Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibronectin fragments (FN-f), including the 110-kDa fragment that binds the alpha5beta1 integrin, stimulate collagenase-3 (MMP-13) production and cartilage destruction. In the present study, treatment of chondrocytes with the 110-kDa FN-f or an activating antibody to the alpha5beta1 integrin was found to increase tyrosine autophosphorylation (Tyr-402) of the proline-rich tyrosine kinase-2 (PYK2) without significant change in autophosphorylation (Tyr-397) of focal adhesion kinase (FAK). The tyrosine kinase inhibitor tyrphostin A9, shown previously to block a PYK2-dependent pathway, blocked the FN-f-stimulated increase in MMP-13, whereas tyrphostin A25 did not. FN-f-stimulated PYK2 phosphorylation and MMP-13 production was also blocked by reducing intracellular calcium levels. Adenovirally mediated overexpression of wild type but not mutant PYK2 resulted in increased MMP-13 production. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate stimulated PYK2 phosphorylation and MMP-13 production. MMP-13 expression stimulated by either phorbol 12-myristate 13-acetate or FN-f was blocked by PKC inhibitors including the PKCdelta inhibitor rottlerin. Furthermore, PKCdelta translocation from cytosol to membrane was noted within 5 min of stimulation with FN-f. Immortalized human chondrocytes, transiently transfected with MMP-13 promoter-luciferase reporter constructs, showed increased promoter activity after FN-f treatment that was inhibited by co-transfection with either of two dominant negative mutants of PYK2 (Y402F and K457A). No inhibition was seen after cotransfection with wild type PYK2, a dominant negative of FAK (FRNK) or empty vector plasmid. FN-f-stimulated MMP-13 promoter activity was also inhibited by chemical inhibitors of ERK, JNK, and p38 mitogen-activated protein (MAP) kinases or by co-transfection of dominant negative MAP kinase mutant constructs. These studies have identified a novel pathway for the MAP kinase regulation of MMP-13 production which involves FN-f stimulation of the alpha5beta1 integrin and activation of the nonreceptor tyrosine kinase PYK2 by PKC, most likely PKCdelta
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PMID:Fibronectin fragment activation of proline-rich tyrosine kinase PYK2 mediates integrin signals regulating collagenase-3 expression by human chondrocytes through a protein kinase C-dependent pathway. 1273 Feb 23

To elucidate the molecular mechanisms by which human epidermal growth factor receptor/heregulin (HER2/HRG) influence the migratory potential of breast cancer cells, we have used phospho-specific antibodies against c-Src kinase and focal adhesion kinase (FAK). This study establishes that HER2/HRG signaling selectively upregulates Tyr phosphorylation of c-Src at Tyr-215 located within the SH2 domain, increases c-Src kinase activity and selectively upregulates Tyr phosphorylation of FAK at Tyr-861. HER2-overexpressing tumors showed increased levels of c-Src phosphorylation at Tyr-215. These findings suggest that HER2/HRG influence metastasis of breast cancer cells through a novel signaling pathway involving phosphorylation of FAK tyrosine 861 via activation of c-Src tyrosine 215.
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PMID:Heregulin and HER2 signaling selectively activates c-Src phosphorylation at tyrosine 215. 1275 9

Protein I/II, a pathogen-associated molecular pattern from oral streptococci, is a potent inducer of interleukin-6 (IL-6) and IL-8 synthesis and release from fibroblast-like synoviocytes (FLSs), cells that are critically involved in joint inflammation. This synthesis implicates ERK 1/2 and JNKs as well as AP-1-binding activity and nuclear translocation of NF-kappaB. The mechanisms by which protein I/II activates MAPKs remain, however, elusive. Because focal adhesion kinase (FAK) was proposed to play a role in signaling to MAPKs, we examined its ability to contribute to the MAPKs-dependent synthesis of IL-6 and IL-8 in response to protein I/II. We used FAK-/- fibroblasts as well as FAK+/+ fibroblasts and FLSs transfected with FRNK, a dominant negative form of FAK. The results demonstrate that IL-6 and IL-8 release in response to protein I/II was strongly inhibited in both protein I/II-stimulated FAK-/- and FRNK-transfected cells. Cytochalasin D, which inhibits protein I/II-induced phosphorylation of FAK (Tyr-397), had no effect either on activation of ERK 1/2 and JNKs or on IL-6 and IL-8 release. Taken together, these results indicate that IL-6 and IL-8 release by protein I/II-activated FLSs is regulated by FAK independently of Tyr-397 phosphorylation.
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PMID:ERK 1/2- and JNKs-dependent synthesis of interleukins 6 and 8 by fibroblast-like synoviocytes stimulated with protein I/II, a modulin from oral streptococci, requires focal adhesion kinase. 1276 Dec 29

