Artykuły w czasopismach: „Kinase”

1

Symons, Antony, Soren Beinke i Steven C. Ley. "MAP kinase kinase kinases and innate immunity". Trends in Immunology 27, nr 1 (styczeń 2006): 40–48. http://dx.doi.org/10.1016/j.it.2005.11.007.

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Buxade, Maria. "The Mnks: MAP kinase-interacting kinases (MAP kinase signal-integrating kinases)". Frontiers in Bioscience Volume, nr 13 (2008): 5359. http://dx.doi.org/10.2741/3086.

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Jouannic, S., A. Hamal, A. S. Leprince, J. W. Tregear, M. Kreis i Y. Henry. "Plant MAP kinase kinase kinases structure, classification and evolution". Gene 233, nr 1-2 (czerwiec 1999): 1–11. http://dx.doi.org/10.1016/s0378-1119(99)00152-3.

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Wang, Qin, Michael Yerukhimovich, William A. Gaarde, Ian J. Popoff i Claire M. Doerschuk. "MKK3 and -6-dependent activation of p38α MAP kinase is required for cytoskeletal changes in pulmonary microvascular endothelial cells induced by ICAM-1 ligation". American Journal of Physiology-Lung Cellular and Molecular Physiology 288, nr 2 (luty 2005): L359—L369. http://dx.doi.org/10.1152/ajplung.00292.2004.

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Previous studies demonstrated that neutrophil adherence induces ICAM-1-dependent cytoskeletal changes in TNF-α-treated pulmonary microvascular endothelial cells that are prevented by a pharmacological inhibitor of p38 MAP kinase. This study determined whether neutrophil adherence induces activation of p38 MAP kinase in endothelial cells, the subcellular localization of phosphorylated p38, which MAP kinase kinases lead to p38 activation, which p38 isoform is activated, and what the downstream targets may be. Confocal microscopy showed that neutrophil adhesion for 2 or 6 min induced an increase in phosphorylated p38 in endothelial cells that was punctate and concentrated in the central region of the endothelial cells. Studies using small interfering RNA (siRNA) to inhibit the protein expression of MAP kinase kinase 3 and 6, either singly or in combination, showed that both MAP kinase kinases were required for p38 phosphorylation. Studies using an antisense oligonucleotide to p38α demonstrated that inhibition of the protein expression of p38α 1) inhibited activation of p38 MAP kinase without affecting the protein expression of p38β; 2) prevented phosphorylation of heat shock protein 27, an actin binding protein that may induce actin polymerization upon phosphorylation; 3) attenuated cytoskeletal changes; and 4) attenuated neutrophil migration to the EC borders. Thus MAP kinase kinase3- and 6-dependent activation of the α-isoform of p38 MAP kinase is required for the cytoskeletal changes induced by neutrophil adherence and influences subsequent neutrophil migration toward endothelial cell junctions.

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5

Takekawa, Mutsuhiro, Kazuo Tatebayashi i Haruo Saito. "Conserved Docking Site Is Essential for Activation of Mammalian MAP Kinase Kinases by Specific MAP Kinase Kinase Kinases". Molecular Cell 18, nr 3 (kwiecień 2005): 295–306. http://dx.doi.org/10.1016/j.molcel.2005.04.001.

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Nemoto, Shino, Joseph A. DiDonato i Anning Lin. "Coordinate Regulation of IκB Kinases by Mitogen-Activated Protein Kinase Kinase Kinase 1 and NF-κB-Inducing Kinase". Molecular and Cellular Biology 18, nr 12 (1.12.1998): 7336–43. http://dx.doi.org/10.1128/mcb.18.12.7336.

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ABSTRACT IκB kinases (IKKα and IKKβ) are key components of the IKK complex that mediates activation of the transcription factor NF-κB in response to extracellular stimuli such as inflammatory cytokines, viral and bacterial infection, and UV irradiation. Although NF-κB-inducing kinase (NIK) interacts with and activates the IKKs, the upstream kinases for the IKKs still remain obscure. We identified mitogen-activated protein kinase kinase kinase 1 (MEKK1) as an immediate upstream kinase of the IKK complex. MEKK1 is activated by tumor necrosis factor alpha (TNF-α) and interleukin-1 and can potentiate the stimulatory effect of TNF-α on IKK and NF-κB activation. The dominant negative mutant of MEKK1, on the other hand, partially blocks activation of IKK by TNF-α. MEKK1 interacts with and stimulates the activities of both IKKα and IKKβ in transfected HeLa and COS-1 cells and directly phosphorylates the IKKs in vitro. Furthermore, MEKK1 appears to act in parallel to NIK, leading to synergistic activation of the IKK complex. The formation of the MEKK1-IKK complex versus the NIK-IKK complex may provide a molecular basis for regulation of the IKK complex by various extracellular signals.

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7

Hurley, Rebecca L., Kristin A. Anderson, Jeanne M. Franzone, Bruce E. Kemp, Anthony R. Means i Lee A. Witters. "The Ca2+/Calmodulin-dependent Protein Kinase Kinases Are AMP-activated Protein Kinase Kinases". Journal of Biological Chemistry 280, nr 32 (24.06.2005): 29060–66. http://dx.doi.org/10.1074/jbc.m503824200.

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Verploegen, Sandra, Jan-Willem J. Lammers, Leo Koenderman i Paul J. Coffer. "Identification and characterization of CKLiK, a novel granulocyte Ca++/calmodulin-dependent kinase". Blood 96, nr 9 (1.11.2000): 3215–23. http://dx.doi.org/10.1182/blood.v96.9.3215.

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Abstract Human granulocytes are characterized by a variety of specific effector functions involved in host defense. Several widely expressed protein kinases have been implicated in the regulation of these effector functions. A polymerase chain reaction–based strategy was used to identify novel granulocyte-specific kinases. A novel protein kinase complementary DNA with an open reading frame of 357 amino acids was identified with homology to calcium-calmodulin–dependent kinase I (CaMKI). This has been termed CaMKI-like kinase (CKLiK). Analysis of CKLiK messenger RNA (mRNA) expression in hematopoietic cells demonstrated an almost exclusive expression in human polymorphonuclear leukocytes (PMN). Up-regulation of CKLiK mRNA occurs during neutrophilic differentiation of CD34+ stem cells. CKLiK kinase activity was dependent on Ca++ and calmodulin as analyzed by in vitro phosphorylation of cyclic adenosine monophosphate responsive element modulator (CREM). Furthermore, CKLiK- transfected cells treated with ionomycin demonstrated an induction of CRE- binding protein (CREB) transcriptional activity compared to control cells. Additionally, CaMK-kinaseα enhanced CKLiK activity. In vivo activation of CKLiK was shown by addition of interleukin (IL)-8 to a myeloid cell line stably expressing CKLiK. Furthermore inducible activation of CKLiK was sufficient to induce extracellular signal-related kinase (ERK) mitogen-activated protein (MAP) kinase activity. These data identify a novel Ca++/calmodulin-dependent PMN- specific kinase that may play a role in Ca++-mediated regulation of human granulocyte functions.

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9

Verploegen, Sandra, Jan-Willem J. Lammers, Leo Koenderman i Paul J. Coffer. "Identification and characterization of CKLiK, a novel granulocyte Ca++/calmodulin-dependent kinase". Blood 96, nr 9 (1.11.2000): 3215–23. http://dx.doi.org/10.1182/blood.v96.9.3215.h8003215_3215_3223.

