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1
Wang, Jun, and Shougang Zhuang. "Src family kinases in chronic kidney disease." American Journal of Physiology-Renal Physiology 313, no. 3 (September 1, 2017): F721—F728. http://dx.doi.org/10.1152/ajprenal.00141.2017.
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Src family kinases (SFKs) belong to nonreceptor protein tyrosine kinases and have been implicated in the regulation of numerous cellular processes, including cell proliferation, differentiation, migration and invasion, and angiogenesis. The role and mechanisms of SFKs in tumorgenesis have been extensively investigated, and some SFK inhibitors are currently under clinical trials for tumor treatment. Recent studies have also demonstrated the importance of SFKs in regulating the development of various fibrosis-related chronic diseases (e.g., idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, and systemic sclerosis). In this article, we summarize the roles of SFKs in various chronic kidney diseases, including glomerulonephritis, diabetic nephropathy, human immunodeficiency virus-associated nephropathy, autosomal dominant form of polycystic kidney disease, and obesity-associated kidney disease, and discuss the mechanisms involved.
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Xiao, Xiang, Yue Yang, Baiping Mao, C. Yan Cheng, and Ya Ni. "Emerging role for SRC family kinases in junction dynamics during spermatogenesis." Reproduction 157, no. 3 (March 2019): R85—R94. http://dx.doi.org/10.1530/rep-18-0440.
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SRC family kinases (SFKs) are known regulators of multiple cellular events, including cell movement, differentiation, proliferation, survival and apoptosis. SFKs are expressed virtually by all mammalian cells. They are non-receptor protein kinases that phosphorylate a variety of cellular proteins on tyrosine, leading to the activation of protein targets in response to environmental stimuli. Among SFKs, SRC, YES and FYN are the ubiquitously expressed and best studied members. In fact, SRC, the prototypical SFK, was the first tyrosine kinase identified in mammalian cells. Studies have shown that SFKs are regulators of cell junctions, and function in endocytosis and membrane trafficking to regulate junction restructuring events. Herein, we briefly summarize the recent findings in the field regarding the role of SFKs in the testis in regulating spermatogenesis, particularly in Sertoli–Sertoli and Sertoli–germ cell adhesion. While it is almost 50 years since the identification of the oncogene v-Src encoded by Rous sarcoma transforming virus, the understanding of SFK involvement during spermatogenesis in the testis remains far behind that in other epithelia and tissues. The goal of this review is to bridge this gap.
3
Senis, Yotis A., Alexandra Mazharian, and Jun Mori. "Src family kinases: at the forefront of platelet activation." Blood 124, no. 13 (September 25, 2014): 2013–24. http://dx.doi.org/10.1182/blood-2014-01-453134.
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Abstract Src family kinases (SFKs) play a central role in mediating the rapid response of platelets to vascular injury. They transmit activation signals from a diverse repertoire of platelet surface receptors, including the integrin αIIbβ3, the immunoreceptor tyrosine–based activation motif–containing collagen receptor complex GPVI-FcR γ-chain, and the von Willebrand factor receptor complex GPIb-IX-V, which are essential for thrombus growth and stability. Ligand-mediated clustering of these receptors triggers an increase in SFK activity and downstream tyrosine phosphorylation of enzymes, adaptors, and cytoskeletal proteins that collectively propagate the signal and coordinate platelet activation. A growing body of evidence has established that SFKs also contribute to Gq- and Gi-coupled receptor signaling that synergizes with primary activation signals to maximally activate platelets and render them prothrombotic. Interestingly, SFKs concomitantly activate inhibitory pathways that limit platelet activation and thrombus size. In this review, we discuss past discoveries that laid the foundation for this fundamental area of platelet signal transduction, recent progress in our understanding of the distinct and overlapping functions of SFKs in platelets, and new avenues of research into mechanisms of SFK regulation. We also highlight the thrombotic and hemostatic consequences of targeting platelet SFKs.
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Xiang, Binggang, Guoying Zhang, and Zhenyu Li. "Src Family Kinases Contribute to GI and Gq-Mediated Platelet Activation." Blood 118, no. 21 (November 18, 2011): 5263. http://dx.doi.org/10.1182/blood.v118.21.5263.5263.
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Abstract Abstract 5263 The Src family kinases (SFKs) play an essential role in collagen- and von Willebrand factor (vWF)-mediated platelet activation. However, the role of SFKs in G protein-coupled receptor (GPCR)-mediated platelet activation is not fully understood, and little is known about the molecular mechanisms by which SFKs are activated by GPCR stimulation. Here we demonstrate that SFKs are activated by the Gq and Gi pathways, respectively and SFKs play important roles in Gq- and Gi-dependent secretion and activation. ADP induced SFK phosphorylation in wild type and Gq−/− platelets, and ADP-induced SFK phosphorylation was inhibited by the P2Y12 antagonist AR-C69931MX or P2Y12 knockout but was not affected by the P2Y1 antagonist MRS-2179. Lyn and Fyn were co-immunoprecipitated with Gi2 in platelets, and ADP-induced SFK phosphorylation was diminished in Lyn−/− platelets. These results demonstrate that ADP induces SFK activation mainly depending on the Gi pathway activated via its receptor P2Y12. Furthermore, epinephrine also dose-dependently induced SFK phosphorylation in mouse platelets. A selective inhibitor of Src family kinase PP2 inhibited ADP-induced Akt phosphorylation, fibrinogen binding, and platelet aggregation. Thus, activation of Gi is sufficient to induce SFK activation, which plays an important role in Gi-dependent platelet activation. We further show that the thrombin receptor PAR4 peptide AYPGKF elicited SFK phosphorylation in P2Y12−/−, but not in Gq−/− platelets, and AYPGKF-induced SFK phosphorylation was inhibited by the calcium chelator dimethyl-BAPTA, suggesting that Gq-dependent SFK phosphorylation is downstream from the Ca2+ signaling. The calcium ionophore, A23187-induced TXA2 synthesis, platelet aggregation and secretion were inhibited by pre-incubation of platelets with PP2. PAR4-induced TXA2 synthesis was also abolished by PP2. Moreover, PAR4-mediated granule secretion, integrin aIIbb3 activation, and aggregation of P2Y12 deficient platelets were partially inhibited by PP2 or a PKC inhibitor Ro-31-8220, but were completely abolished by Ro-31-8220 plus PP2 or dimethyl-BAPTA, suggesting that Ca2+/SFKs and PKC represent two parallel signaling pathways mediating Gq-dependent platelet activation. In summary, SFKs can be activated by Gq/Ca2+-dependent mechanisms and by Gi-dependent mechanisms, and SFKS play important roles in Gq- and Gi-dependent platelet activation. Disclosures: No relevant conflicts of interest to declare.
5
Evangelista, Virgilio, Zehra Pamuklar, Antonio Piccoli, Stefano Manarini, Giuseppe Dell'Elba, Romina Pecce, Nicola Martelli, et al. "Src family kinases mediate neutrophil adhesion to adherent platelets." Blood 109, no. 6 (November 9, 2006): 2461–69. http://dx.doi.org/10.1182/blood-2006-06-029082.
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Abstract Polymorphonuclear leukocyte (PMN)–platelet interactions at sites of vascular damage contribute to local and systemic inflammation. We sought to determine the role of “outside-in” signaling by Src-family tyrosine kinases (SFKs) in the regulation of αMβ2-integrin–dependent PMN recruitment by activated platelets under (patho)physiologic conditions. Activation-dependent epitopes in β2 integrin were exposed at the contact sites between PMNs and platelets and were abolished by SFK inhibitors. PMNs from αMβ2−/−, hck−/−fgr−/−, and hck−/−fgr−/−lyn−/− mice had an impaired capacity to adhere with activated platelets in suspension. Phosphorylation of Pyk2 accompanied PMN adhesion to platelets and was blocked by inhibition as well as by genetic deletion of αMβ2 integrin and SFKs. A Pyk2 inhibitor reduced platelet-PMN adhesion, indicating that Pyk2 may be a downstream effector of SFKs. Analysis of PMN-platelet interactions under flow revealed that SFK signaling was required for αMβ2-mediated shear-resistant adhesion of PMNs to adherent platelets, but was dispensable for P-selectin–PSGL-1–mediated recruitment and rolling. Finally, SFK activity was required to support PMN accumulation along adherent platelets at the site of vascular injury, in vivo. These results definitely establish a role for SFKs in PMN recruitment by activated platelets and suggest novel targets to disrupt the pathophysiologic consequences of platelet-leukocyte interactions in vascular disease.
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Indovina, Paola, Iris Maria Forte, Francesca Pentimalli, and Antonio Giordano. "Targeting SRC Family Kinases in Mesothelioma: Time to Upgrade." Cancers 12, no. 7 (July 11, 2020): 1866. http://dx.doi.org/10.3390/cancers12071866.
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Malignant mesothelioma (MM) is a deadly tumor mainly caused by exposure to asbestos. Unfortunately, no current treatment is able to change significantly the natural history of the disease, which has a poor prognosis in the majority of patients. The non-receptor tyrosine kinase SRC and other SRC family kinase (SFK) members are frequently hyperactivated in many cancer types, including MM. Several works have indeed suggested that SFKs underlie MM cell proliferation, survival, motility, and invasion, overall affecting multiple oncogenic pathways. Consistently, SFK inhibitors effectively counteracted MM cancerous features at the preclinical level. Dasatinib, a multi-kinase inhibitor targeting SFKs, was also assessed in clinical trials either as second-line treatment for patients with unresectable MM or, more recently, as a neoadjuvant agent in patients with resectable MM. Here, we provide an overview of the molecular mechanisms implicating SFKs in MM progression and discuss possible strategies for a more successful clinical application of SFK inhibitors. Our aim is to stimulate discussion and further consideration of these agents in better designed preclinical and clinical studies to make the most of another class of powerful antitumoral drugs, which too often are lost in translation when applied to MM.
7
Singh, Durgesh Kumar, Rohit Kumar Deshmukh, Praveen Kumar Narayanan, Sisinthy Shivaji, and Archana Bharadwaj Siva. "SRC family kinases in hamster spermatozoa: evidence for the presence of LCK." Reproduction 153, no. 5 (May 2017): 655–69. http://dx.doi.org/10.1530/rep-16-0591.
