we use it to deliver pulses of ERK activation during zebrafish embryogenesis, revealing rheostat-like responses of an ERK-dependent morphogenetic event.
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Chilamakuri, Rameswari, and Saurabh Agarwal. "Direct Targeting of the Raf-MEK-ERK Signaling Cascade Inhibits Neuroblastoma Growth." Current Oncology 29, no. 9 (September 10, 2022): 6508–22. http://dx.doi.org/10.3390/curroncol29090512.
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The Raf-MEK-ERK signaling network has been the subject of intense research due to its role in the development of human cancers, including pediatric neuroblastoma (NB). MEK and ERK are the central components of this signaling pathway and are attractive targets for cancer therapy. Approximately 3–5% of the primary NB samples and about 80% of relapsed samples contain mutations in the Raf-MEK-ERK pathway. In the present study, we analyzed the NB patient datasets and revealed that high RAF and MEK expression leads to poor overall survival and directly correlates with cancer progression and relapse. Further, we repurposed a specific small-molecule MEK inhibitor CI-1040 to inhibit the Raf-MEK-ERK pathway in NB. Our results show that CI-1040 potently inhibits NB cell proliferation and clonogenic growth in a dose-dependent manner. Inhibition of the Raf-MEK-ERK pathway by CI-1040 significantly enhances apoptosis, blocks cell cycle progression at the S phase, inhibits expression of the cell cycle-related genes, and significantly inhibits phosphorylation and activation of the ERK1/2 protein. Furthermore, CI-1040 significantly inhibits tumor growth in different NB 3D spheroidal tumor models in a dose-dependent manner and by directly inhibiting spheroidal tumor cells. Overall, our findings highlight that direct inhibition of the Raf-MEK-ERK pathway is a novel therapeutic approach for NB, and further developing repurposing strategies using CI-1040 is a clinically tractable strategy for effectively treating NB.
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Appleton, Tom, Shirine Usmani, John Mort, and Frank Beier. "MOLECULAR CONTROL OF ARTICULAR CARTILAGE DEGENERATION BY TRANSFORMING GROWTH FACTOR ALPHA." Clinical & Investigative Medicine 31, no. 4 (August 1, 2008): 2. http://dx.doi.org/10.25011/cim.v31i4.4787.
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Background: Articular cartilage degeneration is a hallmark of osteoarthritis (OA). We previously identified increased expression of transforming growth factor alpha (TGF?) and chemokine (C-C motif) ligand 2 (CCL2) in articular cartilage from a rat modelof OA (1,2). We subsequently reported that TGF? signalling modified chondrocyte cytoskeletal organization, increased catabolic and decreased anabolic gene expression and suppressed Sox9. Due to other roles in chondrocytes, we hypothesized that the effects ofTGF? on chondrocytes are mediated by Rho/ROCK and MEK/ERK signaling pathways. Methods: Primary cultures of chondrocytes and articularosteochondral explants were treated with pharmacological inhibitors of MEK1/2(U0126), ROCK (Y27632), Rho (C3), p38 MAPK (SB202190) and PI3K (LY294002) to elucidate pathway involvement. Results: Using G-LISA we determined that stimulation of primary chondrocytes with TGF? activates RhoA. Reciprocally, inhibition of RhoA/ROCK but not other signalling pathways prevents modification of the actin cytoskeleton in responseto TGF?. Inhibition of MEK/ERKsignaling rescued suppression of anabolic gene expression by TGF? including SOX9 mRNA and protein levels. Inhibition of MEK/ERK, Rho/ROCK, p38 MAPK and PI3K signalling pathways differentially controlled the induction of MMP13 and TNF? gene expression. TGF? also induced expression of CCL2 specifically through MEK/ERK activation. In turn, CCL2 treatment induced the expression of MMP3 and TNF?. Finally, we assessed cartilage degradation by immunohistochemical detection of type II collagen cleavage fragments generated by MMPs. Blockade of RhoA/ROCK and MEK/ERK signalling pathways reduced the generation of type IIcollagen cleavage fragments in response to TGF? stimulation. Conclusions: Rho/ROCK signalling mediates TGF?-induced changes inchondrocyte morphology, while MEK/ERK signalling mediates the suppression ofSox9 and its target genes, and CCL2 expression. CCL2, in turn, induces the expression of MMP3 and TNF?, two potent catabolic factors known to be involved in OA. These pathways may represent strategic targets for interventional approaches to treating cartilage degeneration in osteoarthritis. References: 1. Appleton CTG et al. Arthritis Rheum 2007;56:1854-68. 2. Appleton CTG et al. Arthritis Rheum 2007; 56:3693-705.
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Xiong, Hui, Zhixuan Guo, Zengqi Tang, Xuechen Ai, Qing Qi, Xiuting Liu, Danqi Huang, Zhaofeng Li, Suyun Ji, and Qing Guo. "Mesenchymal Stem Cells Activate the MEK/ERK Signaling Pathway and Enhance DNA Methylation via DNMT1 in PBMC from Systemic Lupus Erythematosus." BioMed Research International 2020 (November 17, 2020): 1–8. http://dx.doi.org/10.1155/2020/4174082.
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The defective MEK/ERK signaling pathway and downstream hypomethylation pattern of lymphocytes are crucial for the pathogenesis of systemic lupus erythematosus (SLE). However, the role that the mesenchymal stem cells play in the MEK/ERK signaling pathway and DNA methylation of peripheral blood mononuclear cells (PBMC) from SLE patients remains unknown. In this study, we found that the MEK/ERK signaling pathway of PBMC from SLE patients was activated after the coculture with bone marrow-derived mesenchymal stem cells (BM-MSC) compared with that from the control group. In addition, the expression level of DNA methyltransferase 1 (DNMT1) increased while the levels of CD70, integrin, alpha L (ITGAL), selectin-l, and IL-13 were reduced in PBMC from SLE patients. However, no obvious effect of BM-MSC on PBMC from healthy controls was observed. These findings revealed that BM-MSC might downregulate the expression of methylation-sensitive genes and then suppress the autoactivated PBMC via the MEK/ERK signaling pathway. And it may be one of the mechanisms that BM-MSC ameliorated SLE.
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Kim, Kyung-Ah, Jung-Hyun Kim, Yuhui Wang, and Hei Sook Sul. "Pref-1 (Preadipocyte Factor 1) Activates the MEK/Extracellular Signal-Regulated Kinase Pathway To Inhibit Adipocyte Differentiation." Molecular and Cellular Biology 27, no. 6 (January 8, 2006): 2294–308. http://dx.doi.org/10.1128/mcb.02207-06.
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ABSTRACT Preadipocyte factor 1 (Pref-1) is found in preadipocytes but is absent in adipocytes. Pref-1 is made as a transmembrane protein but is cleaved to generate a biologically active soluble form. Although Pref-1 inhibition of adipogenesis has been well studied in vitro and in vivo, the signaling pathway for Pref-1 is not known. Here, by using purified soluble Pref-1 in Pref-1 null mouse embryo fibroblasts (MEF), we show that Pref-1 increases MEK/extracellular signal-regulated kinase (ERK) phosphorylation in a time- and dose-dependent manner. Compared to wild-type MEF, differentiation of Pref-1 null MEF into adipocytes is enhanced, as judged by lipid accumulation and adipocyte marker expression. Both wild-type and Pref-1 null MEF show a transient burst of ERK phosphorylation upon addition of adipogenic agents. Wild-type MEF show a significant, albeit lower, second increase in ERK phosphorylation peaking at day 2. This ERK phosphorylation, corresponding to Pref-1 abundance, is absent during differentiation of Pref-1 null MEF. Prevention of this second increase in ERK1/2 phosphorylation in wild-type MEF by the MEK inhibitor PD98059 or by transient depletion of ERK1/2 via small interfering RNA-enhanced adipocyte differentiation. Furthermore, treatment of Pref-1 null MEF with Pref-1 restores this ERK phosphorylation, resulting in inhibition of adipocyte differentiation primarily by preventing peroxisome proliferator-activated receptor γ2 induction. However, in the presence of PD98059 or depletion of ERK1/2, exogenous Pref-1 cannot inhibit adipocyte differentiation in Pref-1 null MEF. We conclude that Pref-1 activates MEK/ERK signaling, which is required for Pref-1 inhibition of adipogenesis.