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Human granulocytes are characterized by a variety of specific effector functions involved in host defense. Several widely expressed protein kinases have been implicated in the regulation of these effector functions. A polymerase chain reaction–based strategy was used to identify novel granulocyte-specific kinases. A novel protein kinase complementary DNA with an open reading frame of 357 amino acids was identified with homology to calcium-calmodulin–dependent kinase I (CaMKI). This has been termed CaMKI-like kinase (CKLiK). Analysis of CKLiK messenger RNA (mRNA) expression in hematopoietic cells demonstrated an almost exclusive expression in human polymorphonuclear leukocytes (PMN). Up-regulation of CKLiK mRNA occurs during neutrophilic differentiation of CD34+ stem cells. CKLiK kinase activity was dependent on Ca++ and calmodulin as analyzed by in vitro phosphorylation of cyclic adenosine monophosphate responsive element modulator (CREM). Furthermore, CKLiK- transfected cells treated with ionomycin demonstrated an induction of CRE- binding protein (CREB) transcriptional activity compared to control cells. Additionally, CaMK-kinaseα enhanced CKLiK activity. In vivo activation of CKLiK was shown by addition of interleukin (IL)-8 to a myeloid cell line stably expressing CKLiK. Furthermore inducible activation of CKLiK was sufficient to induce extracellular signal-related kinase (ERK) mitogen-activated protein (MAP) kinase activity. These data identify a novel Ca++/calmodulin-dependent PMN- specific kinase that may play a role in Ca++-mediated regulation of human granulocyte functions.

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10

Pang, Kam-Lee, Wei-Li Thong i Siew-Eng How. "Cinnamomum Iners as Mitogen-Activated Protein Kinase Kinase (MKK1) Inhibitor". International Journal of Engineering and Technology 1, nr 4 (2009): 310–13. http://dx.doi.org/10.7763/ijet.2009.v1.61.

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Yamboliev, Ilia A., Kevin M. Wiesmann, Cherie A. Singer, Jason C. Hedges i William T. Gerthoffer. "Phosphatidylinositol 3-kinases regulate ERK and p38 MAP kinases in canine colonic smooth muscle". American Journal of Physiology-Cell Physiology 279, nr 2 (1.08.2000): C352—C360. http://dx.doi.org/10.1152/ajpcell.2000.279.2.c352.

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In canine colon, M2/M3 muscarinic receptors are coupled to extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases. We tested the hypothesis that this coupling is mediated by enzymes of the phosphatidylinositol (PI) 3-kinase family. RT-PCR and Western blotting demonstrated expression of two isoforms, PI 3-kinase-α and PI 3-kinase-γ. Muscarinic stimulation of intact muscle strips (10 μM ACh) activated PI 3-kinase-γ, ERK and p38 MAP kinases, and MAP kinase-activated protein kinase-2, whereas PI 3-kinase-α activation was not detected. Wortmannin (25 μM) abolished the activation of PI 3-kinase-γ, ERK, and p38 MAP kinases. MAP kinase inhibition was a PI 3-kinase-γ-specific effect, since wortmannin did not inhibit recombinant activated murine ERK2 MAP kinase, protein kinase C, Raf-1, or MAP kinase kinase. In cultured muscle cells, newborn calf serum (3%) activated PI 3-kinase-α and PI 3-kinase-γ isoforms, ERK and p38 MAP kinases, and stimulated chemotactic cell migration. Using wortmannin and LY-294002 to inhibit PI 3-kinase activity and PD-098059 and SB-203580 to inhibit ERK and p38 MAP kinases, we established that these enzymes are functionally important for regulation of chemotactic migration of colonic myocytes.

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12

Foukas, L. C., i P. R. Shepherd. "Phosphoinositide 3-kinase: the protein kinase that time forgot". Biochemical Society Transactions 32, nr 2 (1.04.2004): 330–31. http://dx.doi.org/10.1042/bst0320330.

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Class I phosphoinositide 3-kinases were originally characterized as lipid kinases, although more than 10 years ago they were also found to phosphorylate protein serine residues. However, while there is a vast amount of data on the function of this lipid kinase activity, relatively little is known about the function of the protein kinase activity. We discuss the evidence that suggests that the protein kinase activity of phosphoinositide 3-kinases mediates important signalling functions in cells.

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13

Marshall, Christopher J. "MAP kinase kinase kinase, MAP kinase kinase and MAP kinase". Current Opinion in Genetics & Development 4, nr 1 (luty 1994): 82–89. http://dx.doi.org/10.1016/0959-437x(94)90095-7.

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Dong, Lily Q., i Feng Liu. "PDK2: the missing piece in the receptor tyrosine kinase signaling pathway puzzle". American Journal of Physiology-Endocrinology and Metabolism 289, nr 2 (sierpień 2005): E187—E196. http://dx.doi.org/10.1152/ajpendo.00011.2005.

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Activation of members of the protein kinase AGC (cAMP dependent, cGMP dependent, and protein kinase C) family is regulated primarily by phosphorylation at two sites: a conserved threonine residue in the activation loop and a serine/threonine residue in a hydrophobic motif (HM) near the COOH terminus. Although phosphorylation of these kinases in the activation loop has been found to be mediated by phosphoinositide-dependent protein kinase-1 (PDK1), the kinase(s) that catalyzes AGC kinase phosphorylation in the HM remains uncharacterized. So far, at least 10 kinases have been suggested to function as an HM kinase or the so-called “PDK2,” including mitogen-activated protein (MAP) kinase-activated protein kinase-2 (MK2), integrin-linked kinase (ILK), p38 MAP kinase, protein kinase Cα (PKCα), PKCβ, the NIMA-related kinase-6 (NEK6), the mammalian target of rapamycin (mTOR), the double-stranded DNA-dependent protein kinase (DNK-PK), and the ataxia telangiectasia mutated (ATM) gene product. However, whether any or all of these kinases act as a physiological HM kinase remains to be established. Nonetheless, available data suggest that multiple systems may be used in cells to regulate the activation of the AGC family kinases. It is possible that, unlike activation loop phosphorylation, phosphorylation of the HM site in the different AGC family kinases is mediated by distinct kinases. In addition, phosphorylation of the AGC family kinase at the HM site could be cell type, signaling pathway, and substrate specific. Identification and characterization of the bonafide HM kinase(s) will be essential to verify these hypotheses.

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15

Creeden, Justin F., Khaled Alganem, Ali S. Imami, F. Charles Brunicardi, Shi-He Liu, Rammohan Shukla, Tushar Tomar, Faris Naji i Robert E. McCullumsmith. "Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases". International Journal of Molecular Sciences 21, nr 22 (17.11.2020): 8679. http://dx.doi.org/10.3390/ijms21228679.

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Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.

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16

Sclafani, Robert A. "Cyclin dependent kinase activating kinases". Current Opinion in Cell Biology 8, nr 6 (grudzień 1996): 788–94. http://dx.doi.org/10.1016/s0955-0674(96)80079-2.

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Abraham, Robert T. "Phosphatidylinositol 3-kinase related kinases". Current Opinion in Immunology 8, nr 3 (czerwiec 1996): 412–18. http://dx.doi.org/10.1016/s0952-7915(96)80132-4.

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Wille, Christoph, Thomas Seufferlein i Tim Eiseler. "Protein Kinase D family kinases". BioArchitecture 4, nr 3 (12.03.2014): 111–15. http://dx.doi.org/10.4161/bioa.29273.

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Archambault, Vincent, i Mar Carmena. "Polo-like kinase-activating kinases". Cell Cycle 11, nr 8 (15.04.2012): 1490–95. http://dx.doi.org/10.4161/cc.19724.

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Nakano, H., M. Shindo, S. Sakon, S. Nishinaka, M. Mihara, H. Yagita i K. Okumura. "Differential regulation of I B kinase and by two upstream kinases, NF- B-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1". Proceedings of the National Academy of Sciences 95, nr 7 (31.03.1998): 3537–42. http://dx.doi.org/10.1073/pnas.95.7.3537.

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Cuevas, B. D., A. N. Abell i G. L. Johnson. "Role of mitogen-activated protein kinase kinase kinases in signal integration". Oncogene 26, nr 22 (maj 2007): 3159–71. http://dx.doi.org/10.1038/sj.onc.1210409.

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Shibasaki, F., Y. Fukui i T. Takenawa. "Different properties of monomer and heterodimer forms of phosphatidylinositol 3-kinases". Biochemical Journal 289, nr 1 (1.01.1993): 227–31. http://dx.doi.org/10.1042/bj2890227.