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Sperm capacitation is a prerequisite for successful fertilization. Increase in tyrosine phosphorylation is considered the hallmark of capacitation and attempts to understand its regulation are ongoing. In this regard, we attempted to study the role of SRC family kinases (SFKs) in the hamster sperm functions. Interestingly, we found the presence of the lymphocyte-specific protein tyrosine kinase, LCK, in mammalian spermatozoa and further characterized it in terms of its localization and function. LCK was found in spermatozoa of several species, and its transcript was identified in the hamster testis. Autophosphorylation of LCK at the Y394 residue increased as capacitation progressed, indicating an upregulation of LCK activity during capacitation. Inhibition of LCK (and perhaps the other SFKs) with the use of a specific inhibitor showed a significant decrease in protein tyrosine phosphorylation of several proteins, implying LCK/SFKs as key tyrosine kinase(s) regulating tyrosine phosphorylation during hamster sperm capacitation. Dihydrolipoamide dehydrogenase was identified as a substrate for LCK/SFK. LCK/SFKs inhibition significantly reduced the percentage fertilization (in vitro) but had no effect on sperm motility, hyperactivation and acrosome reaction. In summary, this is the first report on the presence of LCK, an SFK of hematopoietic lineage in spermatozoa besides being the first study on the role of SFKs in the spermatozoa of Syrian hamsters.
8
Voisset, Edwige, Fabienne Brenet, Sophie Lopez, and Paulo de Sepulveda. "SRC-Family Kinases in Acute Myeloid Leukaemia and Mastocytosis." Cancers 12, no. 7 (July 21, 2020): 1996. http://dx.doi.org/10.3390/cancers12071996.
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Protein tyrosine kinases have been recognized as important actors of cell transformation and cancer progression, since their discovery as products of viral oncogenes. SRC-family kinases (SFKs) play crucial roles in normal hematopoiesis. Not surprisingly, they are hyperactivated and are essential for membrane receptor downstream signaling in hematological malignancies such as acute myeloid leukemia (AML) and mastocytosis. The precise roles of SFKs are difficult to delineate due to the number of substrates, the functional redundancy among members, and the use of tools that are not selective. Yet, a large num ber of studies have accumulated evidence to support that SFKs are rational therapeutic targets in AML and mastocytosis. These two pathologies are regulated by two related receptor tyrosine kinases, which are well known in the field of hematology: FLT3 and KIT. FLT3 is one of the most frequently mutated genes in AML, while KIT oncogenic mutations occur in 80–90% of mastocytosis. Studies on oncogenic FLT3 and KIT signaling have shed light on specific roles for members of the SFK family. This review highlights the central roles of SFKs in AML and mastocytosis, and their interconnection with FLT3 and KIT oncoproteins.
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Talmor-Cohen, A., R. Tomashov-Matar, E. Eliyahu, R. Shapiro, and R. Shalgi. "Are Src family kinases involved in cell cycle resumption in rat eggs?" Reproduction 127, no. 4 (April 2004): 455–63. http://dx.doi.org/10.1530/rep.1.00104.
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The earliest visible indications for the transition to embryos in mammalian eggs, known as egg activation, are cortical granules exocytosis (CGE) and resumption of meiosis (RM); these events are triggered by the fertilizing spermatozoon through a series of Ca2+transients. The pathways, within the egg, leading to the intracellular Ca2+release and to the downstream cellular events, are currently under intensive investigation. The involvement of Src family kinases (SFKs) in Ca2+release at fertilization is well supported in marine invertebrate eggs but not in mammalian eggs. In a previous study we have shown the expression and localization of Fyn, the first SFK member demonstrated in the mammalian egg. The purpose of the current study was to identify other common SFKs and resolve their function during activation of mammalian eggs. All three kinases examined: Fyn, c-Src and c-Yes are distributed throughout the egg cytoplasm. However, Fyn and c-Yes tend to concentrate at the egg cortex, though only Fyn is localized to the spindle as well. The different localizations of the various SFKs imply the possibility of their different functions within the egg. To examine whether SFKs participate in the signal transduction pathways during egg activation, we employed selective inhibitors of the SFKs activity ((PP2 and SU6656). The results demonstrate that RM, which is triggered by Ca2+elevation, is an SFK-dependent process, while CGE, triggered by either Ca2+elevation or protein kinase C (PKC), is not. The possible involvement of SFKs in the signal transduction pathways that lead from the sperm–egg fusion site downstream of the Ca2+release remains unclear.
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Oneyama, Chitose, Takuya Iino, Kazunobu Saito, Kei Suzuki, Akira Ogawa, and Masato Okada. "Transforming Potential of Src Family Kinases Is Limited by the Cholesterol-Enriched Membrane Microdomain." Molecular and Cellular Biology 29, no. 24 (October 12, 2009): 6462–72. http://dx.doi.org/10.1128/mcb.00941-09.
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ABSTRACT The upregulation of Src family kinases (SFKs) has been implicated in cancer progression, but the molecular mechanisms regulating their transforming potentials remain unclear. Here we show that the transforming ability of all SFK members is suppressed by being distributed to the cholesterol-enriched membrane microdomain. All SFKs could induce cell transformation when overexpressed in C-terminal Src kinase (Csk)-deficient fibroblasts. However, their transforming abilities varied depending on their affinity for the microdomain. c-Src and Blk, with a weak affinity for the microdomain due to a single myristate modification at the N terminus, could efficiently induce cell transformation, whereas SFKs with both myristate and palmitate modifications were preferentially distributed to the microdomain and required higher doses of protein expression to induce transformation. In contrast, disruption of the microdomain by depleting cholesterol could induce a robust transformation in Csk-deficient fibroblasts in which only a limited amount of activated SFKs was expressed. Conversely, the addition of cholesterol or recruitment of activated SFKs to the microdomain via a transmembrane adaptor, Cbp/PAG1, efficiently suppressed SFK-induced cell transformation. These findings suggest that the membrane microdomain spatially limits the transforming potential of SFKs by sequestering them away from the transforming pathways.
11
Bhavaraju, Kamala, Soochong Kim, and Satya P. Kunapuli. "Lyn and Fyn Kinases Positively Regulate Thromboxane Generation in Platelets." Blood 110, no. 11 (November 16, 2007): 3656. http://dx.doi.org/10.1182/blood.v110.11.3656.3656.
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Abstract Src family Kinases (SFKs) are important tyrosine kinases in platelets. The family consists of 9 members (viz., Blk, Fgr, Fyn, Hck, Lck, Lyn, Src, Yes and Yrk) and many of the isoforms are expressed in platelets. SFKs are key kinases in glycoprotein (GPVI) mediated platelet activation and we have shown that these kinases play an important role in thromboxane generation. Until now, the role of specific SFKs downstream of G protein signaling in platelets is not well understood. In the present study we characterized functional roles of specific SFK members Fyn, Lyn, Lck and Src Kinases downstream of ADP receptors. Src, Lyn and Fyn are activated downstream of ADP receptors (P2Y) receptors in a time and concentration dependent manner. The presence of fibrinogen receptor antagonist, GR144053, did not affect the activation of Src and Fyn; however, Lyn is not activated in the presence of GR144053, suggesting that Lyn requires outside-in signaling for it’s activation. On the other hand, Lck kinase is not activated downstream of ADP receptors. ADP activates P2Y1 and P2Y12 receptors which in turn couple to Gq and Gi, respectively. In order to further delineate the Src activation pathways we used P2Y1 and P2Y12 receptor antagonists MRS 2179 and AR-C69931MX respectively. Src activation is not inhibited by either P2Y1 or P2Y12 receptor antagonists, suggesting that both receptors independently contribute to the activation of Src kinase. Platelets from mice deficient in Src, Fyn or Lyn were analyzed for thromboxane generation upon stimulation with ADP. Lyn and Fyn KO mice had reduced levels of thromboxane A2 compared to wild type littermates. However, thromboxane generation from platelets lacking Src was unaffected. Hence, we conclude Lyn and Fyn kinases, but not Src, positively regulate thromboxane generation downstream of ADP receptors. We also conclude that Lyn requires outside-in signaling for its activation.
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Ruiz, Ofelia S., R. Brooks Robey, Yi-Yong Qiu, Long Jiang Wang, Cheng Jin Li, Jianfei Ma, and Jose A. L. Arruda. "Regulation of the renal Na-HCO3 cotransporter. XI. Signal transduction underlying CO2stimulation." American Journal of Physiology-Renal Physiology 277, no. 4 (October 1, 1999): F580—F586. http://dx.doi.org/10.1152/ajprenal.1999.277.4.f580.
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We have previously shown that CO2 stimulation of the renal Na-HCO3 cotransporter (NBC) activity is abrogated by general inhibitors of protein tyrosine kinases. The more selective inhibitor herbimycin also blocked this effect at concentrations known to preferentially inhibit Src family kinases (SFKs). We therefore examined a role for SFKs in CO2-stimulated NBC activity. To this end, we engineered OK cells to express the COOH-terminal Src kinase (Csk), a negative regulator of SFKs. CO2 stimulated NBC activity normally in β-galactosidase-expressing and untransfected control cells. In contrast, Csk-expressing cells had normal baseline NBC activity that was not stimulated by CO2. CO2 stimulation increased both total SFK activity and specific tyrosine phosphorylation of Src. The specific MEK1/2 inhibitor PD-98059 completely inhibited the CO2 stimulation of NBC activity as well as the accompanying phosphorylation and activation of ERK1/2. Our data suggest the involvement of both SFKs, probably Src, and the “classic” MAPK pathway in mediating CO2-stimulated NBC activity in renal epithelial cells.
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Sirvent, Audrey, Rudy Mevizou, Dana Naim, Marie Lafitte, and Serge Roche. "Src Family Tyrosine Kinases in Intestinal Homeostasis, Regeneration and Tumorigenesis." Cancers 12, no. 8 (July 23, 2020): 2014. http://dx.doi.org/10.3390/cancers12082014.