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Wang, Xiaomei, Yuan Lu, Luyi Wu, Chen Zhao, Chunbin Song, Shuguang Yu, Baixiao Zhao, et al. "Moxibustion Inhibits the ERK Signaling Pathway and Intestinal Fibrosis in Rats with Crohn’s Disease." Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/198282.
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Intestinal fibrosis is the main pathological process in Crohn’s disease (CD); acupuncture and moxibustion can inhibit the process of fibrosis in CD rats, but the regulatory mechanism remains unknown. The present study observed the effect of moxibustion on the extracellular signal-regulated kinase (ERK) signaling pathway in the CD rat. The result shows that the phosphorylation of the Ras, Raf-1, MEK-1, and ERK-1/2 proteins and the expression of the corresponding mRNAs in the colon tissue of CD rat were significantly higher than the normal control group. Both treatments with mild moxibustion and with herb-separated moxibustion significantly reduced the expression of the Ras, Raf-1, MEK-1, and ERK-1/2 proteins and Ras and Raf-1 mRNA. MEK-1 and ERK-1/2 mRNA expression in each treatment group showed a downward trend, and the ERK-1/2 mRNA levels were significantly lower in the mild moxibustion group. It indicates that Ras, Raf-1, MEK-1, and ERK-1/2 are involved in the process of intestinal fibrosis in CD rats. Moxibustion can downregulate the abnormal expression of colonic Ras, Raf-1, MEK-1, and ERK-1/2 protein and mRNA levels in CD intestinal fibrosis in rats. Moxibustion may play a role in the treatment of CD intestinal fibrosis by regulating ERK signaling pathway.
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Zhang, Jing, and Harvey F. Lodish. "Constitutive activation of the MEK/ERK pathway mediates all effects of oncogenic H-ras expression in primary erythroid progenitors." Blood 104, no. 6 (September 15, 2004): 1679–87. http://dx.doi.org/10.1182/blood-2004-04-1362.
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Abstract Oncogenic mutations in ras genes frequently occur in patients with myeloid disorders, and in these patients erythropoiesis is often affected. Previously, we showed that expression of oncogenic H-ras in purified mouse primary fetal liver erythroid progenitors blocks terminal erythroid differentiation and supports erythropoietin (Epo)-independent proliferation. As a first step in understanding the underlying molecular mechanisms we examined the signaling pathways downstream of Ras in primary erythroid cells. We found that 3 major pathways are abnormally activated by oncogenic H-ras: Raf/ERK (extracellular signal-regulated kinase), phosphatidyl inositol 3 (PI3)-kinase/Akt, and RalGEF/RalA. However, only constitutive activation of the MEK (MAPK [mitogen-activated protein kinase]/ERK kinase)/ERK pathway alone could recapitulate all of the effects of oncogenic H-ras expression in blocking erythroid differentiation and inducing Epo-independent proliferation. Although expression of a constitutively active Akt kinase (ca.Akt) in erythroid progenitors does not significantly affect erythroid differentiation in the presence of Epo, coexpression of ca.Akt together with a constitutively active MEK causes prolonged Epo-independent proliferation of erythroid progenitors in addition to a block in differentiation. Moreover, the effects of oncogenic H-ras expression on primary erythroid cells are blocked by the addition of U0126, a specific inhibitor of MEK1 and MEK2, allowing normal terminal erythroid proliferation and differentiation. Our data suggest that the interruption of constitutive MEK/ERK signaling is a potential therapeutic strategy to correct impaired erythroid differentiation in patients with myeloid disorders. (Blood. 2004;104: 1679-1687)
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Chen, Qiong, Yuanyuan Hang, Tingting Zhang, Li Tan, Shuangdi Li, and Yuli Jin. "USP10 promotes proliferation and migration and inhibits apoptosis of endometrial stromal cells in endometriosis through activating the Raf-1/MEK/ERK pathway." American Journal of Physiology-Cell Physiology 315, no. 6 (December 1, 2018): C863—C872. http://dx.doi.org/10.1152/ajpcell.00272.2018.
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Endometriosis has been initially described as endometrial-like tissue outside of the uterine cavity. The mitogen-activated protein kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway playing an important role in the regulation of cell proliferation, apoptosis, and migration has been found to be activated in endometriosis. However, regulation of the MEK/ERK signaling pathway in endometriosis has not been fully understood. In this study, primary-cultured endometrial stromal cells were collected from patients with endometriosis and healthy controls, and the proliferation, apoptosis, and migration of ectopic endometrial stromal cells transfected with ubiquitin-specific protease 10 (USP10)-small-interfering RNA (siRNA) or pLVX-Puro-USP10 with or without MEK inhibitor PD-98059 or exogenous signaling stimulation such as epidermal growth factor (EGF) were measured by CCK-8, flow cytometry, and Transwell, respectively. The gene and protein expressions were measured by real-time PCR or Western blot. USP10 overexpression promoted ectopic endometrial stromal cell migration and proliferation, suppressed cell apoptosis, and activated MEK/ERK signaling that is a critical downstream target of the serine/threonine protein kinase Raf-1, which was significantly blocked by PD-98059. USP10 silencing demonstrated the inverse effects, and these effects induced by USP10 silencing were significantly blocked by EGF. USP10 overexpression promoted Raf-1 protein expression, but not mRNA expression, through deubiquitination. In conclusion, these results suggest that USP10 promotes proliferation and migration and inhibits apoptosis of endometrial stromal cells in endometriosis through activating the Raf-1/MEK/ERK pathway.
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Wojtaszewski, Jørgen F. P., Jan Lynge, Allan B. Jakobsen, Laurie J. Goodyear, and Erik A. Richter. "Differential regulation of MAP kinase by contraction and insulin in skeletal muscle: metabolic implications." American Journal of Physiology-Endocrinology and Metabolism 277, no. 4 (October 1, 1999): E724—E732. http://dx.doi.org/10.1152/ajpendo.1999.277.4.e724.
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We have investigated the activation of the extracellular signal-regulated kinases (ERK1 and ERK2) by muscle contraction and insulin in perfused rat skeletal muscle. Both stimuli activated ERK1 and ERK2 by an upstream kinase MAP/ERK kinase (MEK)-dependent mechanism, as the MEK inhibitor PD-98059 inhibited ERK phosphorylation. The presence of the phosphatidylinositol (PI) 3-kinase inhibitors LY-294002 and wortmannin totally eradicated ERK1 and ERK2 phosphorylation in response to insulin but not contraction. Insulin and muscle contraction activated muscle glucose transport, glycogen synthase, and amino acid transport independently of ERK signaling, whereas the PI 3-kinase inhibitors abolished the stimulatory effects of insulin but not those of contraction on these three cellular processes. We conclude that 1) insulin and contraction activate ERK signaling in skeletal muscle; 2) ERK signaling is not necessary for activation of glucose and amino acid transport or glycogen synthase activity by contraction and insulin in skeletal muscle; and 3) insulin-induced activation of MEK, the upstream activator of ERK, is dependent on PI 3-kinase, whereas contraction utilizes a different mechanism.
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Agosto-Marlin, Ibis M., and Gordon S. Mitchell. "Spinal BDNF-induced phrenic motor facilitation requires PKCθ activity." Journal of Neurophysiology 118, no. 5 (November 1, 2017): 2755–62. http://dx.doi.org/10.1152/jn.00945.2016.