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Phosphatidylinositol (PI) 3-kinase plays an important role in the signalling of cell growth. We previously purified two types of PI 3-kinase from bovine thymus, a monomer from (PI 3-kinase I) and a heterodimer form (PI 3-kinase II) [Shibasaki, Homma and Takenawa (1991) J. Biol. Chem. 266, 8108-8114]. Here we examine the properties of these purified PI 3-kinases. Both PI 3-kinases were inhibited strongly by quercetin and isoquercetin. The inhibition of PI 3-kinase I and PI 3-kinase II by quercetin appears to be non-competitive, with apparent Ki values of 4 microM and 2.5 microM respectively. PI 3-kinase II, but not PI 3-kinase I, co-immunoprecipitates with pp60v-src and polyoma middle T (mT)/pp60c-src, even under conditions where the PI 3-kinases are not phosphorylated, suggesting that non-phosphorylated PI 3-kinase recognizes autophosphorylated pp60v-src. PI 3-kinase II is phosphorylated by pp60v-src and binds to it. Anti-p85 (85 kDa subunit of PI 3-kinase II) antibody precipitates not only PI 3-kinase II but also co-immunoprecipitates pp60v-src in src-transformed cells, suggesting that PI 3-kinase II binds to pp60v-src in vivo. These data suggest that the two PI 3-kinases may be regulated independently.

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Jacinto, Estela, i Anja Lorberg. "TOR regulation of AGC kinases in yeast and mammals". Biochemical Journal 410, nr 1 (29.01.2008): 19–37. http://dx.doi.org/10.1042/bj20071518.

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The TOR (target of rapamycin), an atypical protein kinase, is evolutionarily conserved from yeast to man. Pharmacological studies using rapamycin to inhibit TOR and yeast genetic studies have provided key insights on the function of TOR in growth regulation. One of the first bona fide cellular targets of TOR was the mammalian protein kinase p70 S6K (p70 S6 kinase), a member of a family of kinases called AGC (protein kinase A/protein kinase G/protein kinase C-family) kinases, which include PKA (cAMP-dependent protein kinase A), PKG (cGMP-dependent kinase) and PKC (protein kinase C). AGC kinases are also highly conserved and play a myriad of roles in cellular growth, proliferation and survival. The AGC kinases are regulated by a common scheme that involves phosphorylation of the kinase activation loop by PDK1 (phosphoinositide-dependent kinase 1), and phosphorylation at one or more sites at the C-terminal tail. The identification of two distinct TOR protein complexes, TORC1 (TOR complex 1) and TORC2, with different sensitivities to rapamycin, revealed that TOR, as part of either complex, can mediate phosphorylation at the C-terminal tail for optimal activation of a number of AGC kinases. Together, these studies elucidated that a fundamental function of TOR conserved throughout evolution may be to balance growth versus survival signals by regulating AGC kinases in response to nutrients and environmental conditions. This present review highlights this emerging function of TOR that is conserved from budding and fission yeast to mammals.

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Sunderhaus, Allison, Ramsha Imran, Elanzou Enoh, Adesola Adedeji, Taiye Obafemi i May H. Abdel Aziz. "Comparative expression of soluble, active human kinases in specialized bacterial strains". PLOS ONE 17, nr 4 (19.04.2022): e0267226. http://dx.doi.org/10.1371/journal.pone.0267226.

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Kinases act as molecular switches for cellular functions and are involved in multiple human pathogeneses, most notably cancer. There is a continuous need for soluble and active kinases for in-vitro drug discovery and structural biology purposes. Kinases remain challenging to express using Escherichia coli, the most widely utilized host for heterologous expression. In this work, four bacterial strains, BL21 (DE3), BL21 (DE3) pLysS, Rosetta, and Arctic Express, were chosen for parallel expression trials along with BL21 (DE3) complemented with folding chaperones DnaJ/K and GroEL/ES to compare their performance in producing soluble and active human kinases. Three representative diverse kinases were studied, Epidermal Growth Factor Receptor kinase domain, Aurora Kinase A kinase domain, and Mitogen-activated protein Kinase Kinase. The genes encoding the kinases were subcloned into pET15b bacterial plasmid and transformed into the bacterial strains. Soluble kinase expression was tested using different IPTG concentrations (1–0.05 mM) at varying temperatures (37°C– 10°C) and induction times (3–24 hours). The optimum conditions for each kinase in all strains were then used for 1L large scale cultures from which each kinase was purified to compare yield, purity, oligomerization status, and activity. Although using specialized strains achieved improvements in yield and/or activity for the three kinases, none of the tested strains was universally superior, highlighting the individuality in kinase expression.

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SUZUKI, Tomohiko, Yasufumi YAMAMOTO i Masahiro UMEKAWA. "Stichopus japonicus arginine kinase: gene structure and unique substrate recognition system". Biochemical Journal 351, nr 3 (24.10.2000): 579–85. http://dx.doi.org/10.1042/bj3510579.

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Arginine kinase from the sea cucumber Stichopus japonicus underwent a unique molecular evolution. Unlike the monomeric 40kDa arginine kinases from molluscs and arthropods, Stichopus arginine kinase is dimeric, the same as cytoplasmic isoenzymes of the vertebrate creatine kinases. Its entire amino acid sequence is more similar to creatine kinases than to other arginine kinases, but the guanidino specificity region (GS region) is of the arginine kinase type. To elucidate its unusual evolution, the structure of the Stichopus arginine kinase gene was determined. It consisted of seven exons and six introns, and a part of the exon 2 of the Stichopus gene corresponds to the GS region. Compared with the structure of the human muscle creatine kinase gene (seven exons, six introns), the splice junctions of five introns were conserved exactly between the two genes, suggesting that these introns had been conserved for at least 500 million years. The entire sequence of Stichopus arginine kinase is distinctly included in the creatine kinase cluster in all tree construction methods examined. On the other hand, if the tree is constructed only from sequences corresponding to Stichopus exon 2, it is placed in the arginine kinase cluster. Thus we conclude that Stichopus arginine kinase evolved not from the arginine kinase gene but from the creatine kinase gene, and suggest that its GS region, determining substrate specificity, has been replaced by an arginine kinase type via exon shuffling. In typical arginine kinases four residues, Ser63, Gly64, Val65 and Tyr68 (numbering from the Limulus polyphemus sequence), in the GS region are highly conserved and are associated with substrate binding. Among them, Tyr68 appears to play a crucial role by forming a hydrogen bond with the substrate, and is conserved exactly in all arginine kinases. However, in Stichopus arginine kinase, none of these four conserved residues were present. Nevertheless, the enzyme displays an affinity for the substrate arginine (Km = 0.8mM) comparable with other arginine kinases. This implies that a completely different substrate-binding system has been developed in Stichopus arginine kinase. We propose that the His64 in Stichopus arginine kinase acts as a substitute for the Tyr68 in other arginine kinases, and that the imidazole ring of His64 is hydrogen bonded with the substrate arginine, thus stabilizing it.

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Chung, J., R. H. Chen i J. Blenis. "Coordinate regulation of pp90rsk and a distinct protein-serine/threonine kinase activity that phosphorylates recombinant pp90rsk in vitro". Molecular and Cellular Biology 11, nr 4 (kwiecień 1991): 1868–74. http://dx.doi.org/10.1128/mcb.11.4.1868-1874.1991.

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Protein kinase assays that use recombinant pp90rsk as a substrate were developed in an attempt to identify growth-regulated enzymes responsible for the phosphorylation and activation of pp90rsk S6 phosphotransferase activity. With this assay we have ientified a pp60v-src-, growth factor-, phorbol ester-, and vanadate-regulated serine/threonine protein kinase activity that is not related to two other cofactor-independent, growth-regulated protein kinases, pp70-S6 protein kinase and pp90rsk. The pp90rsk-protein kinase activity (referred to as rsk-kinase) is also not related to cofactor-dependent signal transducing protein kinases such as the cyclic AMP-dependent protein kinases, members of the protein kinase C family, or other Ca2(+)-dependent protein kinases. In vitro, partially purified rsk-kinase phosphorylates several of the sites (serine and threonine) that are phosphorylated in growth-stimulated cultured cells. A detailed examination of the mitogen-regulated activation kinetics of rsk-kinase and pp90rsk activities demonstrated that they are coordinately regulated. In addition, protein kinase C is not absolutely required for epidermal and fibroblast growth factor-stimulated activation of rsk-kinase, whereas, like pp90rsk, platelet-derived growth factor- and vanadate-stimulated rsk-kinase activity exhibits a greater dependence on protein kinase C-mediated signal transduction. The characterization and future purification of the rsk-kinase(s) will improve our understanding of the early signaling events regulating cell growth.