Recent experiments have unravelled novel signal transduction pathways that involve the SRC homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites and an SH2 domain and serves a role in generating signaling complexes in response to tyrosine kinase activation. SHB mediates certain responses in platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. Upstream of SHB in some cells lies the SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK). FRK/RAK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where they both induce PC12 cell differentiation and beta-cell proliferation. Furthermore, beta-cell apoptosis is augmented by these proteins under conditions that cause beta-cell degeneration. The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2. Besides regulating apoptosis, proliferation and differentiation, SHB is also a component of the T cell receptor (TCR) signaling response. In Jurkat T cells, SHB links several signaling components with the TCR and is thus required for IL-2 production. In endothelial cells, SHB both promotes apoptosis under conditions that are anti-angiogenic, but is also required for proper mitogenicity, spreading and tubular morphogenesis. In embryonic stem cells, dominant-negative SHB (R522K) prevents early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon, suggesting a role of SHB in development. In summary, SHB is a versatile signal transduction molecule that produces diverse biological responses in different cell types under various conditions. SHB operates downstream of GTK in cells that express this kinase.
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PMID:The FRK/RAK-SHB signaling cascade: a versatile signal-transduction pathway that regulates cell survival, differentiation and proliferation. 1277 87

Humoral factors and extracellular matrix are critical co-regulators of smooth muscle cell (SMC) migration and proliferation. We reported previously that focal adhesion kinase (FAK)-related non-kinase (FRNK) is expressed selectively in SMC and can inhibit platelet-derived growth factor BB homodimer (PDGF-BB)-induced proliferation and migration of SMC by attenuating FAK activity. The goal of the current studies was to identify the mechanism by which FAK/FRNK regulates SMC growth and migration in response to diverse mitogenic signals. Transient overexpression of FRNK in SMC attenuated autophosphorylation of FAK at Tyr-397, reduced Src family-dependent tyrosine phosphorylation of FAK at Tyr-576, Tyr-577, and Tyr-881, and reduced phosphorylation of the FAK/Src substrates Cas and paxillin. However, FRNK expression did not alter the magnitude or dynamics of ERK activation induced by PDGF-BB or angiotensin II. Instead, FRNK expression markedly attenuated PDGF-BB-, angiotensin II-, and integrin-stimulated Rac1 activity and attenuates downstream signaling to JNK. Importantly, constitutively active Rac1 rescued the proliferation defects in FRNK expressing cells. Based on these observations, we hypothesize that FAK activation is required to integrate integrin signals with those from receptor tyrosine kinases and G protein-coupled receptors through downstream activation of Rac1 and that in SMC, FRNK may control proliferation and migration by buffering FAK-dependent Rac1 activation.
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PMID:An endogenous inhibitor of focal adhesion kinase blocks Rac1/JNK but not Ras/ERK-dependent signaling in vascular smooth muscle cells. 1278 22