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Spinal brain-derived neurotrophic factor (BDNF) is necessary and sufficient for certain forms of long-lasting phrenic motor facilitation (pMF). BDNF elicits pMF by binding to its high-affinity receptor, tropomyosin receptor kinase B (TrkB), on phrenic motor neurons, potentially activating multiple downstream signaling cascades. Canonical BDNF/TrkB signaling includes the 1) Ras/RAF/MEK/ERK MAP kinase, 2) phosphatidylinositol 3‐kinase (PI3K)/Akt, and 3) PLCγ/PKC pathways. Here we demonstrate that spinal BDNF-induced pMF requires PLCγ/PKCθ in normal rats but not MEK/ERK or PI3K/Akt signaling. Cervical intrathecal injections of MEK/ERK (U0126) or PI3K/Akt (PI-828; 100 μM, 12 μl) inhibitor had no effect on BDNF-induced pMF (90 min after BDNF; U0126 + BDNF: 59 ± 14%, PI-828 + BDNF: 59 ± 8%, inhibitor vehicle + BDNF: 56 ± 7%; all P ≥ 0.05). In contrast, PKCθ inhibition with theta inhibitory peptide (TIP; 0.86 mM, 12 μl) prevented BDNF-induced pMF (90 min after BDNF; TIP + BDNF: −2 ± 2%; P ≤ 0.05 vs. other groups). Thus BDNF-induced pMF requires downstream PLCγ/PKCθ signaling, contrary to initial expectations. NEW AND NOTEWORTHY We demonstrate that BDNF-induced pMF requires downstream signaling via PKCθ but not MEK/ERK or PI3K/Akt signaling. These data are essential to understand the sequence of the cellular cascade leading to BDNF-dependent phrenic motor plasticity.
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Savoia, Paola, Paolo Fava, Filippo Casoni, and Ottavio Cremona. "Targeting the ERK Signaling Pathway in Melanoma." International Journal of Molecular Sciences 20, no. 6 (March 25, 2019): 1483. http://dx.doi.org/10.3390/ijms20061483.
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The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.
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Fernández, Isabel F., Sandra Blanco, José Lozano, and Pedro A. Lazo. "VRK2 Inhibits Mitogen-Activated Protein Kinase Signaling and Inversely Correlates with ErbB2 in Human Breast Cancer." Molecular and Cellular Biology 30, no. 19 (August 2, 2010): 4687–97. http://dx.doi.org/10.1128/mcb.01581-09.
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ABSTRACT The epidermal growth factor (EGF)-ErbB-mitogen-activated protein kinase (MAPK) transcription signaling pathway is altered in many types of carcinomas, and this pathway can be regulated by new protein-protein interactions. Vaccinia-related kinase (VRK) proteins are Ser-Thr kinases that regulate several signal transduction pathways. In this work, we study the effect of VRK2 on MAPK signaling using breast cancer as a model. High levels of VRK2 inhibit EGF and ErbB2 activation of transcription by the serum response element (SRE). This effect is also detected in response to H-Ras(G12V) or B-Raf(V600E) oncogenes and is accompanied by a reduction in phosphorylated extracellular signal-regulated kinase (ERK) levels, p90RSK levels, and SRE-dependent transcription. Furthermore, VRK2 knockdown has the opposite effect, increasing the transcriptional response to stimulation with EGF and leading to increased levels of ERK phosphorylation. The molecular mechanism lies between MAPK/ERK kinase (MEK) and ERK, since MEK remains phosphorylated while ERK phosphorylation is blocked by VRK2A. This inhibition of the ERK signaling pathway is a consequence of a direct protein-protein interaction between VRK2A, MEK, and kinase suppressor of Ras 1 (KSR1). Identification of new correlations in human cancer can lead to a better understanding of the biology of individual tumors. ErbB2 and VRK2 protein levels were inversely correlated in 136 cases of human breast carcinoma. In ErbB2+ tumors, there is a significant reduction in the VRK2 level, suggesting a role for VRK2A in ErbB2-MAPK signaling. Thus, VRK2 downregulation in carcinomas permits signal transmission through the MEK-ERK pathway without affecting AKT signaling, causing a signal imbalance among pathways that contributes to the phenotype of breast cancer.
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DiCamillo, Sandra J., Shenghong Yang, Maria V. Panchenko, Paul A. Toselli, Estee F. Naggar, Celeste B. Rich, Phillip J. Stone, Matthew A. Nugent, and Mikhail P. Panchenko. "Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-β on tropoelastin mRNA in lung fibroblasts." American Journal of Physiology-Lung Cellular and Molecular Physiology 291, no. 2 (August 2006): L232—L243. http://dx.doi.org/10.1152/ajplung.00530.2005.
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Neutrophil elastase (NE) plays an important role in emphysema, a pulmonary disease associated with excessive elastolysis and ineffective repair of interstitial elastin. Besides its direct elastolytic activity, NE releases soluble epidermal growth factor receptor (EGFR) ligands and initiates EGFR/MEK/ERK signaling to downregulate tropoelastin mRNA in neonatal rat lung fibroblasts (DiCamillo SJ, Carreras I, Panchenko MV, Stone PJ, Nugent MA, Foster JA, and Panchenko MP. J Biol Chem 277: 18938–18946, 2002). We now report that NE downregulates tropoelastin mRNA in the rat fetal lung fibroblast line RFL-6. The tropoelastin mRNA downregulation is preceded by release of EGF-like and TGF-α-like polypeptides and requires EGFR/MEK/ERK signaling, because it is prevented by the EGFR inhibitor AG1478 and the MEK/ERK uncoupler U0126. Tropoelastin expression in RFL-6 fibroblasts is governed by autocrine TGF-β signaling, because TGF-β type I receptor kinase inhibitor or TGF-β neutralizing antibody dramatically decreases tropoelastin mRNA and protein levels. Half-life of tropoelastin mRNA in RFL-6 cells is >24 h, but it is decreased to ∼8 h by addition of TGF-β neutralizing antibody, EGF, TGF-α, or NE. Tropoelastin mRNA destabilization by NE, EGF, or TGF-α is abolished by AG1478 or U0126. EGF-dependent tropoelastin mRNA downregulation is reversed upon ligand withdrawal, whereas chronic EGF treatment leads to persistent downregulation of tropoelastin mRNA and protein levels and decreases insoluble elastin deposition. We conclude that NE-initiated EGFR/MEK/ERK signaling cascade overrides the autocrine TGF-β signaling on tropoelastin mRNA stability and, therefore, decreases the elastogenic response in RFL-6 fibroblasts. We hypothesize that persistent EGFR/MEK/ERK signaling could impede the TGF-β-induced elastogenesis/elastin repair in the chronically inflamed, elastase/anti-elastase imbalanced lung in emphysema.
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Wang, Weiping, Joan X. Chen, Rong Liao, Qingdong Deng, Jennifer J. Zhou, Shuang Huang, and Peiqing Sun. "Sequential Activation of the MEK-Extracellular Signal-Regulated Kinase and MKK3/6-p38 Mitogen-Activated Protein Kinase Pathways Mediates Oncogenic ras-Induced Premature Senescence." Molecular and Cellular Biology 22, no. 10 (May 15, 2002): 3389–403. http://dx.doi.org/10.1128/mcb.22.10.3389-3403.2002.
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ABSTRACT In primary mammalian cells, oncogenic ras induces premature senescence, depending on an active MEK-extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. It has been unclear how activation of the mitogenic MEK-ERK pathway by ras can confer growth inhibition. In this study, we have found that the stress-activated MAPK, p38, is also activated during the onset of ras-induced senescence in primary human fibroblasts. Constitutive activation of p38 by active MKK3 or MKK6 induces senescence. Oncogenic ras fails to provoke senescence when p38 activity is inhibited, suggesting that p38 activation is essential for ras-induced senescence. Furthermore, we have demonstrated that p38 activity is stimulated by ras as a result of an activated MEK-ERK pathway. Following activation of MEK and ERK, expression of oncogenic ras leads to the accumulation of active MKK3/6 and p38 activation in a MEK-dependent fashion and subsequently induces senescence. Active MEK1 induces the same set of changes and provokes senescence relying on active p38. Therefore, oncogenic ras provokes premature senescence by sequentially activating the MEK-ERK and MKK3/6-p38 pathways in normal, primary cells. These studies have defined the molecular events within the ras signaling cascade that lead to premature senescence and, thus, have provided new insights into how ras confers oncogenic transformation in primary cells.
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DuShane, Jeanne K., Colleen L. Mayberry, Michael P. Wilczek, Sarah L. Nichols, and Melissa S. Maginnis. "JCPyV-Induced MAPK Signaling Activates Transcription Factors during Infection." International Journal of Molecular Sciences 20, no. 19 (September 26, 2019): 4779. http://dx.doi.org/10.3390/ijms20194779.