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Chung, J., R. H. Chen i J. Blenis. "Coordinate regulation of pp90rsk and a distinct protein-serine/threonine kinase activity that phosphorylates recombinant pp90rsk in vitro." Molecular and Cellular Biology 11, nr 4 (kwiecień 1991): 1868–74. http://dx.doi.org/10.1128/mcb.11.4.1868.

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Protein kinase assays that use recombinant pp90rsk as a substrate were developed in an attempt to identify growth-regulated enzymes responsible for the phosphorylation and activation of pp90rsk S6 phosphotransferase activity. With this assay we have ientified a pp60v-src-, growth factor-, phorbol ester-, and vanadate-regulated serine/threonine protein kinase activity that is not related to two other cofactor-independent, growth-regulated protein kinases, pp70-S6 protein kinase and pp90rsk. The pp90rsk-protein kinase activity (referred to as rsk-kinase) is also not related to cofactor-dependent signal transducing protein kinases such as the cyclic AMP-dependent protein kinases, members of the protein kinase C family, or other Ca2(+)-dependent protein kinases. In vitro, partially purified rsk-kinase phosphorylates several of the sites (serine and threonine) that are phosphorylated in growth-stimulated cultured cells. A detailed examination of the mitogen-regulated activation kinetics of rsk-kinase and pp90rsk activities demonstrated that they are coordinately regulated. In addition, protein kinase C is not absolutely required for epidermal and fibroblast growth factor-stimulated activation of rsk-kinase, whereas, like pp90rsk, platelet-derived growth factor- and vanadate-stimulated rsk-kinase activity exhibits a greater dependence on protein kinase C-mediated signal transduction. The characterization and future purification of the rsk-kinase(s) will improve our understanding of the early signaling events regulating cell growth.

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Amano, Mutsuki, Tomonari Hamaguchi, Md Hasanuzzaman Shohag, Kei Kozawa, Katsuhiro Kato, Xinjian Zhang, Yoshimitsu Yura i in. "Kinase-interacting substrate screening is a novel method to identify kinase substrates". Journal of Cell Biology 209, nr 6 (22.06.2015): 895–912. http://dx.doi.org/10.1083/jcb.201412008.

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Protein kinases play pivotal roles in numerous cellular functions; however, the specific substrates of each protein kinase have not been fully elucidated. We have developed a novel method called kinase-interacting substrate screening (KISS). Using this method, 356 phosphorylation sites of 140 proteins were identified as candidate substrates for Rho-associated kinase (Rho-kinase/ROCK2), including known substrates. The KISS method was also applied to additional kinases, including PKA, MAPK1, CDK5, CaMK1, PAK7, PKN, LYN, and FYN, and a lot of candidate substrates and their phosphorylation sites were determined, most of which have not been reported previously. Among the candidate substrates for Rho-kinase, several functional clusters were identified, including the polarity-associated proteins, such as Scrib. We found that Scrib plays a crucial role in the regulation of subcellular contractility by assembling into a ternary complex with Rho-kinase and Shroom2 in a phosphorylation-dependent manner. We propose that the KISS method is a comprehensive and useful substrate screen for various kinases.

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Shani, Gidi, Lea Marash, Devrim Gozuacik, Shani Bialik, Lior Teitelbaum, Galit Shohat i Adi Kimchi. "Death-Associated Protein Kinase Phosphorylates ZIP Kinase, Forming a Unique Kinase Hierarchy To Activate Its Cell Death Functions". Molecular and Cellular Biology 24, nr 19 (1.10.2004): 8611–26. http://dx.doi.org/10.1128/mcb.24.19.8611-8626.2004.

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ABSTRACT The death-associated protein (DAP) kinase family includes three protein kinases, DAP kinase, DAP kinase-related protein 1, and ZIP kinase, which display 80% amino acid identity within their catalytic domains and are functionally linked to common subcellular changes occurring during cell death, such as the process of membrane blebbing. Here we show physical and functional cross talk between DAP kinase and ZIP kinase. The two kinases display strong synergistic effects on cell death when coexpressed and physically bind each other via their catalytic domains. Furthermore, DAP kinase phosphorylates ZIP kinase at six specific sites within its extracatalytic C-terminal domain. ZIP kinase localizes to both the nucleus and the cytoplasm and fractionates as monomeric and trimeric forms. Significantly, modification of the DAP kinase phosphorylation sites influences both the localization and oligomerization status of ZIP kinase. A mutant ZIP kinase construct, in which the six serine/threonine residues were mutated to aspartic acid to mimic the phosphorylated state, was found predominantly in the cytoplasm as a trimer and possessed greater cell death-inducing potency. This suggests that DAP kinase and ZIP kinase function in a biochemical pathway in which DAP kinase activates the cellular function of ZIP kinase through phosphorylation, leading to amplification of death-promoting signals.

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Rane, M. J., S. L. Carrithers, J. M. Arthur, J. B. Klein i K. R. McLeish. "Formyl peptide receptors are coupled to multiple mitogen-activated protein kinase cascades by distinct signal transduction pathways: role in activation of reduced nicotinamide adenine dinucleotide oxidase." Journal of Immunology 159, nr 10 (15.11.1997): 5070–78. http://dx.doi.org/10.4049/jimmunol.159.10.5070.

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Abstract Formyl peptide receptor activation of three mitogen-activated protein kinase (MAPK) cascades, extracellular signal-regulated kinases (ERKs), N-terminal kinases (JNKs), and p38 MAPK was examined in differentiated HL-60 granulocytes. FMLP stimulated a concentration- and time-dependent increase in ERK, JNK, and p38 MAPK activities, all of which were dependent on a pertussis toxin-sensitive G protein. Pharmacologic inhibitors were used to examine the roles of tyrosine kinases, phosphatidylinositol 3-kinase, protein kinase C, and phospholipase C. FMLP-stimulated ERK activity was dependent on tyrosine kinases, phosphatidylinositol 3-kinase, protein kinase C, and phospholipase C; p38 MAPK activation was dependent on phosphatidylinositol 3-kinase and phospholipase C; while JNK activation was independent of all of these signaling components. The mitogen-activated protein kinase/ERK kinase inhibitor PD098059 reduced ERK activation by 90%, while an inhibitor of p38 MAPK, SB203580, inhibited p38 MAPK activation by 80%. Both PD098059 and SB203580 inhibited FMLP-stimulated superoxide release, as did inhibitors directed against protein kinase C, tyrosine kinases, and phosphatidylinositol 3-kinase. We conclude that formyl peptide receptors are coupled to three MAPK cascades by Gi proteins. ERKs, p38 MAPK, and JNKs are each activated by distinct proximal signal transduction pathways. Activation of p38 MAPK is necessary for FMLP stimulation of respiratory burst activity; however, a second signal that may involve ERK is also required for this activity.

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31

Wang, Y., M. S. Simonson, J. Pouysségur i M. J. Dunn. "Endothelin rapidly stimulates mitogen-activated protein kinase activity in rat mesangial cells". Biochemical Journal 287, nr 2 (15.10.1992): 589–94. http://dx.doi.org/10.1042/bj2870589.