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Src, originally identified as an oncogene, is a membrane-anchored tyrosine kinase and the Src family kinase (SFK) prototype. SFKs regulate the signalling induced by a wide range of cell surface receptors leading to epithelial cell growth and adhesion. In the intestine, the SFK members Src, Fyn and Yes regulate epithelial cell proliferation and migration during tissue regeneration and transformation, thus implicating conserved and specific functions. In patients with colon cancer, SFK activity is a marker of poor clinical prognosis and a potent driver of metastasis formation. These tumorigenic activities are linked to SFK capacity to promote the dissemination and tumour-initiating capacities of epithelial tumour cells. However, it is unclear how SFKs promote colon tumour formation and metastatic progression because SFK-encoding genes are unfrequently mutated in human cancer. Here, we review recent findings on SFK signalling during intestinal homeostasis, regeneration and tumorigenesis. We also describe the key nongenetic mechanisms underlying SFK tumour activities in colorectal cancer, and discuss how these mechanisms could be exploited in therapeutic strategies to target SFK signalling in metastatic colon cancer.
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Kheilová, Kateřina, Jaroslav Petr, Tereza Žalmanová, Veronika Kučerová-Chrpová, and Dalibor Řehák. "Src family kinases are involved in the meiotic maturation of porcine oocytes." Reproduction, Fertility and Development 27, no. 7 (2015): 1097. http://dx.doi.org/10.1071/rd13352.
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Mammalian meiotic maturation is regulated by changes in the phosphorylation state of proteins involved in signalling pathways. The regulatory proteins include the family of Src tyrosine kinases. Src family kinases (SFKs) are required for meiotic maturation of mouse oocytes, and it remains to be elucidated whether they play the same role in porcine oocytes. To clarify the role of SFKs in the meiotic maturation of porcine oocytes we used inhibition of SFKs, western blotting and immunolocalisation to determine the presence of SFKs and localisation in the oocytes and assays to determine the activity of maturation-promoting factor (MPF) and mitogen-activated protein kinase (MAPK). Inhibition of SFKs resulted in the disruption of oocyte maturation and led to a decline in MPF and MAPK activity. The fluorescence intensity of SFKs in the cytoplasm and membrane of MI oocytes decreased significantly compared with germinal vesicle oocytes. The highest fluorescence intensity for SFKs was detected on the membrane of MII oocytes. Only weak fluorescence was detected in the perichromosomal area of MI and MII oocytes. These results prove that SFKs play an active role in the meiotic maturation of porcine oocytes by regulating MPF and MAPK activity.
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Tibaldi, Elena, Andrea Venerando, Francesca Zonta, Carlo Bidoia, Elisa Magrin, Oriano Marin, Antonio Toninello, et al. "Interaction between the SH3 domain of Src family kinases and the proline-rich motif of HTLV-1 p13: a novel mechanism underlying delivery of Src family kinases to mitochondria." Biochemical Journal 439, no. 3 (October 13, 2011): 505–18. http://dx.doi.org/10.1042/bj20101650.
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The association of the SH3 (Src homology 3) domain of SFKs (Src family kinases) with protein partners bearing proline-rich motifs has been implicated in the regulation of SFK activity, and has been described as a possible mechanism of relocalization of SFKs to subcellular compartments. We demonstrate in the present study for the first time that p13, an accessory protein encoded by the HTLV-1 (human T-cell leukaemia virus type 1), binds the SH3 domain of SFKs via its C-terminal proline-rich motif, forming a stable heterodimer that translocates to mitochondria by virtue of its N-terminal mitochondrial localization signal. As a result, the activity of SFKs is dramatically enhanced, with a subsequent increase in mitochondrial tyrosine phosphorylation, and the recognized ability of p13 to insert itself into the inner mitochondrial membrane and to perturb the mitochondrial membrane potential is abolished. Overall, the present study, in addition to confirming that the catalytic activity of SFKs is modulated by interactors of their SH3 domain, leads us to hypothesize a general mechanism by which proteins bearing a proline-rich motif and a mitochondrial localization signal at the same time may act as carriers of SFKs into mitochondria, thus contributing to the regulation of mitochondrial functions under various pathophysiological conditions.
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Donato, Nicholas J., Ji Wu, Ling-Yuan Kong, Feng Meng, Francis Lee, and Moshe Talpaz. "Constitutive Activation of SRC-Family Kinases in Chronic Myelogenous Leukemia Patients Resistant to Imatinib Mesylate in the Absence of BCR-ABL Mutations: A Rationale for Use of SRC/ABL Dual Kinase Inhibitor-Based Therapy." Blood 106, no. 11 (November 16, 2005): 1087. http://dx.doi.org/10.1182/blood.v106.11.1087.1087.
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Abstract BCR-ABL is an unregulated tyrosine kinase expressed as a consequence of a reciprocal chromosomal translocation that is common in chronic myelogenous and acute lymphocytic leukemia. BCR-ABL induces transformation of hematopoetic stem cells through tyrosine phosphorylation of multiple substrates. The src-family kinases (SFKs), Lyn and Hck, are highly activated by BCR-ABL in leukemic cells and recent studies suggest that they are substrates and essential mediators of BCR-ABL signal transduction and transformation. In cells selected for resistance to the BCR-ABL inhibitor, imatinib mesylate, Lyn kinase is overexpressed and its activation is not dependent on or regulated by BCR-ABL, suggesting that autonomous regulation of SFKs may play a role in imatinib resistant. In this report, activation of Lyn and Hck was compared in CML specimens derived from imatinib responsive and resistant patients that did not express a mutant BCR-ABL protein as their primary mediator of resistance. In imatinib sensitive cell lines and specimens derived from imatinib responsive CML patients imatinib effectively reduced activation of both BCR-ABL and SFKs. However, in multiple specimens from resistant patients, imatinib reduced BCR-ABL kinase activation but failed to reduce SFK activation. The dual ABL/SRC inhibitor, BMS-354825, blocked activation of both BCR-ABL and SFKs expressed in leukemic cells and correlated with clinical responsiveness to this agent. Animal models demonstrated that loss of imatinib-mediated inhibition of Lyn kinase activation significantly impaired its anti-tumor activity which was recovered by treatment with BMS-354825. Direct silencing of Lyn or Hck reduced CML cell survival in imatinib resistant patient specimens and cell models, suggesting a direct role for these kinases in cell survival. Our results show that SFK activation is mediated by BCR-ABL in imatinib responsive cells but these kinases escape control by BCR-ABL in CML patients that develop imatinib resistance in the absence of BCR-ABL point mutations. This form of resistance can effectively be overcome by BMS-354825 through its dual SRC and ABL kinase inhibitory activities. Dual specificity kinase inhibitors may be indicated for the treatment and prevention of imatinib resistance in CML when it is associated with constitutively activated src-family kinases.
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Tamiya, Shigeo, Mansim C. Okafor, and Nicholas A. Delamere. "Purinergic agonists stimulate lens Na-K-ATPase-mediated transport via a Src tyrosine kinase-dependent pathway." American Journal of Physiology-Cell Physiology 293, no. 2 (August 2007): C790—C796. http://dx.doi.org/10.1152/ajpcell.00579.2006.
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The Na-K-ATPase is vital for maintenance of lens transparency. Past studies using intact lens suggested the involvement of tyrosine kinases in short-term regulation of Na-K-ATPase. Furthermore, in vitro phosphorylation of a lens epithelial membrane preparation by Src family kinases (SFKs), a family of nonreceptor tyrosine kinases, resulted in modification of Na-K-ATPase activity. Here, the effect of purinergic agonists, ATP and UTP, on Na-K-ATPase function and SFK activation was examined in the rabbit lens. Na-K-ATPase function was examined using two different approaches, measurement of ouabain-sensitive potassium (86Rb) uptake by the intact lens, and Na-K-ATPase activity in lens epithelial homogenates. ATP and UTP caused a significant increase in ouabain-sensitive potassium (86Rb) uptake. Na-K-ATPase activity was increased in the epithelium of lenses pretreated with ATP. Lenses treated with ATP or UTP displayed activation of SFKs as evidenced by increased Western blot band density of active SFK (phosphorylated at the active loop Y416) and decreased band density of inactive SFKs (phosphorylated at the COOH terminal). A single PY416-Src immunoreactive band at ∼60 kDa was observed, suggesting not all Src family members are activated. Immunoprecipitation studies showed that band density of active Src, and to a lesser extent active Fyn, was significantly increased, while active Yes did not change. Preincubation of the lenses with SFK inhibitor PP2 abolished the ATP-induced increase in ouabain-sensitive potassium (86Rb) uptake. The results suggest selective activation of Src and/or Fyn is part of a signaling mechanism initiated by purinergic agonists that increases Na-K-ATPase-mediated transport in the organ-cultured lens.
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Priyadarshana, Chathura, Rangga Setiawan, Atsushi Tajima, and Atsushi Asano. "Src family kinases-mediated negative regulation of sperm acrosome reaction in chickens (Gallus gallus domesticus)." PLOS ONE 15, no. 11 (November 12, 2020): e0241181. http://dx.doi.org/10.1371/journal.pone.0241181.
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The acrosome reaction (AR) is a strictly-regulated, synchronous exocytosis that is required for sperm to penetrate ova. This all-or-nothing process occurs only once in the sperm lifecycle through a sequence of signaling pathways. Spontaneous, premature AR therefore compromises fertilization potential. Although protein kinase A (PKA) pathways play a central role in AR across species, the signaling network used for AR induction is poorly understood in birds. Mechanistic studies of mammalian sperm AR demonstrate that PKA activity is downstreamly regulated by Src family kinases (SFKs). Using SFK inhibitors, our study shows that in chicken sperm, SFKs play a role in the regulation of PKA activity and spontaneous AR without affecting motility. Furthermore, we examined the nature of SFK phosphorylation using PKA and protein tyrosine phosphatase inhibitors, which demonstrated that unlike in mammals, SFK phosphorylation in birds does not occur downstream of PKA and is primarily regulated by calcium-dependent tyrosine phosphatase activity. Functional characterization of SFKs in chicken sperm showed that SFK activation modulates the membrane potential and plays a role in inhibiting spontaneous AR. Employing biochemical isolation, we also found that membrane rafts are involved in the regulation of SFK phosphorylation. This study demonstrates a unique mechanism for regulating AR induction inherent to avian sperm that ensure fertilization potential despite prolonged storage.
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Berndt, Sandra, and Ines Liebscher. "New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation." International Journal of Molecular Sciences 22, no. 12 (June 17, 2021): 6489. http://dx.doi.org/10.3390/ijms22126489.