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JC polyomavirus (JCPyV), a ubiquitous human pathogen, is the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Like most viruses, JCPyV infection requires the activation of host-cell signaling pathways in order to promote viral replication processes. Previous works have established the necessity of the extracellular signal-regulated kinase (ERK), the terminal core kinase of the mitogen-activated protein kinase (MAPK) cascade (MAPK-ERK) for facilitating transcription of the JCPyV genome. However, the underlying mechanisms by which the MAPK-ERK pathway becomes activated and induces viral transcription are poorly understood. Treatment of cells with siRNAs specific for Raf and MAP kinase kinase (MEK) targets proteins in the MAPK-ERK cascade, significantly reducing JCPyV infection. MEK, the dual-specificity kinase responsible for the phosphorylation of ERK, is phosphorylated at times congruent with early events in the virus infectious cycle. Moreover, a MAPK-specific signaling array revealed that transcription factors downstream of the MAPK cascade, including cMyc and SMAD4, are upregulated within infected cells. Confocal microscopy analysis demonstrated that cMyc and SMAD4 shuttle to the nucleus during infection, and nuclear localization is reduced when ERK is inhibited. These findings suggest that JCPyV induction of the MAPK-ERK pathway is mediated by Raf and MEK and leads to the activation of downstream transcription factors during infection. This study further defines the role of the MAPK cascade during JCPyV infection and the downstream signaling consequences, illuminating kinases as potential therapeutic targets for viral infection.
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Gross, Sean M., and Peter Rotwein. "Quantification of growth factor signaling and pathway cross talk by live-cell imaging." American Journal of Physiology-Cell Physiology 312, no. 3 (March 1, 2017): C328—C340. http://dx.doi.org/10.1152/ajpcell.00312.2016.
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Peptide growth factors stimulate cellular responses through activation of their transmembrane receptors. Multiple intracellular signaling cascades are engaged following growth factor–receptor binding, leading to short- and long-term biological effects. Each receptor-activated signaling pathway does not act in isolation but rather interacts at different levels with other pathways to shape signaling networks that are distinctive for each growth factor. To gain insights into the specifics of growth factor-regulated interactions among different signaling cascades, we developed a HeLa cell line stably expressing fluorescent live-cell imaging reporters that are readouts for two major growth factor-stimulated pathways, Ras–Raf–Mek–ERK and phosphatidylinositol (PI) 3-kinase–Akt. Incubation of cells with epidermal growth factor (EGF) resulted in rapid, robust, and sustained ERK signaling but shorter-term activation of Akt. In contrast, hepatocyte growth factor induced sustained Akt signaling but weak and short-lived ERK activity, and insulin-like growth factor-I stimulated strong long-term Akt responses but negligible ERK signaling. To address potential interactions between signaling pathways, we employed specific small-molecule inhibitors. In cells incubated with EGF or platelet-derived growth factor-AA, Raf activation and the subsequent stimulation of ERK reduced Akt signaling, whereas Mek inhibition, which blocked ERK activation, enhanced Akt and turned transient effects into sustained responses. Our results reveal that individual growth factors initiate signaling cascades that vary markedly in strength and duration and demonstrate in living cells the dramatic effects of cross talk from Raf and Mek to PI 3-kinase and Akt. Our data further indicate how specific growth factors can encode distinct cellular behaviors by promoting complex interactions among signaling pathways.
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Cho, Chung-Hyun, Chang Sup Lee, Mikyung Chang, Il-Ho Jang, Soo Jin Kim, Inhwan Hwang, Sung Ho Ryu, Chin O. Lee, and Gou Young Koh. "Localization of VEGFR-2 and PLD2 in endothelial caveolae is involved in VEGF-induced phosphorylation of MEK and ERK." American Journal of Physiology-Heart and Circulatory Physiology 286, no. 5 (May 2004): H1881—H1888. http://dx.doi.org/10.1152/ajpheart.00786.2003.
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To clarify the role of caveolae in VEGF/VEGF receptor-2 (VEGFR-2)-mediated signaling cascades, primary cultured human umbilical vein endothelial cells (HUVECs) were fractionated to isolate caveolae-enriched cell membranes. Interestingly, VEGFR-2, phospholipase D2 (PLD2), and Ras were enriched in caveolae-enriched fractions. Moreover, VEGF increased PLD activity in a time- and dose-dependent manner in HUVECs, whereas a ligand specific for VEGFR-1 placental growth factor did not change PLD activity. A PLD inhibitor, 1-butanol, almost completely suppressed VEGF-induced ERK phosphorylation and cellular proliferation, whereas the negative control for 1-butanol, 3-butanol, did not produce significant changes. Addition of phosphatidic acid negated the 1-butanol-induced suppression. Pharmacological analyses using several inhibitors indicated that PKC-δ regulates the VEGF-induced activation of PLD/ERK. Thus PLD2 could be involved in MEK/ERK signaling cascades that are induced by the VEGF/VEGFR-2/PKC-δ pathway in endothelial cells. Pretreatment with the cholesterol depletion agent methyl-β-cyclodextrin (MβCD) almost completely disassembled caveolar structures, whereas the addition of cholesterol to MβCD-treated cells restored caveolar structures. Pretreatment with MβCD largely abolished phosphorylation of MEK/ERK by VEGF, whereas the addition of cholesterol restored VEGF-induced MEK/ERK phosphorylations. These results indicate that intact caveolae are required for the VEGF/VEGFR-2-mediated MEK/ERK signaling cascade.
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Cai, Yingyun, Yin Liu, and Xuming Zhang. "Suppression of Coronavirus Replication by Inhibition of the MEK Signaling Pathway." Journal of Virology 81, no. 2 (November 1, 2006): 446–56. http://dx.doi.org/10.1128/jvi.01705-06.
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ABSTRACT We previously demonstrated that infection of cultured cells with murine coronavirus mouse hepatitis virus (MHV) resulted in activation of the mitogen-activated protein kinase (Raf/MEK/ERK) signal transduction pathway (Y. Cai et al., Virology 355:152-163, 2006). Here we show that inhibition of the Raf/MEK/ERK signaling pathway by the MEK inhibitor UO126 significantly impaired MHV progeny production (a reduction of 95 to 99% in virus titer), which correlated with the phosphorylation status of ERK1/2. Moreover, knockdown of MEK1/2 and ERK1/2 by small interfering RNAs suppressed MHV replication. The inhibitory effect of UO126 on MHV production appeared to be a general phenomenon since the effect was consistently observed in all six different MHV strains and in three different cell types tested; it was likely exerted at the postentry steps of the virus life cycle because the virus titers were similarly inhibited from infected cells treated at 1 h prior to, during, or after infection. Furthermore, the treatment did not affect the virus entry, as revealed by the virus internalization assay. Metabolic labeling and reporter gene assays demonstrated that translation of cellular and viral mRNAs appeared unaffected by UO126 treatment. However, synthesis of viral genomic and subgenomic RNAs was severely suppressed by UO126 treatment, as demonstrated by a reduced incorporation of [3H]uridine and a decrease in chloramphenicol acetyltransferase (CAT) activity in a defective-interfering RNA-CAT reporter assay. These findings indicate that the Raf/MEK/ERK signaling pathway is involved in MHV RNA synthesis.
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Santos, Eugenio, and Piero Crespo. "The RAS-ERK pathway: A route for couples." Science Signaling 11, no. 554 (October 30, 2018): eaav0917. http://dx.doi.org/10.1126/scisignal.aav0917.
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Data accumulated over more than three decades demonstrate that the assembly of macrocomplexes, mainly of dimers, is widespread among the members of the different tiers that constitute the RAS-ERK pathway. In this issue of Science Signaling, Yuan et al. report that MEK1 homodimerization is necessary for signal transduction through the RAF-ERK pathway and that cancer-related MEK1 mutations confer enhanced dimerization and resistance to MEK inhibitors. These findings endorse interference with RAS-ERK pathway–component dimerization as a potential therapeutic strategy in cancer patients.
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Wu, Pui-Kei, Andrew Becker, and Jong-In Park. "Growth Inhibitory Signaling of the Raf/MEK/ERK Pathway." International Journal of Molecular Sciences 21, no. 15 (July 30, 2020): 5436. http://dx.doi.org/10.3390/ijms21155436.