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Mitogen-activated protein (MAP) kinases are regarded as switch kinases in the phosphorylation cascade initiated by various agonists. We have investigated whether endothelins (ET), which are constrictor and mitogenic isopeptides, can increase MAP kinase activity in rat mesangial cells, using bovine myelin basic protein (MBP) as a substrate for an in vitro kinase assay. Treatment of quiescent mesangial cells with ET-1 rapidly stimulated a kinase activity which phosphorylated exogenous MBP. This stimulation was dose-dependent, with threshold responses at 1 nM-ET-1. Epidermal growth factor and thrombin also activated this kinase in mesangial cells. We also examined the ET signal transduction pathways leading to activation of MBP kinase. Pertussis toxin had no effect on ET-stimulated MBP kinase activity. Stimulation of protein kinase C by phorbol ester increased MBP kinase activity, and down-regulation of PKC partially inhibited ET-stimulated MBP kinase as well as phorbol ester-stimulated MBP kinase activity. Interestingly, genestein, an inhibitor of protein tyrosine kinases, partially inhibited MBP kinase stimulated by ET but not by phorbol esters. These results suggest that ET stimulates MBP kinase activity in rat mesangial cells via at least two pathways: one which is protein kinase C-dependent and a second one that involves a protein tyrosine kinase. Finally, by raising rabbit antibodies against the two forms of MAP kinase, p44mapk and p42mapk, we demonstrated that both isoforms are expressed in mesangial cells. Antibody alpha 1 Cp42 specifically immunoprecipitated p42mapk and allowed us to demonstrate that ET stimulates MBP kinase activity in the p42mapk immunocomplex. In conclusion, we have provided evidence that, in rat mesangial cells, MAP kinases are rapidly activated by ET-1, a regulatory process that involves at least protein kinase C activation and also a contribution of a tyrosine kinase not yet characterized.

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32

Póti, Ádám L., Laura Dénes, Kinga Papp, Csaba Bató, Zoltán Bánóczi, Attila Reményi i Anita Alexa. "Phosphorylation-Assisted Luciferase Complementation Assay Designed to Monitor Kinase Activity and Kinase-Domain-Mediated Protein–Protein Binding". International Journal of Molecular Sciences 24, nr 19 (3.10.2023): 14854. http://dx.doi.org/10.3390/ijms241914854.

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Protein kinases are key regulators of cell signaling and have been important therapeutic targets for three decades. ATP-competitive drugs directly inhibit the activity of kinases but these enzymes work as part of complex protein networks in which protein–protein interactions (often referred to as kinase docking) may govern a more complex activation pattern. Kinase docking is indispensable for many signaling disease-relevant Ser/Thr kinases and it is mediated by a dedicated surface groove on the kinase domain which is distinct from the substrate-binding pocket. Thus, interfering with kinase docking provides an alternative strategy to control kinases. We describe activity sensors developed for p90 ribosomal S6 kinase (RSK) and mitogen-activated protein kinases (MAPKs: ERK, p38, and JNK) whose substrate phosphorylation is known to depend on kinase-docking-groove-mediated protein–protein binding. The in vitro assays were based on fragment complementation of the NanoBit luciferase, which is facilitated upon substrate motif phosphorylation. The new phosphorylation-assisted luciferase complementation (PhALC) sensors are highly selective and the PhALC assay is a useful tool for the quantitative analysis of kinase activity or kinase docking, and even for high-throughput screening of academic compound collections.

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33

Gutkind, J. S., P. M. Lacal i K. C. Robbins. "Thrombin-dependent association of phosphatidylinositol-3 kinase with p60c-src and p59fyn in human platelets". Molecular and Cellular Biology 10, nr 7 (lipiec 1990): 3806–9. http://dx.doi.org/10.1128/mcb.10.7.3806-3809.1990.

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Recent studies have shown that ligand-activated growth factor receptors as well as transforming versions of nonreceptor protein-tyrosine kinases physically associate with phosphatidylinositol-3 kinase (PI-3 kinase). Reasoning that PI-3 kinase might also play a role in the normal functions of nonreceptor kinases, we sought to determine whether association with PI-3 kinase might serve as a measure of nonreceptor protein-tyrosine kinase activation under physiological conditions. We found that p60c-src as well as p59fyn, the product of another member of the src family of proto-oncogenes, physically associated with a PI kinase activity within 5 s after exposure to thrombin. Furthermore, PI kinase reaction products generated in p60v-src, p60c-src or p59fyn containing immunoprecipitates were indistinguishable, demonstrating the identity of the associated enzyme as PI-3 kinase. These findings demonstrate a thrombin-dependent interaction between p60c-src or p59fyn and PI-3 kinase and suggest a role for nonreceptor protein-tyrosine kinases in human platelet signal transduction.

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34

Gutkind, J. S., P. M. Lacal i K. C. Robbins. "Thrombin-dependent association of phosphatidylinositol-3 kinase with p60c-src and p59fyn in human platelets." Molecular and Cellular Biology 10, nr 7 (lipiec 1990): 3806–9. http://dx.doi.org/10.1128/mcb.10.7.3806.

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Recent studies have shown that ligand-activated growth factor receptors as well as transforming versions of nonreceptor protein-tyrosine kinases physically associate with phosphatidylinositol-3 kinase (PI-3 kinase). Reasoning that PI-3 kinase might also play a role in the normal functions of nonreceptor kinases, we sought to determine whether association with PI-3 kinase might serve as a measure of nonreceptor protein-tyrosine kinase activation under physiological conditions. We found that p60c-src as well as p59fyn, the product of another member of the src family of proto-oncogenes, physically associated with a PI kinase activity within 5 s after exposure to thrombin. Furthermore, PI kinase reaction products generated in p60v-src, p60c-src or p59fyn containing immunoprecipitates were indistinguishable, demonstrating the identity of the associated enzyme as PI-3 kinase. These findings demonstrate a thrombin-dependent interaction between p60c-src or p59fyn and PI-3 kinase and suggest a role for nonreceptor protein-tyrosine kinases in human platelet signal transduction.

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35

Schaap, D., J. van der Wal, W. J. van Blitterswijk, R. L. van der Bend i H. L. Ploegh. "Diacylglycerol kinase is phosphorylated in vivo upon stimulation of the epidermal growth factor receptor and serine/threonine kinases, including protein kinase C-ε". Biochemical Journal 289, nr 3 (1.02.1993): 875–81. http://dx.doi.org/10.1042/bj2890875.

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In signal transduction, diacylglycerol (DG) kinase attenuates levels of the second messenger DG by converting it to phosphatidic acid. A previously cloned full-length human 86 kDa DG kinase cDNA was expressed as fusion protein in Escherichia coli, to aid in the generation of DG-kinase-specific monoclonal antibodies suitable for immunoprecipitation experiments. To investigate whether phosphorylation of DG kinase is a possible mechanism for its regulation, COS-7 cells were transiently transfected with the DG kinase cDNA and phosphorylation of the expressed DG kinase was induced by various stimuli. Activation of both cyclic AMP-dependent protein kinase and protein kinase C (PKC) resulted in phosphorylation of DG kinase on serine residues in vivo, and both kinases induced this phosphorylation within the same tryptic phosphopeptide, suggesting that they may exert similar control over DG kinase. No phosphorylation was observed upon ionomycin treatment, intended to activate Ca2+/calmodulin-dependent kinases. Co-transfections of DG kinase with either PKC-alpha or PKC-epsilon cDNA revealed that both protein kinases, when stimulated, are able to phosphorylate DG kinase. For PKC-epsilon, DG kinase is the first in vivo substrate identified. Stimulation with epidermal growth factor (EGF) of COS-7 cells transfected with both DG kinase and EGF-receptor cDNA results mainly in phosphorylation of DG kinase on tyrosine. Since the EGF receptor has an intrinsic tyrosine kinase activity, this finding implies that DG kinase may be a direct substrate for the activated EGF receptor.

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36

Nick, J. A., N. J. Avdi, P. Gerwins, G. L. Johnson i G. S. Worthen. "Activation of a p38 mitogen-activated protein kinase in human neutrophils by lipopolysaccharide." Journal of Immunology 156, nr 12 (15.06.1996): 4867–75. http://dx.doi.org/10.4049/jimmunol.156.12.4867.