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Src family kinases (SFKs) are key regulators of cell proliferation, differentiation, and survival. The expression of these non-receptor tyrosine kinases is strongly correlated with cancer development and tumor progression. Thus, this family of proteins serves as an attractive drug target. The activation of SFKs can occur via multiple signaling pathways, yet many of them are poorly understood. Here, we summarize the current knowledge on G protein-coupled receptor (GPCR)-mediated regulation of SFKs, which is of considerable interest because GPCRs are among the most widely used pharmaceutical targets. This type of activation can occur through a direct interaction between the two proteins or be allosterically regulated by arrestins and G proteins. We postulate that a rearrangement of binding motifs within the active conformation of arrestin-3 mediates Src regulation by comparison of available crystal structures. Therefore, we hypothesize a potentially different activation mechanism compared to arrestin-2. Furthermore, we discuss the probable direct regulation of SFK by GPCRs and investigate the intracellular domains of exemplary GPCRs with conserved polyproline binding motifs that might serve as scaffolding domains to allow such a direct interaction. Large intracellular domains in GPCRs are often understudied and, in general, not much is known of their contribution to different signaling pathways. The suggested direct interaction between a GPCR and a SFK could allow for a potential immediate allosteric regulation of SFKs by GPCRs and thereby unravel a novel mechanism of SFK signaling. This overview will help to identify new GPCR–SFK interactions, which could serve to explain biological functions or be used to modulate downstream effectors.
20
Bagnato, Giulia, Martina Leopizzi, Enrica Urciuoli, and Barbara Peruzzi. "Nuclear Functions of the Tyrosine Kinase Src." International Journal of Molecular Sciences 21, no. 8 (April 11, 2020): 2675. http://dx.doi.org/10.3390/ijms21082675.
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Src is the representative member of the Src-family kinases (SFKs), a group of tyrosine kinases involved in several cellular processes. Its main function has been for long confined to the plasma membrane/cytoplasm compartment, being a myristoylated protein anchored to the cell membrane and functioning downstream to receptors, most of them lacking intrinsic kinase activity. In the last decades, new roles for some SFKs have been described in the nuclear compartment, suggesting that these proteins can also be involved in directly regulating gene transcription or nucleoskeleton architecture. In this review, we focused on those nuclear functions specifically attributable to Src, by considering its function as both tyrosine kinase and adapting molecule. In particular, we addressed the Src involvement in physiological as well as in pathological conditions, especially in tumors.
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Nagy, Zoltan, Jun Mori, Vanesa-Sindi Ivanova, Alexandra Mazharian, and Yotis A. Senis. "Interplay between the tyrosine kinases Chk and Csk and phosphatase PTPRJ is critical for regulating platelets in mice." Blood 135, no. 18 (April 30, 2020): 1574–87. http://dx.doi.org/10.1182/blood.2019002848.
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Abstract The Src family kinases (SFKs) Src, Lyn, and Fyn are essential for platelet activation and also involved in megakaryocyte (MK) development and platelet production. Platelet SFKs are inhibited by C-terminal Src kinase (Csk), which phosphorylates a conserved tyrosine in their C-terminal tail, and are activated by the receptor-type tyrosine phosphatase PTPRJ (CD148, DEP-1), which dephosphorylates the same residue. Deletion of Csk and PTPRJ in the MK lineage in mice results in increased SFK activity, but paradoxically hypoactive platelets resulting from negative feedback mechanisms, including upregulation of Csk homologous kinase (Chk) expression. Here, we investigate the role of Chk in platelets, functional redundancy with Csk, and the physiological consequences of ablating Chk, Csk, and PTPRJ in mice. Platelet count was normal in Chk knockout (KO) mice, reduced by 92% in Chk;Csk double KO (DKO) mice, and partially rescued in Chk;Csk;Ptprj triple KO (TKO) mice. Megakaryocyte numbers were significantly increased in both DKO and TKO mice. Phosphorylation of the inhibitory tyrosine of SFKs was almost completely abolished in DKO platelets, which was partially rescued in Src and Fyn in TKO platelets. This residual phosphorylation was abolished by Src inhibitors, revealing an unexpected mechanism in which SFKs autoinhibit their activity by phosphorylating their C-terminal tyrosine residues. We demonstrate that reduced inhibitory phosphorylation of SFKs leads to thrombocytopenia, with Csk being the dominant inhibitor in platelets and Chk having an auxiliary role. PTPRJ deletion in addition to Chk and Csk ameliorates the extent of thrombocytopenia, suggesting targeting it may have therapeutic benefits in such conditions.
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Jin, Wook. "Regulation of Src Family Kinases during Colorectal Cancer Development and Its Clinical Implications." Cancers 12, no. 5 (May 23, 2020): 1339. http://dx.doi.org/10.3390/cancers12051339.
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Src family kinases (SFKs) are non-receptor kinases that play a critical role in the pathogenesis of colorectal cancer (CRC). The expression and activity of SFKs are upregulated in patients with CRC. Activation of SFKs promotes CRC cell proliferation, metastases to other organs and chemoresistance, as well as the formation of cancer stem cells (CSCs). The enhanced expression level of Src is associated with decreased survival in patients with CRC. Src-mediated regulation of CRC progression involves various membrane receptors, modulators, and suppressors, which regulate Src activation and its downstream targets through various mechanisms. This review provides an overview of the current understanding of the correlations between Src and CRC progression, with a special focus on cancer cell proliferation, invasion, metastasis and chemoresistance, and formation of CSCs. Additionally, this review discusses preclinical and clinical strategies to improve the therapeutic efficacy of drugs targeting Src for treating patients with CRC.
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Vara, Juan Ángel Fresno, Ma Aurora Domı́nguez Cáceres, Augusto Silva, and Jorge Martı́n-Pérez. "Src Family Kinases Are Required for Prolactin Induction of Cell Proliferation." Molecular Biology of the Cell 12, no. 7 (July 2001): 2171–83. http://dx.doi.org/10.1091/mbc.12.7.2171.
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Prolactin (PRL) is a pleiotropic cytokine promoting cellular proliferation and differentiation. Because PRL activates the Src family of tyrosine kinases (SFK), we have studied the role of these kinases in PRL cell proliferation signaling. PRL induced [3H]thymidine incorporation upon transient transfection of BaF-3 cells with the PRL receptor. This effect was inhibited by cotransfection with the dominant negative mutant of c-Src (K>A295/Y>F527, SrcDM). The role of SFK in PRL-induced proliferation was confirmed in the BaF-3 PRL receptor-stable transfectant, W53 cells, where PRL induced Fyn and Lyn activation. The SFK-selective inhibitors PP1/PP2 and herbimycin A blocked PRL-dependent cell proliferation by arresting the W53 cells in G1, with no evident apoptosis. In parallel, PP1/PP2 inhibited PRL induction of cell growth-related genes c-fos, c-jun, c-myc, andodc. These inhibitors have no effect on PRL-mediated activation of Ras/Mapk and Jak/Start pathways. In contrast, they inhibited the PRL-dependent stimulation of the SFKs substrate Sam68, the phosphorylation of the tyrosine phosphatase Shp2, and the PI3K-dependent Akt and p70S6k serine kinases. Consistently, transient expression of SrcDM in W53 cells also blocked PRL activation of Akt. These results demonstrate that activation of SFKs is required for cell proliferation induced by PRL.
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Tanaka, Masamitsu, Kazuki Sasaki, Reiko Kamata, Yukari Hoshino, Kazuyoshi Yanagihara, and Ryuichi Sakai. "A Novel RNA-Binding Protein, Ossa/C9orf10, Regulates Activity of Src Kinases To Protect Cells from Oxidative Stress-Induced Apoptosis." Molecular and Cellular Biology 29, no. 2 (November 17, 2008): 402–13. http://dx.doi.org/10.1128/mcb.01035-08.
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ABSTRACT During the process of tumor progression and clinical treatments, tumor cells are exposed to oxidative stress. Tumor cells are frequently resistant to such stress by producing antiapoptotic signaling, including activation of Src family kinases (SFKs), although the molecular mechanism is not clear. In an attempt to identify the SFK-binding proteins selectively phosphorylated in gastric scirrhous carcinoma, we identified an uncharacterized protein, C9orf10. Here we report that C9orf10 (designated Ossa for oxidative stress-associated Src activator) is a novel RNA-binding protein that guards cancer cells from oxidative stress-induced apoptosis by activation of SFKs. Exposure to oxidative stress such as UV irradiation induces the association of Ossa/C9orf10 with regulatory domains of SFKs, which activates these kinases and causes marked tyrosine phosphorylation of C9orf10 in turn. Tyrosine-phosphorylated Ossa recruits p85 subunits of phosphatidylinositol 3-kinase (PI3-kinase) and behaves as a scaffolding protein for PI3-kinase and SFKs, which activates the Akt-mediated antiapoptotic pathway. On the other hand, the carboxyl terminus of Ossa has a distinct function that directly binds RNAs such as insulin-like growth factor II (IGF-II) mRNA and promotes the extracellular secretion of IGF-II. Our findings indicate that Ossa is a dual-functional protein and might be a novel therapeutic target which modulates the sensitivity of tumors to oxidative stress.
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Martellucci, Stefano, Letizia Clementi, Samantha Sabetta, Vincenzo Mattei, Lorenzo Botta, and Adriano Angelucci. "Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned So Far." Cancers 12, no. 6 (June 2, 2020): 1448. http://dx.doi.org/10.3390/cancers12061448.
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Src is the prototypal member of Src Family tyrosine Kinases (SFKs), a large non-receptor kinase class that controls multiple signaling pathways in animal cells. SFKs activation is necessary for the mitogenic signal from many growth factors, but also for the acquisition of migratory and invasive phenotype. Indeed, oncogenic activation of SFKs has been demonstrated to play an important role in solid cancers; promoting tumor growth and formation of distant metastases. Several drugs targeting SFKs have been developed and tested in preclinical models and many of them have successfully reached clinical use in hematologic cancers. Although in solid tumors SFKs inhibitors have consistently confirmed their ability in blocking cancer cell progression in several experimental models; their utilization in clinical trials has unveiled unexpected complications against an effective utilization in patients. In this review, we summarize basic molecular mechanisms involving SFKs in cancer spreading and metastasization; and discuss preclinical and clinical data highlighting the main challenges for their future application as therapeutic targets in solid cancer progression
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Rathore, Vipul B., Masato Okada, Peter J. Newman, and Debra K. Newman. "Paxillin family members function as Csk-binding proteins that regulate Lyn activity in human and murine platelets." Biochemical Journal 403, no. 2 (March 26, 2007): 275–81. http://dx.doi.org/10.1042/bj20061618.