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In response to extracellular stimuli, the Raf/MEK/extracellular signal-regulated kinase (ERK) pathway regulates diverse cellular processes. While mainly known as a mitogenic signaling pathway, the Raf/MEK/ERK pathway can mediate not only cell proliferation and survival but also cell cycle arrest and death in different cell types. Growing evidence suggests that the cell fate toward these paradoxical physiological outputs may be determined not only at downstream effector levels but also at the pathway level, which involves the magnitude of pathway activity, spatial-temporal regulation, and non-canonical functions of the molecular switches in this pathway. This review discusses recent updates on the molecular mechanisms underlying the pathway-mediated growth inhibitory signaling, with a major focus on the regulation mediated at the pathway level.
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Luna, Adrian J., Rosa T. Sterk, Anastacia M. Griego-Fisher, Joon-Yong Chung, Kiersten L. Berggren, Virginie Bondu, Pamela Barraza-Flores, et al. "MEK/ERK signaling is a critical regulator of high-risk human papillomavirus oncogene expression revealing therapeutic targets for HPV-induced tumors." PLOS Pathogens 17, no. 1 (January 22, 2021): e1009216. http://dx.doi.org/10.1371/journal.ppat.1009216.
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Intracellular pathogens have evolved to utilize normal cellular processes to complete their replicative cycles. Pathogens that interface with proliferative cell signaling pathways risk infections that can lead to cancers, but the factors that influence malignant outcomes are incompletely understood. Human papillomaviruses (HPVs) predominantly cause benign hyperplasia in stratifying epithelial tissues. However, a subset of carcinogenic or “high-risk” HPV (hr-HPV) genotypes are etiologically linked to nearly 5% of all human cancers. Progression of hr-HPV-induced lesions to malignancies is characterized by increased expression of the E6 and E7 oncogenes and the oncogenic functions of these viral proteins have been widely studied. Yet, the mechanisms that regulate hr-HPV oncogene transcription and suppress their expression in benign lesions remain poorly understood. Here, we demonstrate that EGFR/MEK/ERK signaling, influenced by epithelial contact inhibition and tissue differentiation cues, regulates hr-HPV oncogene expression. Using monolayer cells, epithelial organotypic tissue models, and neoplastic tissue biopsy materials, we show that cell-extrinsic activation of ERK overrides cellular control to promote HPV oncogene expression and the neoplastic phenotype. Our data suggest that HPVs are adapted to use the EGFR/MEK/ERK signaling pathway to regulate their productive replicative cycles. Mechanistic studies show that EGFR/MEK/ERK signaling influences AP-1 transcription factor activity and AP-1 factor knockdown reduces oncogene transcription. Furthermore, pharmacological inhibitors of EGFR, MEK, and ERK signaling quash HPV oncogene expression and the neoplastic phenotype, revealing a potential clinical strategy to suppress uncontrolled cell proliferation, reduce oncogene expression and treat HPV neoplasia.
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Huang, Jyun-Bin, Shih-Pin Hsu, Hsiu-Yung Pan, Shang-Der Chen, Shu-Fang Chen, Tsu-Kung Lin, Xuan-Ping Liu, et al. "Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling." International Journal of Molecular Sciences 21, no. 19 (September 30, 2020): 7247. http://dx.doi.org/10.3390/ijms21197247.
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Status epilepticus may cause molecular and cellular events, leading to hippocampal neuronal cell death. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) is an important regulator of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), also known as fetal liver kinase receptor 1 (Flk-1). Resveratrol is an activator of PGC-1α. It has been suggested to provide neuroprotective effects in epilepsy, stroke, and neurodegenerative diseases. In the present study, we used microinjection of kainic acid into the left hippocampal CA3 region in Sprague Dawley rats to induce bilateral prolonged seizure activity. Upregulating the PGC-1α pathway will increase VEGF/VEGFR2 (Flk-1) signaling and further activate some survival signaling that includes the mitogen activated protein kinase kinase (MEK)/mitogen activated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways and offer neuroprotection as a consequence of apoptosis in the hippocampal neurons following status epilepticus. Otherwise, downregulation of PGC-1α by siRNA against pgc-1α will inhibit VEGF/VEGFR2 (Flk-1) signaling and suppress pro-survival PI3K/AKT and MEK/ERK pathways that are also accompanied by hippocampal CA3 neuronal cell apoptosis. These results may indicate that the PGC-1α induced VEGF/VEGFR2 pathway may trigger the neuronal survival signaling, and the PI3K/AKT and MEK/ERK signaling pathways. Thus, the axis of PGC-1α/VEGF/VEGFR2 (Flk-1) and the triggering of downstream PI3K/AKT and MEK/ERK signaling could be considered an endogenous neuroprotective effect against apoptosis in the hippocampus following status epilepticus.
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Tan, Andy Hee-Meng, and Kong-Peng Lam. "Pharmacologic Inhibition of MEK–ERK Signaling Enhances Th17 Differentiation." Journal of Immunology 184, no. 4 (January 8, 2010): 1849–57. http://dx.doi.org/10.4049/jimmunol.0901509.
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Tang, Fen, Mario Thiego F. Pacheco, Ping Chen, Dan Liang, and Wei Li. "Secretogranin III promotes angiogenesis through MEK/ERK signaling pathway." Biochemical and Biophysical Research Communications 495, no. 1 (January 2018): 781–86. http://dx.doi.org/10.1016/j.bbrc.2017.11.080.
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Wang, Ao-Xue, and Xiao-Yi Qi. "Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma." IUBMB Life 65, no. 9 (July 29, 2013): 748–58. http://dx.doi.org/10.1002/iub.1193.
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Stansfield, Brian K., Waylan K. Bessler, Raghuveer Mali, Julie A. Mund, Brandon D. Downing, Reuben Kapur, and David A. Ingram. "Ras-Mek-Erk Signaling Regulates Nf1 Heterozygous Neointima Formation." American Journal of Pathology 184, no. 1 (January 2014): 79–85. http://dx.doi.org/10.1016/j.ajpath.2013.09.022.
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Bruner, Joshua Kyle, Li Li, Hayley S. Ma, Alice Can Ran Qin, Mark J. Levis, Keith W. Pratz, Christine A. Pratilas, and Donald Small. "Signaling Adaptation to TKI Treatment Reactivates ERK Signaling in FLT3/ITD Leukemia." Blood 128, no. 22 (December 2, 2016): 33. http://dx.doi.org/10.1182/blood.v128.22.33.33.