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Abstract Stimulation of human neutrophils by LPS is central to the pathogenesis of sepsis and the adult respiratory distress syndrome. The intracellular signaling pathway that results in cellular responses following LPS stimulation in neutrophils is unknown. We report that exposure of neutrophils to LPS results in the phosphorylation and activation of a p38 mitogen-activated protein (MAP) kinase, occurring in a concentration-dependent manner, with maximum response at 20 to 25 min. Partial purification of a p38 MAP kinase by ion exchange chromatography established it as distinct from the p42/p44 (extracellular signal-regulated kinases (ERK-1 and ERK-2) MAP kinases). Activation of the p38 MAP kinase by LPS in human neutrophils occurs via CD14, a proposed LPS receptor, and requires the presence of plasma containing the LPS-binding protein. This intracellular signaling pathway is independent of protein kinase C and does not involve Raf, MAP/ERK kinase kinase-1, MAP/ERK kinase-1, or MAP/ERK kinase-2 and does not result in the activation of the p42/p44 ERK MAP kinases or the c-jun N-terminal kinases.

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Fu, Zheng, Melanie J. Schroeder, Jeffrey Shabanowitz, Philipp Kaldis, Kasumi Togawa, Anil K. Rustgi, Donald F. Hunt i Thomas W. Sturgill. "Activation of a Nuclear Cdc2-Related Kinase within a Mitogen-Activated Protein Kinase-Like TDY Motif by Autophosphorylation and Cyclin-Dependent Protein Kinase-Activating Kinase". Molecular and Cellular Biology 25, nr 14 (lipiec 2005): 6047–64. http://dx.doi.org/10.1128/mcb.25.14.6047-6064.2005.

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ABSTRACT Male germ cell-associated kinase (MAK) and intestinal cell kinase (ICK) are nuclear Cdc2-related kinases with nearly identical N-terminal catalytic domains and more divergent C-terminal noncatalytic domains. The catalytic domain is also related to mitogen-activated protein kinases (MAPKs) and contains a corresponding TDY motif. Nuclear localization of ICK requires subdomain XI and interactions of the conserved Arg-272, but not kinase activity or, surprisingly, any of the noncatalytic domain. Further, nuclear localization of ICK is required for its activation. ICK is activated by dual phosphorylation of the TDY motif. Phosphorylation of Tyr-159 in the TDY motif requires ICK autokinase activity but confers only basal kinase activity. Full activation requires additional phosphorylation of Thr-157 in the TDY motif. Coexpression of ICK with constitutively active MEK1 or MEK5 fails to increase ICK phosphorylation or activity, suggesting that MEKs are not involved. ICK and MAK are related to Ime2p in budding yeast, and cyclin-dependent protein kinase-activating kinase Cak1p has been placed genetically upstream of Ime2p. Recombinant Cak1p phosphorylates Thr-157 in the TDY motif of recombinant ICK and activates its activity in vitro. Coexpression of ICK with wild-type CAK1 but not kinase-inactive CAK1 in cells also increases ICK phosphorylation and activity. Our studies establish ICK as the prototype for a new group of MAPK-like kinases requiring dual phosphorylation at TDY motifs.

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LANG, Mark L., Yih-Wen CHEN, Li SHEN, Hong GAO, Gillian A. LANG, Terri K. WADE i William F. WADE. "IgA Fc receptor (FcαR) cross-linking recruits tyrosine kinases, phosphoinositide kinases and serine/threonine kinases to glycolipid rafts". Biochemical Journal 364, nr 2 (1.06.2002): 517–25. http://dx.doi.org/10.1042/bj20011696.

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The human IgA Fc receptor (FcαR, CD89) triggers several important physiological functions, including phagocytosis, NADPH oxidase activation and antigen presentation. Efforts are underway to delineate FcαR signal-transduction pathways that control these functions. In a previous study, we demonstrated that cross-linking of FcαR increased its partitioning into membrane glycolipid rafts and was accompanied by γ-chain-dependent recruitment and phosphorylation of the tyrosine kinases Lck/Yes-related novel protein tyrosine kinase (Lyn) and Bruton's tyrosine kinase (Btk). Here we have performed a more extensive characterization of signalling effectors recruited to rafts on FcαR cross-linking. We demonstrate that in addition to tyrosine kinases Lyn and Btk, FcαR cross-linking also recruits B-lymphocyte kinase (Blk) and spleen tyrosine kinase (Syk) to rafts. We show recruitment of phosphoinositide kinases, including 3-phosphoinositide 3-kinase and phospholipase Cγ2, and serine/threonine kinases such as protein kinase C (PKC) α, PKC∊, and protein kinase B (PKB) α. This suggests that lipid rafts serve as sites for FcαR-triggered recruitment of multiple classes of signalling effectors. We further demonstrate that tyrosine kinases and PKCα have a sustained association with rafts, whereas phosphoinositide 3-kinase and its downstream effectors have a transient association with rafts. This is consistent with temporally regulated divergence of FcαR signalling pathways in rafts. Furthermore, we suggest the spatial separation of signalling effectors by transport of phosphoinositide 3-kinase, phosphoinositide-dependent kinase 1, PKBα and PKC∊ to endocytic compartments containing internalized FcαR.

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Ishizuka, Tamotsu, Kosuke Chayama, Katsuyuki Takeda, Eckard Hamelmann, Naohiro Terada, Gordon M. Keller, Gary L. Johnson i Erwin W. Gelfand. "Mitogen-Activated Protein Kinase Activation Through Fcε Receptor I and Stem Cell Factor Receptor Is Differentially Regulated by Phosphatidylinositol 3-Kinase and Calcineurin in Mouse Bone Marrow-Derived Mast Cells". Journal of Immunology 162, nr 4 (15.02.1999): 2087–94. http://dx.doi.org/10.4049/jimmunol.162.4.2087.

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Abstract Aggregation of high affinity FcR for IgE (FcεRI) on mast cells activates intracellular signal transduction pathways, including the activation of protein tyrosine kinases, phosphatidylinositol 3-kinase (PI3-kinase), and protein kinase C. Binding of stem cell factor (SCF) to its receptor (SCFR, c-Kit) on mast cells also induces increases in intrinsic tyrosine kinase activity and activation of PI3-kinase. Although ligation of both receptors induces Ras and Raf-1 activation, the downstream consequences of these early activation events are not well defined, except for the activation of extracellular signal-regulated kinases (ERK). Addition of Ag (OVA) to mouse bone marrow-derived mast cells (BMMC) sensitized with anti-OVA IgE triggers the activation of three members of the mitogen-activated protein (MAP) kinase family, c-Jun amino-terminal kinase (JNK), p38 MAP kinase (p38), and extracellular signal-regulated kinases. SCF similarly activates all three MAP kinases. Wortmannin, an inhibitor of PI3-kinase, inhibited both FcεRI- and SCFR-mediated JNK activation and partially inhibited FcεRI, but not SCFR-mediated p38 activation. Cyclosporin A inhibited FcεRI-mediated JNK and p38 activation, but did not affect the activation of these kinases when stimulated through the SCFR. Wortmannin and cyclosporin A inhibited FcεRI-mediated production of TNF-α and IL-4 in addition to serotonin release in BMMC. These results indicate that both PI3-kinase and calcineurin may contribute to the regulation of cytokine gene transcription and the degranulation response by modulating JNK activity in BMMC.

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Ibrahim, Samar H., Petra Hirsova, Harmeet Malhi i Gregory J. Gores. "Nonalcoholic Steatohepatitis Promoting Kinases". Seminars in Liver Disease 40, nr 04 (11.06.2020): 346–57. http://dx.doi.org/10.1055/s-0040-1713115.

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AbstractNonalcoholic hepatitis (NASH) is the progressive inflammatory form of nonalcoholic fatty liver disease. Although the mechanisms of hepatic inflammation in NASH remain incompletely understood, emerging literature implicates the proinflammatory environment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. Interestingly, numerous NASH-promoting kinases in hepatocytes, immune cells, and adipocytes are activated by the lipotoxic insult associated with obesity. In the current review, we discuss recent advances in NASH-promoting kinases as disease mediators and therapeutic targets. The focus of the review is mainly on the mitogen-activated protein kinases including mixed lineage kinase 3, apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 MAPK; the endoplasmic reticulum (ER) stress kinases protein kinase RNA-like ER kinase and inositol-requiring protein-1α; as well as the Rho-associated protein kinase 1. We also discuss various pharmacological agents targeting these stress kinases in NASH that are under different phases of development.