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SFKs (Src family kinases) contribute importantly to platelet function in haemostasis. SFK activity is controlled by Csk (C-terminal Src kinase), which phosphorylates a C-terminal tyrosine residue on SFKs, resulting in inhibition of SFK activity. Csk is recruited to sites of SFK activity by tyrosine-phosphorylated Csk-binding proteins. Paxillin, a multidomain adaptor protein, has been shown to act as a Csk-binding protein and to inhibit Src activity during growth factor signalling. Human platelets express Hic-5, a member of the paxillin family; however, its ability to act as a Csk-binding protein has not been characterized. We sought to identify and characterize the ability of paxillin family members to act as Csk-binding proteins during platelet activation. We found that murine and human platelets differ in the complement of paxillin family members expressed. Human platelets express Hic-5, whereas murine platelets express paxillin and leupaxin in addition to Hic-5. In aggregating human platelets, Hic-5 was tyrosine phosphorylated and recruited Csk via its SH2 domains. In aggregating murine platelets, however, Csk bound preferentially to paxillin, even though both paxillin and Hic-5 were abundantly present and became tyrosine phosphorylated. The SFK Lyn, but not Src or Fyn, was associated with paxillin family members in resting and aggregated human and murine platelets. Lyn, however, was phosphorylated on its C-terminal inhibitory tyrosine residue only following platelet aggregation, which was coincident with recruitment of Csk to paxillin and/or Hic-5 in a manner dependent on prior αIIbβ3 engagement. These observations support the notion that Hic-5 and paxillin function as negative feedback regulators of SFKs in aggregated platelets and that, when both are present, paxillin is preferentially used.
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Sen, Banibrata, and Faye M. Johnson. "Regulation of Src Family Kinases in Human Cancers." Journal of Signal Transduction 2011 (April 4, 2011): 1–14. http://dx.doi.org/10.1155/2011/865819.
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The nonreceptor protein tyrosine kinase Src plays a crucial role in the signal transduction pathways involved in cell division, motility, adhesion, and survival in both normal and cancer cells. Although the Src family kinases (SFKs) are activated in various types of cancers, the exact mechanisms through which they contribute to the progression of individual tumors remain to be defined. The activation of Src in human cancers may occur through a variety of mechanisms that include domain interaction and structural remodeling in response to various activators or upstream kinases and phosphatastes. Because of Src's prominent roles in invasion and tumor progression, epithelial-to-mesenchymal transition, angiogenesis, and the development of metastasis, Src is a promising target for cancer therapy. Several small molecule inhibitors of Src are currently being investigated in clinical trials. In this article, we will summarize the mechanisms regulating Src kinase activity in normal and cancer cells and discuss the status of Src inhibitor development against various types of cancers.
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Colognato, Holly, Shwetha Ramachandrappa, Inger M. Olsen, and Charles ffrench-Constant. "Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development." Journal of Cell Biology 167, no. 2 (October 25, 2004): 365–75. http://dx.doi.org/10.1083/jcb.200404076.
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Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling. Here, we report that the Src family kinases (SFKs) Fyn and Lyn regulate each of these distinct integrin-driven behaviors. Fyn associates with α6β1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation). However, earlier in the lineage Lyn, not Fyn, is required to drive αVβ3-dependent progenitor proliferation. The two SFKs respond to integrin ligation by different mechanisms: Lyn, by increased autophosphorylation of a catalytic tyrosine; and Fyn, by reduced Csk phosphorylation of the inhibitory COOH-terminal tyrosine. These findings illustrate how different SFKs can act as effectors for specific cell responses during development within a single cell lineage, and, furthermore, provide a molecular mechanism to explain similar region-specific hypomyelination in laminin- and Fyn-deficient mice.
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Katoh, Kazuo. "Regulation of Fibroblast Cell Polarity by Src Tyrosine Kinase." Biomedicines 9, no. 2 (February 1, 2021): 135. http://dx.doi.org/10.3390/biomedicines9020135.
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Src protein tyrosine kinases (SFKs) are a family of nonreceptor tyrosine kinases that are localized beneath the plasma membrane and are activated during cell adhesion, migration, and elongation. Due to their involvement in the activation of signal transduction cascades, SFKs have been suggested to play important roles in the determination of cell polarity during cell extension and elongation. However, the mechanism underlying Src-mediated polarity formation remains unclear. The present study was performed to investigate the mechanisms underlying Src-induced cell polarity formation and cell elongation using Src knockout fibroblasts (SYFs) together with an inhibitor of Src. Normal and Src knockout fibroblasts were also transfected with a wild-type c-Src, dominant negative c-Src, or constitutively active c-Src gene to analyze the changes in cell morphology. SYF cells cultured on a glass substrate elongated symmetrically into spindle-shaped cells, with the formation of focal adhesions at both ends of the cells. When normal fibroblasts were treated with Src Inhibitor No. 5, a selective inhibitor of Src tyrosine kinases, they elongated into symmetrical spindle-shaped cells, similar to SYF cells. These results suggest that cell polarity during extension and elongation may be regulated by SFKs and that the expression and regulation of Src are important for the formation of polarity during cell elongation.
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Piazza, Timothy M., Juu-Chin Lu, Kristopher C. Carver, and Linda A. Schuler. "Src Family Kinases Accelerate Prolactin Receptor Internalization, Modulating Trafficking and Signaling in Breast Cancer Cells." Molecular Endocrinology 23, no. 2 (February 1, 2009): 202–12. http://dx.doi.org/10.1210/me.2008-0341.
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Abstract Despite the growing body of evidence supporting prolactin (PRL) actions in human breast cancer, little is known regarding PRL regulation of its own receptor in these cells. Ligand-initiated endocytosis is a key process in the regulation of receptor availability and signaling cascades that may lead to oncogenic actions. Although exposure to exogenous PRL accelerates degradation of the long isoform of the PRL receptor (lPRLR), neither the signals initiated by PRL that lead to lPRLR internalization and subsequent down-regulation, nor the relationship to downstream pathways are understood in breast cancer cells. In this study, we showed that PRL-induced down-regulation of the lPRLR was reduced by inhibition of src family kinases (SFKs), but not Janus kinase 2, in MCF-7 cells. Inhibition of SFKs also resulted in accumulation of a PRL-induced PRLR fragment containing the extracellular domain, which appeared to be generated from newly synthesized PRLR. lPRLR was constitutively associated with SFKs in lipid rafts. PRL-induced SFK activation led to recruitment of the guanosine triphosphatase, dynamin-2, to an internalization complex, resulting in endocytosis. Inhibition of endocytosis by small interfering RNA-mediated knockdown of dynamin-2 blocked PRL-induced down-regulation of lPRLR, confirming that internalization is essential for this process. Endocytosis also was required for optimal phosphorylation of ERK1/2 and Akt, but not for Janus kinase 2 or signal transducer and activator of transcription 5, indicating that internalization selectively modulates signaling cascades. Together, these data indicate that SFKs are key mediators of ligand-initiated lPRLR internalization, down-regulation, and signal transduction in breast cancer cells, and underscore the importance of target cell context in receptor trafficking and signal transduction.
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Teixeira, João, Héctor Fuentes, Stasė Bielskutė, Margarida Gairi, Szymon Żerko, Wiktor Koźmiński, and Miquel Pons. "The Two Isoforms of Lyn Display Different Intramolecular Fuzzy Complexes with the SH3 Domain." Molecules 23, no. 11 (October 23, 2018): 2731. http://dx.doi.org/10.3390/molecules23112731.
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The function of the intrinsically disordered Unique domain of the Src family of tyrosine kinases (SFK), where the largest differences between family members are concentrated, remains poorly understood. Recent studies in c-Src have demonstrated that the Unique region forms transient interactions, described as an intramolecular fuzzy complex, with the SH3 domain and suggested that similar complexes could be formed by other SFKs. Src and Lyn are members of a distinct subfamily of SFKs. Lyn is a key player in the immunologic response and exists in two isoforms originating from alternative splicing in the Unique domain. We have used NMR to compare the intramolecular interactions in the two isoforms and found that the alternatively spliced segment interacts specifically with the so-called RT-loop in the SH3 domain and that this interaction is abolished when a polyproline ligand binds to the SH3 domain. These results support the generality of the fuzzy complex formation in distinct subfamilies of SFKs and its physiological role, as the naturally occurring alternative splicing modulates the interactions in this complex.
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Knox, Renatta, and Xiangning Jiang. "Fyn in Neurodevelopment and Ischemic Brain Injury." Developmental Neuroscience 37, no. 4-5 (2015): 311–20. http://dx.doi.org/10.1159/000369995.
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The Src family kinases (SFKs) are nonreceptor protein tyrosine kinases that are implicated in many normal and pathological processes in the nervous system. The SFKs Fyn, Src, Yes, Lyn, and Lck are expressed in the brain. This review will focus on Fyn, as Fyn mutant mice have striking phenotypes in the brain and Fyn has been shown to be involved in ischemic brain injury in adult rodents and, with our work, in neonatal animals. An understanding of Fyn's role in neurodevelopment and disease will allow researchers to target pathological pathways while preserving protective ones.
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Lannutti, Brian J., and Jonathan G. Drachman. "Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors." Blood 103, no. 10 (May 15, 2004): 3736–43. http://dx.doi.org/10.1182/blood-2003-10-3566.
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Abstract In this study we demonstrate that thrombopoietin (TPO)–stimulated Src family kinases (SFKs) inhibit cellular proliferation and megakaryocyte differentiation. Using the Src kinase inhibitors pyrolopyrimidine 1 and 2 (PP1, PP2), we show that TPO-dependent proliferation of BaF3/Mpl cells was enhanced at concentrations that are specific for SFKs. Similarly, proliferation is increased after introducing a dominant-negative form of Lyn into BaF3/Mpl cells. Murine marrow cells from Lyn-deficient mice or wild-type mice cultured in the presence of the Src inhibitor, PP1, yielded a greater number of mature megakaryocytes and increased nuclear ploidy. Truncation and targeted mutation of the Mpl cytoplasmic domain indicate that Y112 is critical for Lyn activation. Examining the molecular mechanism for this antiproliferative effect, we determined that SFK inhibitors did not affect tyrosine phosphorylation of Janus kinase 2 (JAK2), Shc, signal transducer and activator of transcription (STAT)5, or STAT3. In contrast, pretreatment of cells with PP2 increased Erk1/2 (mitogen-activated protein kinase [MAPK]) phosphorylation and in vitro kinase activity, particularly after prolonged TPO stimulation. Taken together, our results show that Mpl stimulation results in the activation of Lyn kinase, which appears to limit the proliferative response through a signaling cascade that regulates MAPK activity. These data suggest that SFKs modify the rate of TPO-induced proliferation and are likely to affect cell cycle regulation during megakaryocytopoiesis.