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Abstract FMS-like tyrosine kinase-3 (FLT3) is one of the most commonly mutated genes in acute myeloid leukemia (AML). The internal tandem duplication (FLT3/ITD) is an established driver mutation in AML and results in constitutive activation of the receptor, activating downstream signaling pathways including STAT5, PI3K/AKT, and RAF/MEK/ERK. The use of FLT3 tyrosine kinase inhibitors (TKIs) for the treatment of FLT3/ITD AML has been explored as a promising strategy for over a decade, but clinical responses have remained limited. In some cancers driven by mutated oncogenes, small molecule inhibition of the target is known to result in reactivation of downstream signaling pathways. This response has been observed in the context of PI3K/AKT/mTOR and BRAF inhibition, but it remains unclear whether this phenomenon extends to cancers driven by receptor tyrosine kinase (RTK) activation, such as FLT3/ITD AML. We hypothesized that FLT3/ITD leukemia cells exhibit mechanisms of intrinsic signaling adaptation to FLT3 TKI treatment that are associated with an incomplete biologic response. To test this, we treated FLT3/ITD AML cell lines (Molm14 and MV4;11) with FLT3 TKIs for up to 48 hours. We observed a rebound in ERK phosphorylation beginning as early as 6 hours and continuing for the duration of treatment, while no such rebound was observed in the phosphorylation of downstream targets AKT or STAT5. When these cells were treated with inhibitors of both FLT3 and MEK in combination, little to no pERK rebound was observed, and the anti-leukemia effects were more pronounced compared to either drug alone, both in vitro and in vivo. In vitro, the addition of low dose MEK inhibitor to FLT3 TKI treatment synergistically increased cell death and decreased cell proliferation. In a xenograft transplant model of leukemia, the addition of low-dose MEK inhibitor to FLT3 TKI treatment resulted in a significant reduction of both peripheral blood and bone marrow blasts (p < 0.05). We next sought to determine whether rebound in ERK signaling following FLT3 inhibition was likely to occur in patients as well. We first examined whether primary leukemic cells from patients with FLT3/ITD AML also exhibit the same phenomenon observed in FLT3/ITD cell lines. After 24 hours of sorafenib treatment, the majority of samples revealed a similar rebound in ERK phosphorylation, despite sustained inhibition of phospho-STAT5. As observed with the cell lines, the addition of a MEK inhibitor to sorafenib treatment resulted in sustained pERK inhibition after 24 hours. Next, we explored whether signaling adaptation observed in culture conditions would be recapitulated by the concentrations of sorafenib present in human plasma from patients being treated with this FLT3 TKI. To replicate these conditions, we cultured Molm14 cells in plasma samples obtained from AML patients treated with sorafenib for a prolonged period. Using a variant of the plasma inhibitory activity assay, Molm14 cells were treated in either normal human plasma for one hour or patient plasma for either one or 24 hours. For all plasma samples, profound pERK rebound was observed by 24 hours after treatment, despite maximal inhibition at one hour and persistent inhibition of FLT3 and STAT5 phosphorylation over the duration. Finally, we sought to determine whether TKI-mediated rebound in ERK activity was restricted to FLT3/ITD AML or may also occur in the context of other RTK-driven cancers, such as those driven by EGFR mutation or HER2 amplification. We treated an EGFR mutant lung cancer (PC-9) and a HER2 amplified breast cancer (SKBR3) cell line with the EGFR/HER2 inhibitor lapatinib. As was seen for FLT3/ITD driven AML, pERK rebound was observed following 24 hours of TKI treatment despite persistent inhibition of the receptor and downstream target AKT. Again, the rebound could be overcome with the addition of low concentrations of MEK inhibitor. Together, these studies reveal that FLT3/ITD and other RTK driven cancer cells demonstrate an adaptive feedback mechanism capable of reactivating ERK signaling in response to upstream target inhibition. This adaptation limits the efficacy of TKI treatment and can be abrogated by the addition of a MEK inhibitor. Our data suggest that the addition of low-dose MEK inhibitor to TKI treatment as a means to overcome signaling adaptation may improve outcomes for patients with FLT3/ITD AML and possibly other RTK-driven cancer types. Disclosures Levis: Novartis: Consultancy, Honoraria, Research Funding; Millennium: Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria.
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Huang, Qin, Ying Huang, Lan He, Hongyan Zhao, Yang Lu, and Ling Jiang. "Bone Marrow Mesenchymal Stem Cell (BMSC) Downregulates Vascular Endothelial Growth Factor (VEGF) and Promotes the Apoptosis of Melanoma Cells." Journal of Biomaterials and Tissue Engineering 12, no. 8 (August 1, 2022): 1594–601. http://dx.doi.org/10.1166/jbt.2022.3088.
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This study assessed BMSC’s effect on melanoma cells. The melanoma A375 cells were assigned into blank group, BMSC group, ERK agonist group, AKT agonist group, ERK + AKT agonist group and ERK + AKT repressor group followed by analysis of VEGF expression, cell apoptotic rate, and the expression of MEK/ERK and PI3K/AKT signal proteins. ERK and AKT agonist group showed highest VEGF expression, lowest cell apoptosis and Bcl-2 and Bcl-2/Bax expression as well as highest MEK/ERK and PI3K/AKT signaling proteins followed by ERK agonist group and AKT agonist group. The apoptosis of melanoma cells could be prompted by BMSC which might be through restraining the activity of MEK/ERK and PI3K/AKT signal pathway. In conclusion, the apoptosis of melanoma cells is prompted by BMSC through restraining the activity of MEK/ERK and PI3K/AKT signal pathway, indicating that BMSC might be used as a novel approach for the treatment of melanoma.
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Cesta Incani, Ursula, Anais Del Curatolo, Cristina Di Sanza, Italia Falcone, Francesco Cognetti, Ludovica Ciuffreda, and Michele Milella. "Synergistic activity of vertical combinations of agents targeting multiple steps along the RAF/MEK/ERK cascade as a therapeutic strategy in human tumors." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e13572-e13572. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13572.
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e13572 Background: BRAF-selective kinase inhibitors have potent antitumor effects in mutant BRAF(V600E) tumors; however, in BRAF-wt cells, they paradoxically activate MEK/ERK. In addition, MEK blockade may induce compensatory signaling through both upstream pathway elements (RAF) and parallel pathways (PI3K/AKT/mTOR). Methods: We set out to define molecular and functional effects of single and combined BRAF (GSK2118436A, BRAF-I) and MEK (GSK1120212B, MEK-I) inhibition, using WB analysis to dissect signaling and a fixed dose-ratio experimental design to assess functional synergism by conservative isobologram analysis. Results: In A549 lung adenocarcinoma (KRAS G12S), BRAF-I (10 μM) induces hyperphosphorylation of CRAF, MEK, ERK, and p90RSK, while MEK-I (10 nM), alone or in combination with BRAF-I, potently offsets MAPK activation. Combined BRAF-I and MEK-I suppress malignant growth and survival at 72 h with highly synergistic effects in the A549 (lung, KRAS G12S), H1299 (lung, NRAS), HCT116 (colon, KRAS G13D), and MIAPACA (pancreatic, KRAS G12V) models, with combination indexes (CI), ranging from 1.37 to 0.12. Conversely, in other lung cancer models (H460, Calu-1, Calu-3) the combination of BRAF-I and MEK-I produced modestly additive to highly antagonistic antitumor effects. In BRAF-mutant melanoma and colon carcinoma models (M14 and HT29), there was no paradoxical activation of the MEK/ERK module in response to BRAF-I and both BRAF-I and MEK-I had pronounced growth inhibitory effects as single agents, but were frankly antagonistic in combination. Similarly, the pan-RAF inhibitor RAF265 did not cause MAPK activation and did not result in synergistic growth inhibition when combined with the MEK-I in the A549 and MIAPACA cell lines. Conclusions: Overall, our data indicate that combined inhibition of multiple signaling elements along the RAF/MEK/ERK pathway results in strongly synergistic growth inhibition, particularly in tumors with RAS mutations. Additional studies to better define genetic determinants of sensitivity/resistance and molecular mechanisms of therapeutic synergism of combined BRAF-I and MEK-I are currently ongoing.
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Xu, Long, Ming Liu, Tanxiao Huang, Suo Peisu, Lele Song, Yuanyuan Liu, Mimi Fu, Chunmei Zhang, Jeremy Edwards, and Shifu Chen. "Association of Ras-Raf-MEK-Erk/JNK pathway mutations with overall survival for lung squamous cell carcinoma patients." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14754-e14754. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14754.
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e14754 Background: Genomic alterations often lead to aberrant signaling pathways which play an important role in tumorigenesis and development. Here we report the mutational status of genes associated with the Ras-Raf-MEK-Erk/JNK signaling pathway as a biomarker for predicting overall survival (OS) for Lung squamous cell carcinoma (SQCC) patients. Methods: We used the cBioPortal platform to analyze a cohort of 494 SQCC samples from TCGA data. The general Ras-Raf-MEK-Erk/JNK signaling pathway includes 26 genes (KRAS, HRAS, BRAF, RAF1, MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K5, MAPK1, MAPK3, MAPK4, MAPK6, MAPK7, MAPK8, MAPK9, MAPK12, MAPK14, DAB2, RASSF1, RAB25). We analyzed the number of samples with/without mutations in the Ras-Raf-MEK-Erk/JNK pathway and found is 214 and 284 that had, or didn’t have, mutations in this pathway, respectively. The overall survival of these two groups was analyzed using the Kaplan-Meier Estimate, and the statistical difference between these groups was calculated using the log-rank test afterwards. Results: The log-rank test p-value is 2.086e-3, which indicates a significant difference in the overall survival between the two groups. It shows that the group with alterations in the Ras-Raf-MEK-Erk/JNK signaling pathway had a longer overall survival than the group without those alterations. The details are as follows: Conclusions: Ras-Raf-MEK-Erk/JNK pathway mutations are significantly associated with longer OS for lung SQCC patients. Mutations in this pathway can be a potential indicator for SQCC patients, but the biological reasons behind this relationship remain to be explored.[Table: see text]
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Pashirzad, Mehran, Reihaneh Khorasanian, Maryam Mahmoudi Fard, Mohammad-Hassan Arjmand, Hadis Langari, Majid Khazaei, Saman Soleimanpour, et al. "The Therapeutic Potential of MAPK/ERK Inhibitors in the Treatment of Colorectal Cancer." Current Cancer Drug Targets 21, no. 11 (December 2021): 932–43. http://dx.doi.org/10.2174/1568009621666211103113339.