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41

Nyati, Shyam, Rajesh Ranga, Brian D. Ross, Alnawaz Rehemtulla i Mahaveer Swaroop Bhojani. "Molecular imaging of glycogen synthase kinase-3β and casein kinase-1α kinases". Analytical Biochemistry 405, nr 2 (październik 2010): 246–54. http://dx.doi.org/10.1016/j.ab.2010.06.020.

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Zhao, Quan, i Frank S. Lee. "Mitogen-activated Protein Kinase/ERK Kinase Kinases 2 and 3 Activate Nuclear Factor-κB through IκB Kinase-α and IκB Kinase-β". Journal of Biological Chemistry 274, nr 13 (26.03.1999): 8355–58. http://dx.doi.org/10.1074/jbc.274.13.8355.

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Lee, K. S., K. Irie, Y. Gotoh, Y. Watanabe, H. Araki, E. Nishida, K. Matsumoto i D. E. Levin. "A yeast mitogen-activated protein kinase homolog (Mpk1p) mediates signalling by protein kinase C". Molecular and Cellular Biology 13, nr 5 (maj 1993): 3067–75. http://dx.doi.org/10.1128/mcb.13.5.3067-3075.1993.

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Mitogen-activated protein (MAP) kinases are activated in response to a variety of stimuli through a protein kinase cascade that results in their phosphorylation on tyrosine and threonine residues. The molecular nature of this cascade is just beginning to emerge. Here we report the isolation of a Saccharomyces cerevisiae gene encoding a functional analog of mammalian MAP kinases, designated MPK1 (for MAP kinase). The MPK1 gene was isolated as a dosage-dependent suppressor of the cell lysis defect associated with deletion of the BCK1 gene. The BCK1 gene is also predicted to encode a protein kinase which has been proposed to function downstream of the protein kinase C isozyme encoded by PKC1. The MPK1 gene possesses a 1.5-kb uninterrupted open reading frame predicted to encode a 53-kDa protein. The predicted Mpk1 protein (Mpk1p) shares 48 to 50% sequence identity with Xenopus MAP kinase and with the yeast mating pheromone response pathway components, Fus3p and Kss1p. Deletion of MPK1 resulted in a temperature-dependent cell lysis defect that was virtually indistinguishable from that resulting from deletion of BCK1, suggesting that the protein kinases encoded by these genes function in a common pathway. Expression of Xenopus MAP kinase suppressed the defect associated with loss of MPK1 but not the mating-related defects associated with loss of FUS3 or KSS1, indicating functional conservation between the former two protein kinases. Mutation of the presumptive phosphorylated tyrosine and threonine residues of Mpk1p individually to phenylalanine and alanine, respectively, severely impaired Mpk1p function. Additional epistasis experiments, and the overall architectural similarity between the PKC1-mediated pathway and the pheromone response pathway, suggest that Pkc1p regulates a protein kinase cascade in which Bck1p activates a pair of protein kinases, designated Mkk1p and Mkk2p (for MAP kinase-kinase), which in turn activate Mpk1p.

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44

Lee, K. S., K. Irie, Y. Gotoh, Y. Watanabe, H. Araki, E. Nishida, K. Matsumoto i D. E. Levin. "A yeast mitogen-activated protein kinase homolog (Mpk1p) mediates signalling by protein kinase C." Molecular and Cellular Biology 13, nr 5 (maj 1993): 3067–75. http://dx.doi.org/10.1128/mcb.13.5.3067.

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Mitogen-activated protein (MAP) kinases are activated in response to a variety of stimuli through a protein kinase cascade that results in their phosphorylation on tyrosine and threonine residues. The molecular nature of this cascade is just beginning to emerge. Here we report the isolation of a Saccharomyces cerevisiae gene encoding a functional analog of mammalian MAP kinases, designated MPK1 (for MAP kinase). The MPK1 gene was isolated as a dosage-dependent suppressor of the cell lysis defect associated with deletion of the BCK1 gene. The BCK1 gene is also predicted to encode a protein kinase which has been proposed to function downstream of the protein kinase C isozyme encoded by PKC1. The MPK1 gene possesses a 1.5-kb uninterrupted open reading frame predicted to encode a 53-kDa protein. The predicted Mpk1 protein (Mpk1p) shares 48 to 50% sequence identity with Xenopus MAP kinase and with the yeast mating pheromone response pathway components, Fus3p and Kss1p. Deletion of MPK1 resulted in a temperature-dependent cell lysis defect that was virtually indistinguishable from that resulting from deletion of BCK1, suggesting that the protein kinases encoded by these genes function in a common pathway. Expression of Xenopus MAP kinase suppressed the defect associated with loss of MPK1 but not the mating-related defects associated with loss of FUS3 or KSS1, indicating functional conservation between the former two protein kinases. Mutation of the presumptive phosphorylated tyrosine and threonine residues of Mpk1p individually to phenylalanine and alanine, respectively, severely impaired Mpk1p function. Additional epistasis experiments, and the overall architectural similarity between the PKC1-mediated pathway and the pheromone response pathway, suggest that Pkc1p regulates a protein kinase cascade in which Bck1p activates a pair of protein kinases, designated Mkk1p and Mkk2p (for MAP kinase-kinase), which in turn activate Mpk1p.

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Toshima, Jiro, Junko Y. Toshima, Toru Amano, Neng Yang, Shuh Narumiya i Kensaku Mizuno. "Cofilin Phosphorylation by Protein Kinase Testicular Protein Kinase 1 and Its Role in Integrin-mediated Actin Reorganization and Focal Adhesion Formation". Molecular Biology of the Cell 12, nr 4 (kwiecień 2001): 1131–45. http://dx.doi.org/10.1091/mbc.12.4.1131.

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Testicular protein kinase 1 (TESK1) is a serine/threonine kinase with a structure composed of a kinase domain related to those of LIM-kinases and a unique C-terminal proline-rich domain. Like LIM-kinases, TESK1 phosphorylated cofilin specifically at Ser-3, both in vitro and in vivo. When expressed in HeLa cells, TESK1 stimulated the formation of actin stress fibers and focal adhesions. In contrast to LIM-kinases, the kinase activity of TESK1 was not enhanced by Rho-associated kinase (ROCK) or p21-activated kinase, indicating that TESK1 is not their downstream effector. Both the kinase activity of TESK1 and the level of cofilin phosphorylation increased by plating cells on fibronectin. Y-27632, a specific inhibitor of ROCK, inhibited LIM-kinase-induced cofilin phosphorylation but did not affect fibronectin-induced or TESK1-induced cofilin phosphorylation in HeLa cells. Expression of a kinase-negative TESK1 suppressed cofilin phosphorylation and formation of stress fibers and focal adhesions induced in cells plated on fibronectin. These results suggest that TESK1 functions downstream of integrins and plays a key role in integrin-mediated actin reorganization, presumably through phosphorylating and inactivating cofilin. We propose that TESK1 and LIM-kinases commonly phosphorylate cofilin but are regulated in different ways and play distinct roles in actin reorganization in living cells.

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Moens, Ugo, i Sergiy Kostenko. "Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases". Biological Chemistry 394, nr 9 (1.09.2013): 1115–32. http://dx.doi.org/10.1515/hsz-2013-0149.