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Xiao, Xiang, Ya Ni, Chenhuan Yu, Linxi Li, Baiping Mao, Yue Yang, Dongwang Zheng, Bruno Silvestrini, and C. Yan Cheng. "Src family kinases (SFKs) and cell polarity in the testis." Seminars in Cell & Developmental Biology 81 (September 2018): 46–53. http://dx.doi.org/10.1016/j.semcdb.2017.11.024.
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Harrison, M., G. Nash, S. Watson, and G. Rainger. "Platelet SRC family kinases (SFKS) mediate leukocyte recruitment in atherosclerosis." Atherosclerosis 241, no. 1 (July 2015): e42. http://dx.doi.org/10.1016/j.atherosclerosis.2015.04.151.
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Cary, Leslie A., Richard A. Klinghoffer, Christoph Sachsenmaier, and Jonathan A. Cooper. "Src Catalytic but Not Scaffolding Function Is Needed for Integrin-Regulated Tyrosine Phosphorylation, Cell Migration, and Cell Spreading." Molecular and Cellular Biology 22, no. 8 (April 15, 2002): 2427–40. http://dx.doi.org/10.1128/mcb.22.8.2427-2440.2002.
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ABSTRACT Src family kinases (SFKs) are crucial for signaling through a variety of cell surface receptors, including integrins. There is evidence that integrin activation induces focal adhesion kinase (FAK) autophosphorylation at Y397 and that Src binds to and is activated by FAK to carry out subsequent phosphorylation events. However, it has also been suggested that Src functions as a scaffolding molecule through its SH2 and SH3 domains and that its kinase activity is not necessary. To examine the role of SFKs in integrin signaling, we have expressed various Src molecules in fibroblasts lacking other SFKs. In cells plated on fibronectin, FAK could indeed autophosphorylate at Y397 independently of Src but with lower efficiency than when Src was present. This step was promoted by kinase-inactive Src, but Src kinase activity was required for full rescue. Src kinase activity was also required for phosphorylation of additional sites on FAK and for other integrin-directed functions, including cell migration and spreading on fibronectin. In contrast, Src mutations in the SH2 or SH3 domain greatly reduced binding to FAK, Cas, and paxillin but had little effect on tyrosine phosphorylation or biological assays. Furthermore, our indirect evidence indicates that Src kinase activity does not need to be regulated to promote cell migration and FAK phosphorylation. Although Src clearly plays important roles in integrin signaling, it was not concentrated in focal adhesions. These results indicate that the primary role of Src in integrin signaling is as a kinase. Indirect models for Src function are proposed.
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Bauer, S., G. D. Demetri, and J. A. Fletcher. "Evaluation of SRC-family kinases in gastrointestinal stromal tumors." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 9529. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9529.
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9529 Background: Inhibition of KIT oncoproteins by imatinib mesylate (IM) induces clinical responses in most GIST patients. However, many patients develop IM-resistance and novel KIT-Inhibitors show clinical benefit in only a minority of patients. SRC-family kinases (SFK) are important participants in kinase oncoprotein signaling pathways in ALL and CML, and dual-specificity SRC/ABL-inhibitors show promising activity in IM-resistant CML in vitro. However, little is known about SFK functional roles in IM-resistant GIST. Methods: GIST were analyzed for SFK expression and activation by western blotting. Biological consequences of KIT inhibition alone (IM), SFK inhibition (SU6656) and combined KIT/SFK inhibition (PP1, PP2, SU6656+IM) were determined by immunoblotting for protein activation, and—in GIST cell lines—by luminescence assays for cell proliferation. Results: Primary GIST and GIST cell lines showed weak SFK activation compared to Jurkat (T-cell ALL) controls. Variable expression of the SFK proteins FYN, LYN and SRC (but not BLK and LCK) was shown in the cell lines and primary GIST. Expression of SFK proteins HCK and FGR was found in 2 primary GIST only. KIT and KIT signaling pathways (pAKT, pS6, pSTAT3) were affected by IM and combined KIT inhibitors but not by SU6656 at 1μM in GIST882 (IM-sensitive cell line) and GIST48 (IM-resistant cell line). SRC phosphorylation (Y418) was not affected by IM or SFK-inhibitors at 1μM. IM showed superior inhibition of proliferation compared to PP1 and PP2 (1μM) in GIST882 (IM: 67%, PP1: 1%, PP2: 0%) and comparable inhibition in GIST48 (IM:30%, PP1: 29%, PP2: 29%). No effects on proliferation were seen with SU6656 alone or in combination with IM; no antagonistic effects were observed. Conclusions: Our analysis showed expression and weak activation of several SFK in GIST. Expression of heme-associated SFKs in primary GIST may be explained by lymphocellular infiltration. Biochemical inhibition of SFK alone does not have antiproliferative effects in GIST cell lines, and no synergies or antagonisms were found in combination with IM or with combined KIT/SFK inhibitors. Therefore, targeting of SFK may be of less therapeutic value in GIST than in kinase-driven haematological cancers. No significant financial relationships to disclose.
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Jha, Vibhu, Marco Macchia, Tiziano Tuccinardi, and Giulio Poli. "Three-Dimensional Interactions Analysis of the Anticancer Target c-Src Kinase with Its Inhibitors." Cancers 12, no. 8 (August 18, 2020): 2327. http://dx.doi.org/10.3390/cancers12082327.
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Src family kinases (SFKs) constitute the biggest family of non-receptor tyrosine kinases considered as therapeutic targets for cancer therapy. An aberrant expression and/or activation of the proto-oncogene c-Src kinase, which is the oldest and most studied member of the family, has long been demonstrated to play a major role in the development, growth, progression and metastasis of numerous human cancers, including colon, breast, gastric, pancreatic, lung and brain carcinomas. For these reasons, the pharmacological inhibition of c-Src activity represents an effective anticancer strategy and a few compounds targeting c-Src, together with other kinases, have been approved as drugs for cancer therapy, while others are currently undergoing preclinical studies. Nevertheless, the development of potent and selective inhibitors of c-Src aimed at properly exploiting this biological target for the treatment of cancer still represents a growing field of study. In this review, the co-crystal structures of c-Src kinase in complex with inhibitors discovered in the past two decades have been described, highlighting the key ligand–protein interactions necessary to obtain high potency and the features to be exploited for addressing selectivity and drug resistance issues, thus providing useful information for the design of new and potent c-Src kinase inhibitors.
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Imada, Shinya, Yoji Murata, Takenori Kotani, Masaki Hatano, Chunxiao Sun, Tasuku Konno, Jung-ha Park, et al. "Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis." Molecular and Cellular Biology 36, no. 22 (August 22, 2016): 2811–23. http://dx.doi.org/10.1128/mcb.00311-16.
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Proper regulation of epithelial cell turnover is important for the structural integrity and homeostasis of various tissues, including the intestine. Here we show that ablation of Csk, a negative regulator of Src family kinases (SFKs), specifically in intestinal epithelial cells (IECs) resulted in the development of hyperplasia throughout the intestinal epithelium of mice. Such conditional ablation of Csk also increased the proliferative activity and turnover of IECs, disturbed the differentiation of Paneth and goblet cells, reduced the number of intestinal stem cells, and attenuated the expression of Wnt target genes in the intestine. Moreover, the tyrosine phosphorylation of focal adhesion kinase (FAK) and the activities of both Rac and Yes-associated protein (YAP) were increased in intestinal crypts or organoids of the mutant mice, whereas inhibition of Rac or YAP activity rescued the mutant phenotypes. Our results thus suggest that SFKs promote the proliferation of IECs in intestinal crypts through activation of Rac or YAP and that they thereby contribute to the proper regulation of IEC turnover and intestinal homeostasis.
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Wayne, Chad M., Heng-Yu Fan, Xiaodong Cheng, and JoAnne S. Richards. "Follicle-Stimulating Hormone Induces Multiple Signaling Cascades: Evidence that Activation of Rous Sarcoma Oncogene, RAS, and the Epidermal Growth Factor Receptor Are Critical for Granulosa Cell Differentiation." Molecular Endocrinology 21, no. 8 (August 1, 2007): 1940–57. http://dx.doi.org/10.1210/me.2007-0020.
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Abstract FSH regulates ovarian granulosa cell differentiation not only by activating adenylyl cyclase and protein kinase A (PKA) but also by other complex mechanisms. Using primary rat granulosa cell cultures, we provide novel evidence that FSH rapidly activates two small GTP-binding proteins RAP1 and RAS. FSH activation of RAP1 requires cAMP-mediated activation of exchange factor activated by cAMP/RAPGEF3 whereas FSH activation of RAS and downstream signaling cascades involves multiple factors. Specifically, FSH activation of RAS required Rous sarcoma oncogene (SRC) family tyrosine kinase (SFK) and epidermal growth factor receptor (EGFR) tyrosine kinase activities but not PKA. FSH-induced phosphorylation of ERK1/2 was blocked by dominant-negative RAS as well as by inhibitors of EGFR tyrosine kinase, metalloproteinases involved in growth factor shedding, and SFKs. In contrast, FSH-induced phosphorylation of protein kinase B (PKB/AKT) and the Forkhead transcription factor, FOXO1a occurred by SFK-dependent but RAS-independent mechanisms. The SFKs, c-SRC and FYN, and the SRC-related tyrosine kinase ABL were present and phosphorylated rapidly in response to FSH. Lastly, the EGF-like factor amphiregulin (AREG) activated RAS and ERK1/2 phosphorylation in granulosa cells by mechanisms that were selectively blocked by an EGFR antagonist but not by an SFK antagonist. However, AREG-mediated phosphorylation of PKB and FOXO1a required both EGFR and SFK activation. Moreover, we show that FSH induces AREG and that activation of the EGFR impacts granulosa cell differentiation and the expression of genes characteristic of the luteal cell phenotype. Thus, FSH orchestrates the coordinate activation of three diverse membrane-associated signaling cascades (adenylyl cyclase, RAS, and SFKs) that converge downstream to activate specific kinases (PKA, ERK1/2, and PKB/FOXO1a) that control granulosa cell function and differentiation.