Endothelial cell migration, a key process in angiogenesis, requires the coordinated integration of motogenic signals elicited by the adhesion of endothelial cells to extracellular matrices and by angiogenic cytokines such as the vascular endothelial growth factor (VEGF). In this study, we found that addition of VEGF to human umbilical vein endothelial cells cultivated on vitronectin triggers a synergistic interaction between the VEGF receptor VEGFR2 and the clustered integrin receptor alphavbeta3. The interaction between VEGFR2 and alphavbeta3 is required for full phosphorylation of VEGFR2 and to drive the activation of motogenic pathways involving focal adhesion kinase (FAK) and stress-activated protein kinase-2/p38 (SAPK2/p38). The signal emanating from the VEGFR2 and alphavbeta3 interaction and leading to SAPK2/p38 activation proceeds directly from VEGFR2. The chaperone Hsp90 is found in a complex that coprecipitates with inactivated VEGFR2, and the association is increased by VEGF and decreased by geldanamycin, a specific inhibitor of Hsp90-mediated events. Geldanamycin also impairs the phosphorylation of FAK that results from the interaction between VEGFR2 and alphavbeta3, and this is accompanied by an inhibition of the recruitment of vinculin to VEGFR2. We conclude that a necessary cross talk should occur between VEGFR2 and the integrin alphavbeta3, to transduce the VEGF signals to SAPK2/p38 and FAK and that Hsp90 is instrumental in the building up of focal adhesions by allowing the phosphorylation of FAK and the recruitment of vinculin to VEGFR2.
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PMID:Integrin alphavbeta3, requirement for VEGFR2-mediated activation of SAPK2/p38 and for Hsp90-dependent phosphorylation of focal adhesion kinase in endothelial cells activated by VEGF. 1282 Jun 53

Activated hepatic stellate cells (HSCs) are the main producers of extracellular matrix in the fibrotic liver and are involved in the regulation of hepatic inflammation. The aim of this study was to characterize the role of regulated on activation, normal T-cell expressed, and presumably secreted (RANTES) in activated HSCs. RANTES mRNA and protein secretion were strongly induced after stimulating HSCs with TNF-alpha, IL-1beta, or CD40L. RANTES production was NF-kappaB dependent, because inhibitor-kappaB (IkappaB) superrepressor and dominant-negative IkappaB kinase-2 almost completely blocked RANTES expression. NF-kappaB activation was sufficient to drive RANTES expression as demonstrated by the strong induction of RANTES in HSCs expressing NF-kappaB-inducing kinase. The JNK/activator protein-1 pathway also contributed to RANTES expression as demonstrated by the blocking effects of the JNK inhibitor SP600125. HSCs responded to stimulation with recombinant human (rh)RANTES with an increase in intracellular calcium concentration and a rapid increase in free radical formation. Furthermore, rhRANTES induced ERK phosphorylation, ERK-dependent [3H]thymidine incorporation, and HSC proliferation. Additionally, rhRANTES induced focal adhesion kinase phosphorylation and a substantial increase in HSC migration. HSCs functionally expressed chemokine receptor-5 (CCR5), as shown by flow-cytometric analysis and RT-PCR, and the inhibitory effects of a blocking CCR5 antibody on rhRANTES-induced ERK activation, proliferation, and migration. Diphenylene iodonium and N-acetylcysteine inhibited rhRANTES-induced ERK activation and HSC proliferation, indicating that NADPH oxidase-dependent production of reactive oxygen species was required. In conclusion, RANTES and CCR5 represent potential mediators of 1) HSC migration and proliferation and 2) a cross-talk between HSCs and leukocytes during fibrogenesis.
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PMID:Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. 1282 40