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Abstract Mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways that control pivotal cellular processes including proliferation, differentiation, survival, apoptosis, gene regulation, and motility. MAPK pathways consist of a relay of consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinases, and MAPKs. Conventional MAPKs are characterized by a conserved Thr-X-Tyr motif in the activation loop of the kinase domain, while atypical MAPKs lack this motif and do not seem to be organized into the classical three-tiered kinase cascade. One functional group of conventional and atypical MAPK substrates consists of protein kinases known as MAPK-activated protein kinases. Eleven mammalian MAPK-activated protein kinases have been identified, and they are divided into five subgroups: the ribosomal-S6-kinases RSK1-4, the MAPK-interacting kinases MNK1 and 2, the mitogen- and stress-activated kinases MSK1 and 2, the MAPK-activated protein kinases MK2 and 3, and the MAPK-activated protein kinase MK5 (also referred to as PRAK). MK5/PRAK is the only MAPK-activated protein kinase that is a substrate for both conventional and atypical MAPK, while all other MAPKAPKs are exclusively phosphorylated by conventional MAPKs. This review focuses on the structure, activation, substrates, functions, and possible implications of MK5/PRAK in malignant and nonmalignant diseases.

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CHIARIELLO, Mario, Eliana GOMEZ i J. Silvio GUTKIND. "Regulation of cyclin-dependent kinase (Cdk) 2 Thr-160 phosphorylation and activity by mitogen-activated protein kinase in late G1 phase". Biochemical Journal 349, nr 3 (25.07.2000): 869–76. http://dx.doi.org/10.1042/bj3490869.

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Mitogen-activated protein (MAP) kinases, p42MAPK and p44MAPK, are central components of growth-promoting signalling pathways. However, how stimulation of MAP kinases culminates in cell-cycle progression is still poorly understood. Here we show that mitogenic stimulation of NIH 3T3 cells causes a sustained activation of MAP kinases, which lasts until cells begin progressing through the G1/S boundary. Furthermore, we observed that disruption of the MAP-kinase pathway with a selective MEK (MAP kinase/extracellular-signal-regulated protein kinase kinase) inhibitor, PD98059, prevents the activation of cyclin-dependent kinase (Cdk) 2 and DNA synthesis, even when added during late G1 phase, once the known mechanisms by which MAP kinase controls G1 progression, accumulation of G1 cyclins and degradation of Cdk inhibitors have already taken place. Moreover, we provide evidence indicating that MAP kinases control Cdk2 Thr-160 activating phosphorylation and function, possibly by regulating the activity of a Cdk-activating kinase, thus promoting the re-initiation of DNA synthesis. These findings suggest the existence of a novel mechanism whereby signal-transducing pathways converging on MAP kinases can affect the cell-cycle machinery and, ultimately, participate in cell-growth control.

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Zhang, Mingzhen, Yonglan Liu, Hyunbum Jang i Ruth Nussinov. "Abstract 2085: Structural principles of kinase-selectivity drug design". Cancer Research 83, nr 7_Supplement (4.04.2023): 2085. http://dx.doi.org/10.1158/1538-7445.am2023-2085.

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Abstract Kinase drug selectivity is one of the main challenges in cancer research. The kinases encoded byhuman genome share the highly similar catalytic kinase domains. As a result, the drug that isdesigned to target one kinase frequently binds to another, leading to the off-target toxicity. Despitethe high structural similarity, the kinase drug pockets at the atomic level are not completelyidentical. We ask that whether there are some inhibitor-accessible geometric features in the kinasepockets that only exist in one kinase but not in all others. To target these unique features in thekinase pockets may help design the kinase drugs with the kinome-wide selectivity. In this work,we describe a transformation invariant protocol (binary network with unsupervised clustering) andperform the kinome-wide structural bioinformatic analysis by integrating the experimental andartificial intelligence (AI)-based kinase structures. The results show that ~ 66.8 % kinases containthe unique features that may distinguish them from all others and the geometric features shared byless than seven other kinases can be found in all the analyzed kinases. We apply the binary networkto EGFR tyrosine kinase and AKT1 serine/threonine kinases, illustrating the potential structuralstrategies to design the high-selectivity kinase drugs. Finally, we develop a cross-platformsoftware, named as KDS (Kinase Drug Selectivity), to achieve the customized real-timevisualization and mutation analysis of the binary networks in the human kinome. Citation Format: Mingzhen Zhang, Yonglan Liu, Hyunbum Jang, Ruth Nussinov. Structural principles of kinase-selectivity drug design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2085.

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49

KIM, Sung-Jin, i Ronald C. KAHN. "Insulin regulation of mitogen-activated protein kinase kinase (MEK), mitogen-activated protein kinase and casein kinase in the cell nucleus: a possible role in the regulation of gene expression". Biochemical Journal 323, nr 3 (1.05.1997): 621–27. http://dx.doi.org/10.1042/bj3230621.

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After insulin receptor activation, many cytoplasmic enzymes, including mitogen-activated protein (MAP) kinase, MAP kinase kinase (MEK) and casein kinase II (CKII) are activated, but exactly how insulin signalling progresses to the nucleus remains poorly understood. In Chinese hamster ovary cells overexpressing human insulin receptors [CHO(Hirc)], MEK, CKII and the MAP kinases ERK I and ERK II can be detected by immunoblotting in the nucleus, as well as in the cytoplasm, in the unstimulated state. Nuclear localization of MAP kinase is also observed in 3T3-F442A adipocytes, NIH-3T3 cells and Fao hepatoma cells, whereas MEK is found in the nucleus only in Fao and CHO cells. Insulin treatment for 5–30 min induces a translocation of MEK from the cytoplasm to the nucleus, whereas the MAP kinases and CKII are not translocated into the nucleus in response to insulin during this period. However, nuclear MAP kinase and CKII activities increase by 2–3-fold within 1–10 min after stimulation with insulin. By using gel-shift assays, it has been shown that insulin also stimulates nuclear protein binding to an AP-1 site with kinetics similar to MEK translocation and MAP kinase and CKII activation. Treatment of the extracts in vitro with protein phosphatase 2A or treatment of the intact cells with 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole, a cell-permeable inhibitor of CKII, almost completely blocks the insulin-induced DNA-binding activity, whereas incubation of cells with a MEK inhibitor produces only a slight decrease. These results suggest that insulin signalling results in the activation of serine kinases in the nucleus via two pathways: (1) insulin stimulates the nuclear translocation of some kinases, such as MEK, which might directly phosphorylate nuclear protein substrates or activate other nuclear kinases, and (2) insulin activates nuclear kinases without translocation. The latter is true of CKII, which seems to regulate the binding of nuclear proteins to the AP-1 site, possibly by phosphorylation of AP-1 transcription factors.

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50

Lebakken, Connie S., Hee Chol Kang i Kurt W. Vogel. "A Fluorescence Lifetime–Based Binding Assay to Characterize Kinase Inhibitors". Journal of Biomolecular Screening 12, nr 6 (21.05.2007): 828–41. http://dx.doi.org/10.1177/1087057107304480.

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The authors present a fluorescence lifetime—based kinase binding assay that identifies and characterizes compounds that bind to the adenosine triphosphate (ATP)—binding pocket of a range of tyrosine and serine/threonine kinases. The assay is based on displacement of an Alexa Fluor® 647 conjugate of staurosporine from the ATP-binding site of a kinase, which is detected by a change in the fluorescence lifetime of the probe between the free (displaced) and kinase-bound states. The authors screened 257 kinases for specific binding and displacement of the Alexa Fluor® 647-staurosporine probe and found that approximately half of the kinases tested could potentially be assayed with this method. They present inhibitor binding data against 4 selected serine/threonine kinases and 4 selected tyrosine kinases, using 6 commonly used kinase inhibitors. Two of these kinases were chosen for further studies, in which inhibitor binding data were compared to inhibition of kinase activity using 2 separate activity assay formats. Rank-order potencies of compounds were similar, but not identical, between the binding and activity assays. It was postulated that these differences could be caused by the fact that the assays are measuring distinct phenomena, namely, activity versus binding, and in a purified recombinant kinase preparation, there can exist a mixture of active and nonactivated kinases. To explore this possibility, the authors compared binding affinity for the probe using 2 kinases in their respective nonactivated and activated (phosphorylated) forms and found a kinase-dependent difference between the 2 forms. This assay format therefore represents a simple method for the identification and characterization of small-molecule kinase inhibitors that may be useful in screening a wide range of kinases and may be useful in identifying small molecules that bind to kinases in their active or nonactivated states. ( Journal of Biomolecular Screening 2007:828-841)

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