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Nie, Lingdi, Liwen Jiang, John Quinn, Blair Grubb, and Minyan Wang. "TRPA1-Mediated Src Family Kinases Activity Facilitates Cortical Spreading Depression Susceptibility and Trigeminovascular System Sensitization." International Journal of Molecular Sciences 22, no. 22 (November 12, 2021): 12273. http://dx.doi.org/10.3390/ijms222212273.
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Transient receptor potential ankyrin 1 (TRPA1) plays a role in migraine and is proposed as a promising target for migraine therapy. However, TRPA1-induced signaling in migraine pathogenesis is poorly understood. In this study, we explored the hypothesis that Src family kinases (SFKs) transmit TRPA1 signaling in regulating cortical spreading depression (CSD), calcitonin gene-related peptide (CGRP) release and neuroinflammation. CSD was monitored in mouse brain slices via intrinsic optical imaging, and in rats using electrophysiology. CGRP level and IL-1β gene expression in mouse trigeminal ganglia (TG) was detected using Enzyme-linked Immunosorbent Assay and Quantitative Polymerase Chain Reaction respectively. The results showed a SFKs activator, pYEEI (EPQY(PO3H2)EEEIPIYL), reversed the reduced cortical susceptibility to CSD by an anti-TRPA1 antibody in mouse brain slices. Additionally, the increased cytosolic phosphorylated SFKs at Y416 induced by CSD in rat ipsilateral cerebral cortices was attenuated by pretreatment of the anti-TRPA1 antibody perfused into contralateral ventricles. In mouse TG, a SFKs inhibitor, saracatinib, restored the CGRP release and IL-1β mRNA level increased by a TRPA1 activator, umbellulone. Moreover, umbellulone promoted SFKs phosphorylation, which was reduced by a PKA inhibitor, PKI (14–22) Amide. These data reveal a novel mechanism of migraine pathogenesis by which TRPA1 transmits signaling to SFKs via PKA facilitating CSD susceptibility and trigeminovascular system sensitization.
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Mittaud, Peggy, Alain A. Camilleri, Raffaella Willmann, Susanne Erb-Vögtli, Steven J. Burden, and Christian Fuhrer. "A Single Pulse of Agrin Triggers a Pathway That Acts To Cluster Acetylcholine Receptors." Molecular and Cellular Biology 24, no. 18 (September 15, 2004): 7841–54. http://dx.doi.org/10.1128/mcb.24.18.7841-7854.2004.
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ABSTRACT Agrin triggers signaling mechanisms of high temporal and spatial specificity to achieve phosphorylation, clustering, and stabilization of postsynaptic acetylcholine receptors (AChRs). Agrin transiently activates the kinase MuSK; MuSK activation has largely vanished when AChR clusters appear. Thus, a tyrosine kinase cascade acts downstream from MuSK, as illustrated by the agrin-evoked long-lasting activation of Src family kinases (SFKs) and their requirement for AChR cluster stabilization. We have investigated this cascade and report that pharmacological inhibition of SFKs reduces early but not later agrin-induced phosphorylation of MuSK and AChRs, while inhibition of Abl kinases reduces late phosphorylation. Interestingly, SFK inhibition applied selectively during agrin-induced AChR cluster formation caused rapid cluster dispersal later upon agrin withdrawal. We also report that a single 5-min agrin pulse, followed by extensive washing, triggered long-lasting MuSK and AChR phosphorylation and efficient AChR clustering. Following the pulse, MuSK phosphorylation increased and, beyond a certain level, caused maximal clustering. These data reveal novel temporal aspects of tyrosine kinase action in agrin signaling. First, during AChR cluster formation, SFKs initiate early phosphorylation and an AChR stabilization program that acts much later. Second, a kinase mechanism rapidly activated by agrin acts thereafter autonomously in agrin's absence to further increase MuSK phosphorylation and cluster AChRs.
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Huang, Hui, Zachary Waldon, Gordon Chan, Helen Zhu, Hanno Steen, Gen-Sheng Feng, Benjamin Neel, and Alan Cantor. "Tyrosine Phosphorylation of Runx1 In Megakaryocytes by Src Family Kinases." Blood 116, no. 21 (November 19, 2010): 742. http://dx.doi.org/10.1182/blood.v116.21.742.742.
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Abstract Abstract 742 Runx1 and its cofactor, CBF-beta, are the most frequent targets of chromosomal translocations in human leukemias. Point mutations in Runx-1 also occur in some cases of myelodysplastic syndrome and undifferentiated leukemia. During normal hematopoiesis, Runx1 is required for the ontogeny of all definitive hematopoietic stem cells and for the proper maturation of megakaryocytes (Mks) and lymphocytes. Despite these critical roles, the regulation of Runx1 activity via cell signaling pathways remains incompletely understood. Here, we report that Runx-1 is tyrosine phosphorylated in Mks. This occurs on multiple residues and is mediated by src-family tyrosine kinases (SFKs). Loss of Runx1 tyrosine phosphorylation correlates with phorbol ester induced differentiation of L8057 megakaryoblastic cells, suggesting a negative regulatory function. Consistent with this model, retroviral expression of a tyrosine non-phosphorylatable mutant Runx1 molecule increases primary murine fetal liver Mk maturation and Runx1 target gene expression to a greater extent than wild type Runx1. Moreover, treatment of wild type primary Mks with SFK inhibitors markedly enhances Mk maturation, as previously reported (Lannutti BJ, et al 2005 Blood;105:3875-3878). Treatment of L8057 cells with the pan-tyrosine phosphatase inhibitor Na3VO4, significantly increases Runx1 tyrosine phosphorylation levels, suggesting that tyrosine phosphorylation of Runx1 is dynamically regulated under steady-state conditions. Using a proteomic approach, we found that Runx1 physically interacts with the non-receptor tyrosine phosphatase SHP-2 (Ptpn11). We validated this interaction and showed that it occurs via direct interactions involving the Runx1 runt domain. ShRNA mediated knock down of SHP-2 in L8057 cells increases Runx1 tyrosine phosphorylation levels. Conditional knockout of SHP-2 in Mks using SHP-2fl/fl, PF4-Cre mice leads to reduced peripheral blood platelet counts and delayed platelet recovery following transient anti-GPIb antibody induced immune thrombocytopenia. Lastly, we show that treatment of TPA-induced L8057 cells with Na3VO4 markedly diminishes binding between Runx1 and the key Mk transcription factor GATA-1. Taken together, our data suggest that tyrosine phosphorylation of Runx1 via SFKs inhibits Runx1 function. Dephosphorylation, at least in part via SHP-2, relieves this inhibition and promotes Mk maturation. These effects are likely mediated through altered protein-protein interactions. Disclosures: No relevant conflicts of interest to declare.
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Dos Santos, Cedric, Tinisha McDonald, Yin Wei Ho, Hongjun Liu, Allen Lin, Stephen J. Forman, Ya-Huei Kuo, and Ravi Bhatia. "The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents." Blood 122, no. 11 (September 12, 2013): 1900–1913. http://dx.doi.org/10.1182/blood-2012-11-466425.
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Key Points SRC family kinases are activated in AML stem/progenitor cells and contribute to AML stem cell survival and proliferation. Combined inhibition of SFKs and c-KIT with dasatinib enhances p53-mediated elimination of AML stem cells.
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Ren, Liangliang, Chaoying Li, Youliang Wang, Yan Teng, Huichuan Sun, Baocai Xing, Xiao Yang, Ying Jiang, and Fuchu He. "In Vivo Phosphoproteome Analysis Reveals Kinome Reprogramming in Hepatocellular Carcinoma." Molecular & Cellular Proteomics 17, no. 6 (February 22, 2018): 1067–83. http://dx.doi.org/10.1074/mcp.ra117.000421.
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Aberrant kinases contribute to cancer survival and proliferation. Here, we quantitatively characterized phosphoproteomic changes in an HBx-transgenic mouse model of hepatocellular carcinoma (HCC) using high-resolution mass spectrometry, profiled 22,539 phosphorylation sites on 5431 proteins. Using a strategy to interpret kinase- substrate relations in HCC and to uncover predominant kinases in tumors, our results, revealed elevated kinase activities of Src family kinases (SFKs), PKCs, MAPKs, and ROCK2 in HCC, representatives of which were further validated in cell models and clinical HBV-positive HCC samples. Inhibitor combinations targeting Src and PKCs or ROCK2 both synergized significantly to inhibit cell growth. In addition, we demonstrated that phosphorylation at Src Ser17 directly affects its kinase activity. Our phosphoproteome data facilitated the construction of a detailed molecular landscape in HCC and should serve as a resource for the cancer community. Our strategy is generally applicable to targeted therapeutics, also highlights potential mechanisms of kinase regulation.
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Zhao, Xiaoxian, Andrew E. Schade, and Eric Hsi. "Distinct Role of Src Family Kinase Inhibitors in Burkitt Lymphoma Cells Vs. Diffuse Large B-Cell Lymphoma Cells." Blood 112, no. 11 (November 16, 2008): 3765. http://dx.doi.org/10.1182/blood.v112.11.3765.3765.