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: The MAPK/ERK signaling pathway regulates cancer cell proliferation, apoptosis, inflammation, angiogenesis, metastasis and drug resistance. Mutations and up-regulation of components of the MAPK/ERK signaling pathway, as well as over-activation of this critical signaling pathway, are frequently observed in colorectal carcinomas. Targeting the MAPK/ERK signaling pathway, using specific pharmacological inhibitors, elicits potent anti-tumor effects, supporting the therapeutic potential of these inhibitors in the treatment of CRC. Several drugs have recently been developed for the inhibition of the MEK/ERK pathway in preclinical and clinical settings, such as MEK162 and MK-2206. MEK1/2 inhibitors demonstrate promising efficacy and anticancer activity for the treatment of this malignancy. This review summarizes the current knowledge on the role of the MAPK/ERK signaling pathway in the pathogenesis of CRC and the potential clinical value of synthetic inhibitors of this pathway in preventing CRC progression for a better understanding, and hence, better management of colorectal cancer.
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Morita, Ken, Keisuke Kataoka, Junji Koya, Takako Tsuruta, Tomohiko Sato, and Mineo Kurokawa. "BAALC Acts As a Scaffold-Like Protein In The ERK Signaling Pathway and Promotes Leukemogenesis By Facilitating MEK–mediated ERK Activation." Blood 122, no. 21 (November 15, 2013): 2509. http://dx.doi.org/10.1182/blood.v122.21.2509.2509.
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Abstract Significance of BAALC (brain and acute leukemia, cytoplasmic) as a poor prognostic factor for patients with cytogenetically normal acute myeloid leukemia (CN-AML) and acute lymphoblastic leukemia (ALL) has now been widely established, however, its molecular mechanisms are still mostly unknown. Available evidence suggests that BAALC is a cytoplasmic protein. Based on this finding, we carried out phosphoprotein array of cytoplasmic signal transduction-related proteins and sought to find out the deregulated signaling underlying BAALC-mediated leukemogenesis. Using BAALC-overexpressed HEK293T cells, we found enhanced phosphorylation of Extracellular signal-regulated kinase (ERK), and its downstream target p90RSK. Besides, Jurkat cells, a human ALL cell line, showed sustained phosphorylation of ERK when BAALC is overexpressed. These results suggest that BAALC acts as a scaffold-like molecule for the cytoplasmic mitogen-activated protein kinase kinase (MEK), upstream ERK activator and activates ERK signaling pathway. Immunoprecipitation assay revealed that BAALC binds to MEK in HEK293T cells. Co-localization of BAALC and MEK in the cytoplasm of HEK293T was also detected by immunofluorescence experiment. The proportion of the phosphorylated form in the MEK-bound ERK was increased compared to its control, indicating that BAALC binds to MEK and directly up-regulates its kinase activity to phosphorylate ERK. BAALC accelerated cell growth and increased the phosphorylation of ERK when overexpressed in Jurkat or HEL cells. Those cells showed accelerated cell cycling with no change of apoptotic status. On the other hand, BAALC knockdown decreased cellular proliferation as well as phosphorylation of ERK in the human leukemia cell line expressing a high level of BAALC, such as Kasumi-1 cells. Decelerated cell cycling was also observed in the BAALC-knocked down cells. Notably, the proportion of the phosphorylated ERK bound to MEK was decreased when BAALC was knocked down, which is consistent with BAALC-overexpressed experiments. Interestingly, in AML cell lines without active Ras mutations, the expression of BAALC was positively correlated to its sensitivity to MEK inhibitor (U0126). Moreover, growth advantage of BAALC overexpression in leukemic cell lines was canceled by the treatment with U0126, implying that BAALC-induced growth advantage depends on MEK-ERK signaling activity. Analysis of deletion mutants of BAALC revealed that binding ability of BAALC to MEK resides in its N-terminal region, which is highly conserved among mammals. This N-terminal region of BAALC was necessary for phosphorylation of ERK and the mutant lacking this region failed to promote proliferation of the leukemic cell lines. Taken together, BAALC acts as a scaffold-like protein that binds to MEK in the cytoplasm and directly up-regulates MEK-ERK signal transduction pathway. The fact that overexpression of BAALC significantly promotes proliferation of leukemic cells is consistent with the clinical observation that BAALC-high leukemia has a poor prognosis. The novel function of BAALC as a scaffold-like protein that activates MEK-ERK signal transduction pathway may account for the underlying mechanism for the generation of aggressive form of leukemia and would be a promising therapeutic target of BAALC-high leukemia. Disclosures: Kurokawa: Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Research Funding.
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Yin, Dexin, Changgeng Fu, and Dajun Sun. "Silence of lncRNA UCA1 Represses the Growth and Tube Formation of Human Microvascular Endothelial Cells Through miR-195." Cellular Physiology and Biochemistry 49, no. 4 (2018): 1499–511. http://dx.doi.org/10.1159/000493454.
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Background/Aims: Recent studies have suggested that several lncRNAs contribute to the angiogenic function of endothelial cells. Herein, we set out to reveal whether lncRNA UCA1 has functions in endothelial angiogenesis. Methods: The expression levels of lncRNA UCA1, miR-195 and CCND1 in human microvascular endothelial HMEC-1 cells were altered by transfection. Subsequently, cell viability, migration, tube formation and apoptosis of HMEC-1 cells were respectively assessed. The cross-talk between lncRNA UCA1, miR-195, CCND1, and MEK/ERK and mTOR signaling pathways were investigated by performing qRT-PCR and Western blotting. Results: Silence of lncRNA UCA1 repressed HMEC-1 cells viability, migration, tube formation, and induced apoptosis. Meanwhile, silence of lncRNA UCA1 significantly up-regulated miR-195 expression. These alterations induced by lncRNA UCA1 were further enhanced by miR-195 overexpression, while were attenuated by miR-195 suppression. Moreover, silence of lncRNA UCA1 deactivated MEK/ERK and mTOR signaling pathways via a miR-195-dependent regulation. And the deactivation of MEK/ERK and mTOR signaling pathways led to a down-regulation of CCND1. Conclusion: This study demonstrates that silence of lncRNA UCA1 largely represses microvascular endothelial cells growth and tube formation. Silence of lncRNA UCA1 exerts its function possibly via up-regulation of miR-195, which in turn inactivates MEK/ERK and mTOR signaling pathways, and ultimately represses CCND1 expression.
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Chu, Zhili, Jiangang Ma, Caiying Wang, Kejia Lu, Xiaoqin Li, Haijin Liu, Xinglong Wang, Sa Xiao, and Zengqi Yang. "Newcastle Disease Virus V Protein Promotes Viral Replication in HeLa Cells through the Activation of MEK/ERK Signaling." Viruses 10, no. 9 (September 12, 2018): 489. http://dx.doi.org/10.3390/v10090489.