Vascular endothelial growth factor (VEGF) plays a significant role in blood-brain barrier breakdown and angiogenesis after brain injury. VEGF-induced endothelial cell migration is a key step in the angiogenic response and is mediated by an accelerated rate of focal adhesion complex assembly and disassembly. In this study, we identified the signaling mechanisms by which VEGF regulates human brain microvascular endothelial cell (HBMEC) integrity and assembly of focal adhesions, complexes comprised of scaffolding and signaling proteins organized by adhesion to the extracellular matrix. We found that VEGF treatment of HBMECs plated on laminin or fibronectin stimulated cytoskeletal organization and increased focal adhesion sites. Pretreating cells with VEGF antibodies or with the specific inhibitor SU-1498, which inhibits Flk-1/KDR receptor phosphorylation, blocked the ability of VEGF to stimulate focal adhesion assembly. VEGF induced the coupling of focal adhesion kinase (FAK) to integrin alphavbeta5 and tyrosine phosphorylation of the cytoskeletal components paxillin and p130cas. Additionally, FAK and related adhesion focal tyrosine kinase (RAFTK)/Pyk2 kinases were tyrosine-phosphorylated by VEGF and found to be important for focal adhesion sites. Overexpression of wild type RAFTK/Pyk2 increased cell spreading and the migration of HBMECs, whereas overexpression of catalytically inactive mutant RAFTK/Pyk2 markedly suppressed HBMEC spreading ( approximately 70%), adhesion ( approximately 82%), and migration ( approximately 65%). Furthermore, blocking of FAK by the dominant-interfering mutant FRNK (FAK-related non-kinase) significantly inhibited HBMEC spreading and migration and also disrupted focal adhesions. Thus, these studies define a mechanism for the regulatory role of VEGF in focal adhesion complex assembly in HBMECs via activation of FAK and RAFTK/Pyk2.
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PMID:Vascular endothelial growth factor regulates focal adhesion assembly in human brain microvascular endothelial cells through activation of the focal adhesion kinase and related adhesion focal tyrosine kinase. 1284 92

We have previously shown that the integrin beta6 is neo-expressed in invasive oral squamous cell carcinoma (SCC) and is correlated with oral tumor progression. However, the mechanism by which the integrin beta6 promotes oral tumor progression is not well understood. The purpose of the present study was to determine whether integrin beta6 signaling activates Fyn and thus promotes oral squamous cell carcinoma progression. We analyzed the integrin beta6 signaling complex and investigated the function of these signaling molecules in oral SCC cells. We found that, upon ligation of the integrin beta6 with fibronectin, beta6 complexed with Fyn and activated it. The activation of Fyn recruited and activated focal adhesion kinase to this complex. This complex was necessary to activate Shc and to couple beta6 signaling to the Raf-ERK/MAPK pathway. This pathway transcriptionally activated the matrix metalloproteinase-3 gene and promoted oral SCC cell proliferation and experimental metastasis in vivo. These findings indicate that integrin beta6 signaling activates Fyn and thus promotes oral cancer progression.
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PMID:Alphavbeta6-Fyn signaling promotes oral cancer progression. 1291 46

The granulin-epithelin precursor, progranulin, PC-cell-derived growth factor or acrogranin, is a high molecular weight secreted mitogen. It is abundantly expressed in rapidly cycling epithelial cells, in the immune system and in neurons, such as cerebellar Purkinje cells. Progranulin contributes to tumorigenesis in diverse cancers, including breast cancer, clear cell renal carcinoma, invasive ovarian carcinoma and glioblastoma. It regulates the rate of epithelial cell division in responsive epithelial cells, and confers an invasive phenotype on these cells. It is involved in the wound response. During embryogenesis, progranulin accelerates blastocyst formation, and is a growth factor for trophectodermal cells. In the neonate, progranulin, regulates the hormone-dependent virilization of the hypothalamus. It activates phosphorylation of Shc, and p44/42 MAPK (mitogen activated protein kinase) in the ERK (extracellular regulated kinase) signaling pathway; PI3K (phosophatidyl inositol-3-kinase), AKT/protein kinase B, and p70S6kinase in the phosophatidyl inositol-3-kinase pathway; and focal adhesion kinase in the adhesion/motility pathway. The signaling properties of progranulin are apparently similar to those of classic growth factors, but the functional properties of progranulin distinguish it from these molecules. Deleting the insulin-like growth factor I receptor from murine embryonic fibroblasts blocks proliferation in response to all classic growth factors, such as epidermal growth factor, or platelet-derived growth factor, whereas progranulin retains mitotic activity on these cells. The defined biological actions of progranulin probably represent a small fraction of its overall functions. Transcriptome analyses show that the progranulin gene is induced in numerous situations that vary from obesity to the transcriptional response of cells to antineoplastic drugs. Here, the biological roles of progranulin will be reviewed, with an emphasis on cancer and cell proliferation.
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PMID:Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis. 1297 94


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