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Abstract Introduction: The Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies, with approximately 85% of NHL belonging to the B-cell lineage. Src family kinases (SFKs) are non-receptor intracellular tyrosine kinases which are important in the regulation of multiple signaling pathways including cell proliferation, tumor invasiveness, angiogenesis and apoptosis. Syk is another predominant tyrosine kinase expressed in B-cell lines in addition to SFKs. We attempted to correlate SFK and Syk inhibitor efficacy with the presence of phospho-SFK or phospho-Syk in lymphoma cell lines and tissues. Methods: Cell proliferation was measured with WST-1 reagent. Apoptotic assay was performed with Annexin-V and 7-AAD by flow cytometry (FC, FACSCalibur, BD Bioscience). Phospho-Src (Y416) antibody (cell signaling Technology, CSL) was used for immunoblotting and immunohistochemistry. (IHC, Discovery, Ventana Medical Systems). Phospho-Syk (Y525/526) antibody (CSL) was used for FC and immunoblotting. Results: In a screening for the effects of different kinases’ inhibitors on B-cell lymphoma lines, we observed that SFK inhibitors, PP2 and dasatinib (Sprycel, Bristol Myers Squibb), inhibited proliferation and caused dose-dependent apoptosis induction at 24 h (PP2: 31% at 10 mM; dasatinib: 39% at 100 nM) in Burkitt’s lymphoma cell line Raji. The apoptotic induction was associated with cleavage of caspase-3 and caspase-8. The ability of SFK inhibitors to induce apoptosis in Raji cells paralleled high level expression of constitutive phospho- SFK (Y416). In contrast to this Burkitt’s line, diffuse large B-cell lymphoma (DLBCL) lines (Sud-HL4, Sud-HL-6 and OCI-LY3, OCI-LY10) were less-sensitive to these SFK inhibitors but showed apoptosis induction upon exposure to the Syk inhibitor (piceatannol & syk inhibitor IV). Interestingly, the DLBCL lines that were resistant to SFK inhibitors had undectable or low levels of phospho-SFK (Y416); while their susceptibility to the Syk inhibitor-induced apoptosis paralleled detectable constitutive phospho-Syk (Y525/526). Immunohistochemical staining of burkitt’s lymphoma tissues and a tissue microarray panel of NHL indicated 13/20 (65%) of Burkitt’s lymphoma, 3/5 of small lymphocytic lymphoma, 2/5 of mantle cell lymphoma, 3/10 of follicular lymphoma, 2/5 of DLBCL, 2/5 of marginal zone lymphoma, 1/5 of lymphoblastic lymphoma are positive for phospho-Src (Y416). Staining of normal tonsil tissue showed germinal center cells are strong positive for phospho-Src (Y416), while marginal zone cells are weak positive and plasma cells are negative. We are currently testing the correlation of phospho-Src (Y416) expression in fresh NHL tissues and their sensitivity to Src family kinase inhibitors. Conclusion: These data suggest that rational application of molecularly targeted therapy for aggressive NHL is possible by directly examining key signaling nodes promoting survival and proliferation. For instance, the clinical SFK inhibitor dasatinib is currently being examined in a clinical trial for NHL (NCT00550615). Our results suggest that profiling patients’ lymphoma cells for phospho-SFK could optimize therapeutic efficacy and minimize unnecessary treatment-related side effects.
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Piemonte, Katrina, Elyse Donaubauer, and Ruth Keri. "Abstract PD3-06: The SRC family kinase, YES1, controls chromosomal stability and promotes growth of triple negative breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): PD3–06—PD3–06. http://dx.doi.org/10.1158/1538-7445.sabcs21-pd3-06.
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Abstract Triple negative breast cancer (TNBC) is a collection of heterogeneous diseases with limited therapeutic options primarily involving cytotoxic chemotherapy. The distinct molecular profile and increased chromosomal instability (CIN) of TNBC make it a difficult disease to treat. While many patients initially respond to treatment, resistance is common, resulting in poor patient outcomes. Thus identifying vulnerabilities in this disease is necessary to improve TNBC patient outcomes. To identify potential therapeutic targets in this disease, we focused on Src Family Kinases (SFKs). The SFK family is comprised of 9 non-receptor tyrosine kinases that interact with upstream signaling partners to regulate cell phenotypes such as adhesion, motility, survival and mitosis. Five SFKs are overexpressed in breast cancer, including Src, the founding member of the family. Within the basal breast cancer subtype, one of the most highly overexpressed SFKs is YES1. High YES1 expression is also associated with poorer outcomes in TNBC patients when compared to tumors with low YES1 expression. We have found that TNBC cells are reliant on sustained YES1 expression for viability, growth, cell cycle progression, and maintenance of genomic stability. Transiently silencing YES1 causes a significant decrease in cell growth and increase in apoptosis. Furthermore, loss of YES1 expression induces features of whole chromosomal instability (w-CIN), including micronucleation, multinucleation, and dysmorphic nuclei. An increase in γ-H2AX positive staining was also noted in cells with decreased YES1 expression, indicating an accumulation of double strand DNA breaks (DSB) that are indicative of structural chromosomal instability (s-CIN). These findings were recapitulated using several pan-SFK inhibitors, including FDA approved agents dasatinib and saracatinib. Loss of YES1 function also results in perturbed cell cycle progression, particularly a G2/M delay. RNA-sequencing and Reverse Phase Protein Array (RPPA) revealed alterations in mitotic, replication stress, and DNA repair pathways following the loss of YES1. These data demonstrate that YES1 is a previously understudied signaling component of mitotic- and DNA damage-regulating pathways in TNBC. More broadly, they suggest that YES1 may be a therapeutically targetable vulnerability that could be paired with other DNA damaging or mitotic inhibitors to improve treatment efficacy in TNBC. Current SFK-targeted agents globally impact all SFKs. The data presented here support efforts to identify a YES1 selective inhibitor that should be more specific for treating TNBC with less toxicity that pan-SFK drugs. Citation Format: Katrina Piemonte, Elyse Donaubauer, Ruth Keri. The SRC family kinase, YES1, controls chromosomal stability and promotes growth of triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD3-06.
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Nie, Lingdi, Kai Sun, Ziyang Gong, Haoyang Li, John P. Quinn, and Minyan Wang. "Src Family Kinases Facilitate the Crosstalk between CGRP and Cytokines in Sensitizing Trigeminal Ganglion via Transmitting CGRP Receptor/PKA Pathway." Cells 11, no. 21 (November 4, 2022): 3498. http://dx.doi.org/10.3390/cells11213498.
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The communication between calcitonin gene-related peptide (CGRP) and cytokines plays a prominent role in maintaining trigeminal ganglion (TG) and trigeminovascular sensitization. However, the underlying regulatory mechanism is elusive. In this study, we explored the hypothesis that Src family kinases (SFKs) activity facilitates the crosstalk between CGRP and cytokines in sensitizing TG. Mouse TG tissue culture was performed to study CGRP release by enzyme-linked immunosorbent assay, cytokine release by multiplex assay, cytokine gene expression by quantitative polymerase chain reaction, and phosphorylated SFKs level by western blot. The results demonstrated that a SFKs activator, pYEEI (YGRKKRRQRRREPQY(PO3H2)EEIPIYL) alone, did not alter CGRP release or the inflammatory cytokine interleukin-1β (IL-1β) gene expression in the mouse TG. In contrast, a SFKs inhibitor, saracatinib, restored CGRP release, the inflammatory cytokines IL-1β, C-X-C motif ligand 1, C-C motif ligand 2 (CCL2) release, and IL-1β, CCL2 gene expression when the mouse TG was pre-sensitized with hydrogen peroxide and CGRP respectively. Consistently with this, the phosphorylated SFKs level was increased by both hydrogen peroxide and CGRP in the mouse TG, which was reduced by a CGRP receptor inhibitor BIBN4096 and a protein kinase A (PKA) inhibitor PKI (14–22) Amide. The present study demonstrates that SFKs activity plays a pivotal role in facilitating the crosstalk between CGRP and cytokines by transmitting CGRP receptor/PKA signaling to potentiate TG sensitization and ultimately trigeminovascular sensitization.
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Irtegun-Kandemir, Sevgi, Irmak Icen-Taskin, Mehtap Bozkurt, and Sevgi Kalkanli-Tas. "mRNA Expression Profile of SFKs and Involvement of SFKs in the Regulation of LPS-Induced Erk1/2 Signaling in PBMCs of Active BD Patients." Endocrine, Metabolic & Immune Disorders - Drug Targets 19, no. 6 (September 3, 2019): 809–17. http://dx.doi.org/10.2174/1871530319666190119101756.
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Background: Behcet’s Disease (BD) is a multisystemic inflammatory disorder affecting large vessels, lungs joints, gastrointestinal and neurological systems. The pathogenesis of BD remains poorly understood. Identifying the key signaling pathway is crucial for a complete understanding of the pathogenesis of BD. Objective: The aim of this study was to determine mRNA expression level of Src family kinases (SFKs) members and their involvement in lipopolysaccharide (LPS)-induced mitogen-activated protein kinases (MAPKs) regulation in peripheral blood mononuclear cells (PBMCs) of active BD patients. Methods: Twenty- five active BD patients and twenty-five healthy controls were included in the study. PBMCs were isolated from total blood by density gradient centrifugation. The mRNA expression levels of SFKs members were measured by real-time quantitative PCR (RT-qPCR). The effect of SFKs activity on LPS-induced activation MAPKs (Erk1/2, p38 and JNK) was examined by Western blot. Results: The mRNA expression levels of Hck, Src, Lyn, Yes and Fyn were found to be slightly decreased in active BD patients compared to the control subjects, but a slight change in mRNA level of SFKs members did not impact on protein levels and protein activity. LPS-induced Erk1/2 phosphorylation was significantly increased in the absence of SFKs activity in active BD patients. However, inhibition of SFKs activity had no effect on LPS-induced phosphorylation of p38 and JNK in both controls and active BD patients. Conclusion: SFKs downregulate LPS-induced Erk1/2 phosphorylation in PBMCs of active BD patients.
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Kılıç, Zühal, Fatma Şener, Yasemin G. İşgör, Tülay Çoban, and Süreyya Ölgen. "N-Substituted Indole-3-imine Derivatives and their Amine Congeners: Antioxidant and Src Kinase Inhibitory Effects." Zeitschrift für Naturforschung C 65, no. 5-6 (June 1, 2010): 347–54. http://dx.doi.org/10.1515/znc-2010-5-606.
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Current evidences demonstrated that the activity of protein kinases can be controlled through oxidative stress induced by reactive oxygen species (ROS) and normalized by antioxidants. Recent studies with ROS, generated by mitochondria, suggested the potential signalling role of these species, where ROS, especially hydrogen peroxide, were proposed as membrane-related signalling components. The protein regulation by cellular redox states has shown that protein tyrosine kinase members, such as Src kinase and some of the members of the Src family kinases (SFKs), are proteins regulated by the cellular oxidation and reduction status. In this context, the oxidant or antioxidant potential of the synthetic Src kinase inhibitors previously synthesized and studied by our research group, such as N-substituted indole-3-imine and -amine derivatives, were investigated employing various acellular in vitro methods including microsomal NADPH-dependent inhibition of lipid peroxidation (LP), interaction of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and scavenging of superoxide anion radicals. Here, we report that some of the synthetic inhibitors designed for Src kinase target have both antioxidant and kinase inhibition properties.