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Newcastle disease virus (NDV) can infect a wide range of domestic and wild bird species. The non-structural V protein of NDV plays an important role in antagonizing innate host defenses to facilitate viral replication. However, there is a lack of knowledge related to the mechanisms through which the V protein regulates viral replication. The extracellular signal-regulated kinase (ERK) signaling pathway in the host is involved in a variety of functions and is activated by several stimuli, including viral replication. In this study, we show that both the lentogenic strain, La Sota, and the velogenic strain, F48E9, of NDV activate the mitogen-activated protein kinase (MEK)/ERK signaling pathway. The pharmacological inhibition of ERK1/2 phosphorylation using the highly selective inhibitors U0126 and SCH772984 resulted in the reduced levels of NDV RNA in cells and virus titers in the cell supernatant, which established an important role for the MEK/ERK signaling pathway in NDV replication. Moreover, the overexpression of the V protein in HeLa cells increased the phosphorylation of ERK1/2 and induced the transcriptional changes in the genes downstream of the MEK/ERK signaling pathway. Taken together, our results demonstrate that the V protein is involved in the ERK signaling pathway-mediated promotion of NDV replication and thus, can be investigated as a potential antiviral target.
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Ho, Kenneth K. Y., Siddhartha Srivastava, Patrick C. Kinnunen, Krishna Garikipati, Gary D. Luker, and Kathryn E. Luker. "Oscillatory ERK Signaling and Morphology Determine Heterogeneity of Breast Cancer Cell Chemotaxis via MEK-ERK and p38-MAPK Signaling Pathways." Bioengineering 10, no. 2 (February 18, 2023): 269. http://dx.doi.org/10.3390/bioengineering10020269.
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Chemotaxis, regulated by oscillatory signals, drives critical processes in cancer metastasis. Crucial chemoattractant molecules in breast cancer, CXCL12 and EGF, drive the activation of ERK and Akt. Regulated by feedback and crosstalk mechanisms, oscillatory signals in ERK and Akt control resultant changes in cell morphology and chemotaxis. While commonly studied at the population scale, metastasis arises from small numbers of cells that successfully disseminate, underscoring the need to analyze processes that cancer cells use to connect oscillatory signaling to chemotaxis at single-cell resolution. Furthermore, little is known about how to successfully target fast-migrating cells to block metastasis. We investigated to what extent oscillatory networks in single cells associate with heterogeneous chemotactic responses and how targeted inhibitors block signaling processes in chemotaxis. We integrated live, single-cell imaging with time-dependent data processing to discover oscillatory signal processes defining heterogeneous chemotactic responses. We identified that short ERK and Akt waves, regulated by MEK-ERK and p38-MAPK signaling pathways, determine the heterogeneous random migration of cancer cells. By comparison, long ERK waves and the morphological changes regulated by MEK-ERK signaling, determine heterogeneous directed motion. This study indicates that treatments against chemotaxis in consider must interrupt oscillatory signaling.
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Li, Yong Q., Charles S. T. Hii, Maurizio Costabile, David Goh, Channing J. Der, and Antonio Ferrante. "Regulation of Lymphotoxin Production by the p21ras-raf-MEK-ERK Cascade in PHA/PMA-Stimulated Jurkat Cells." Journal of Immunology 162, no. 6 (March 15, 1999): 3316–20. http://dx.doi.org/10.4049/jimmunol.162.6.3316.
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Abstract Although the production of lymphotoxin (LT) from activated Th1 lymphocytes has been reported extensively, the intracellular signaling mechanisms that regulate this T cell function remain totally undefined. We have examined whether the p21ras-raf-1-mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) kinase (MEK)-ERK cascade plays a role in regulating the production of LT, because the activity of these signaling molecules is up-regulated in activated T lymphocytes. Transfection of Jurkat leukemic T cells with a dominant negative mutant of p21ras (ras17N or ras15A), raf-1 (raf 1–130), or ERK1 (Erk1-K71R) resulted in the suppression of the mitogen/phorbol ester-stimulated production/secretion of LT. This suppression was accompanied by a parallel inhibition of mitogen-stimulated ERK activation. The selective antagonist of MEK1 activation, PD98059, also attenuated the mitogen-stimulated or anti-CD3 Ab and phorbol ester-stimulated production of LT from Jurkat cells or peripheral blood T lymphocytes. This study provides, for the first time, direct evidence that the p21ras-raf-MEK-ERK cascade plays a vital role in regulating the production of LT.
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Purkerson, Jeffrey M., and David C. Parker. "Differential Coupling of Membrane Ig and CD40 to the Extracellularly Regulated Kinase Signaling Pathway." Journal of Immunology 160, no. 5 (March 1, 1998): 2121–29. http://dx.doi.org/10.4049/jimmunol.160.5.2121.
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Abstract Coupling of membrane Ig (mIg) and CD40 to the extracellularly regulated kinase (ERK) signal transduction pathway was examined in the WEHI-231 B lymphoma and normal mouse B cells. Cross-linking mIg induces ERK activation in both WEHI-231 and normal B cells. In contrast, CD40 cross-linking failed to induce ERK activation in WEHI-231, but signals through CD40 were more effective than mIg as a stimulus for ERK activation in normal B cells. However, several lines of evidence suggest that CD40 and the B cell Ag regulate ERK through distinct pathways that converge at the level of MEK-1, mitogen-activated protein kinase kinase. Abs to mIg or CD40 induced MEK-1 activation with different kinetics. Cross-linking of mIg, but not CD40, induced tyrosine phosphorylation of the SHC adapter molecule that couples receptors to Ras-dependent signaling pathways. Finally, agents that elevate cAMP, causing protein kinase A-mediated inhibition of Raf-1, inhibited activation of ERK in response to mIg cross-linking, but had no affect on ERK activation in response to anti-CD40 or Jun N-terminal kinase activation by signals through either receptor. Thus, CD40 uses an unidentified protein kinase A-insensitive MEK kinase, rather than Raf-1, to regulate ERK activity.
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Zou, Qiang, Jin Jin, Yichuan Xiao, Hongbo Hu, Xiaofei Zhou, Zuliang Jie, Xiaoping Xie, James Y. H. Li, Xuhong Cheng, and Shao-Cong Sun. "T cell development involves TRAF3IP3-mediated ERK signaling in the Golgi." Journal of Experimental Medicine 212, no. 8 (July 20, 2015): 1323–36. http://dx.doi.org/10.1084/jem.20150110.
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Generation of T lymphocytes in the thymus is guided by signal transduction from the T cell receptor (TCR), but the underlying mechanism is incompletely understood. Here we have identified a Golgi-associated factor, TRAF3-interacting protein 3 (TRAF3IP3), as a crucial mediator of thymocyte development. TRAF3IP3 deficiency in mice attenuates the generation of mature thymocytes caused by impaired thymocyte-positive selection. TRAF3IP3 mediates TCR-stimulated activation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK) and its upstream kinase mitogen/extracellular signal-regulated kinase (MEK). Interestingly, TRAF3IP3 exerts this signaling function through recruiting MEK to the Golgi and, thereby, facilitating the interaction of MEK with its activator BRAF. Transgenic expression of a constitutively active MEK rescues the T cell development block in Traf3ip3 knockout mice. These findings establish TRAF3IP3 as a novel regulator of T cell development and suggest a Golgi-specific ERK signaling mechanism that regulates thymocyte development.
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Modi, Prashant Kumar, Narayana Komaravelli, Neha Singh, and Pushkar Sharma. "Interplay between MEK-ERK signaling, cyclin D1, and cyclin-dependent kinase 5 regulates cell cycle reentry and apoptosis of neurons." Molecular Biology of the Cell 23, no. 18 (September 15, 2012): 3722–30. http://dx.doi.org/10.1091/mbc.e12-02-0125.
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In response to neurotoxic signals, postmitotic neurons make attempts to reenter the cell cycle, which results in their death. Although several cell cycle proteins have been implicated in cell cycle–related neuronal apoptosis (CRNA), the molecular mechanisms that underlie this important event are poorly understood. Here, we demonstrate that neurotoxic agents such as β-amyloid peptide cause aberrant activation of mitogen-activated kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) signaling, which promotes the entry of neurons into the cell cycle, resulting in their apoptosis. The MEK-ERK pathway regulates CRNA by elevating the levels of cyclin D1. The increase in cyclin D1 attenuates the activation of cyclin-dependent kinase 5 (cdk5) by its neuronal activator p35. The inhibition of p35-cdk5 activity results in enhanced MEK-ERK signaling, leading to CRNA. These studies highlight how neurotoxic signals reprogram and alter the neuronal signaling machinery to promote their entry into the cell cycle, which eventually leads to neuronal cell death.