Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently identified SH2-Bbeta as a JAK2-binding protein and substrate involved in the signaling of receptors for growth hormone and interferon-gamma. In this work, we report that SH2-Bbeta also functions as a signaling molecule for platelet-derived growth factor (PDGF). SH2-Bbeta fused to glutathione S-transferase (GST) bound PDGF receptor (PDGFR) from PDGF-treated but not control cells. GST fusion protein containing only the SH2 domain of SH2-Bbeta also bound PDGFR from PDGF-treated cells. An Arg to Glu mutation within the FLVRQS motif in the SH2 domain of SH2-Bbeta inhibited GST-SH2-Bbeta binding to tyrosyl-phosphorylated PDGFR. The N-terminal truncated SH2-Bbeta containing the entire SH2 domain interacted directly with tyrosyl-phosphorylated PDGFR from PDGF-treated cells but not unphosphorylated PDGFR from control cells in a Far Western assay. These results suggest that the SH2 domain of SH2-Bbeta is necessary and sufficient to mediate the interaction between SH2-Bbeta and PDGFR. PDGF stimulated coimmunoprecipitation of endogenous SH2-Bbeta with endogenous PDGFR in both 3T3-F442A and NIH3T3 cells. PDGF stimulated the rapid and transient phosphorylation of SH2-Bbeta on tyrosines and most likely on serines and/or threonines. Similarly, epidermal growth factor stimulated the phosphorylation of SH2-Bbeta; however, phosphorylation appears to be predominantly on serines and/or threonines. In response to PDGF, SH2-Bbeta associated with multiple tyrosyl-phosphorylated proteins, at least one of which (designated p84) does not bind to PDGFR. Taken together, these data strongly argue that, in response to PDGF, SH2-Bbeta directly interacts with PDGFR and is phosphorylated on tyrosine and most likely on serines and/or threonines, and acts as a signaling protein for PDGFR.
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PMID:Platelet-derived growth factor (PDGF) stimulates the association of SH2-Bbeta with PDGF receptor and phosphorylation of SH2-Bbeta. 969 82

The accumulation and organization of extracellular matrix (ECM) components play critical roles in development, maintenance, and pathogenesis of most organ systems. These processes are regulated by the precisely orchestrated expression of ECM components, their receptors, and matrix proteases. The collagen gel culture system has been extensively used as a model to examine ECM remodeling similar to that which occurs during development and wound healing. Growth factors, including transforming growth factor-beta, platelet-derived growth factor, insulin-like growth factor, and angiotensin II, have been shown to stimulate collagen gel contraction. The present studies were undertaken to begin to examine the mechanisms through which angiotensin II stimulates collagen remodeling and gel contraction. These studies indicate that angiotensin II stimulates collagen gel contraction by isolated heart fibroblasts in a dose-dependent manner and that this response is inhibited by the AT1 receptor antagonist Losartan. Furthermore, stimulation of collagen gel contraction by angiotensin II is also blocked by the src-related tyrosine kinase inhibitors genistein and herbimycin, indicating that activation of tyrosine kinases plays critical roles in this process. Stimulation of gel contraction by angiotensin II also involves the activation of JAK2, a member of the JAK/STAT pathways of transcriptional activation. Immunoprecipitation of surface-labeled fibroblasts indicate that cell surface levels of collagen-binding integrins also increase in response to angiotensin II treatment. Determining the underlying mechanisms regulating ECM remodeling is essential to understanding the role of ECM organization in development and disease.
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PMID:Angiotensin II-stimulated collagen gel contraction by heart fibroblasts: role of the AT1 receptor and tyrosine kinase activity. 976 19

Fibronectin seems to play an important role in promoting the characteristic changes of vascular smooth muscle cells in diabetes mellitus including overexpression of the platelet-derived growth factor beta-receptor. To determine the regulatory mechanism of the beta-receptor by fibronectin, we have analyzed the effect of fibronectin on the expression of the beta-receptor in cultured rat aortic smooth muscle cells using the beta-receptor promoter/luciferase expression vector system. Fibronectin was found to stimulate the expression of the beta-receptor at the transcriptional level. Both a MEK1 inhibitor PD98059 and a tyrosine kinase inhibitor herbimycin A significantly inhibited the fibronectin-stimulated receptor transcription. Herbimycin A also completely inhibited the fibronectin-stimulated increase in tyrosine phosphorylation of focal adhesion kinase. These data suggest the involvement of the integrin-mediated mitogen-activated protein kinase pathway downstream of fibronectin stimulation in the activation process of the beta-receptor promoter.
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PMID:Fibronectin stimulates transcription of the platelet-derived growth factor beta-receptor in cultured rat aortic smooth muscle cells. 979 Sep 68

Identification of cytokine-inducible genes is imperative for determining the mechanisms of cytokine action. A cytokine-inducible gene, mrg1 [melanocyte-specific gene (msg1) related gene], was identified through mRNA differential display of interleukin (IL) 9-stimulated and unstimulated mouse helper T cells. In addition to IL-9, mrg1 can be induced by other cytokines and biological stimuli, including IL-1alpha, -2, -4, -6, and -11, granulocyte/macrophage colony-stimulating factor, interferon gamma, platelet-derived growth factor, insulin, serum, and lipopolysaccharide in diverse cell types. The induction of mrg1 by these stimuli appears to be transient, with induction kinetics similar to other primary response genes, implicating its role in diverse biological processes. Deletion or point mutations of either the Box1 motif (binds Janus kinase 1) or the signal transducer and activator of transcription 3 binding site-containing region within the intracellular domain of the IL-9 receptor ligand binding subunit abolished or greatly reduced mrg1 induction by IL-9, suggesting that the Janus kinase/signal transducer and activator of transcription signaling pathway is required for mrg1 induction, at least in response to IL-9. Transfection of mrg1 cDNA into TS1, an IL-9-dependent mouse T cell line, converted these cells to IL-9-independent growth through a nonautocrine mechanism. Overexpression of mrg1 in Rat1 cells resulted in loss of cell contact inhibition, anchorage-independent growth in soft agar, and tumor formation in nude mice, demonstrating that mrg1 is a transforming gene. MRG1 is a transcriptional activator and may represent a founding member of an additional family of transcription factors.
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PMID:MRG1, the product of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity. 981 38

The tumor suppressor PTEN dephosphorylates focal adhesion kinase (FAK) and inhibits integrin-mediated cell spreading and cell migration. We demonstrate here that expression of PTEN selectively inhibits activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. PTEN expression in glioblastoma cells lacking the protein resulted in inhibition of integrin-mediated MAP kinase activation. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)- induced MAPK activation were also blocked. To determine the specific point of inhibition in the Ras/Raf/ MEK/ERK pathway, we examined these components after stimulation by fibronectin or growth factors. Shc phosphorylation and Ras activity were inhibited by expression of PTEN, whereas EGF receptor autophosphorylation was unaffected. The ability of cells to spread at normal rates was partially rescued by coexpression of constitutively activated MEK1, a downstream component of the pathway. In addition, focal contact formation was enhanced as indicated by paxillin staining. The phosphatase domain of PTEN was essential for all of these functions, because PTEN with an inactive phosphatase domain did not suppress MAP kinase or Ras activity. In contrast to its effects on ERK, PTEN expression did not affect c-Jun NH2-terminal kinase (JNK) or PDGF-stimulated Akt. Our data suggest that a general function of PTEN is to down-regulate FAK and Shc phosphorylation, Ras activity, downstream MAP kinase activation, and associated focal contact formation and cell spreading.
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PMID:Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. 983 64

Reactive oxygen species (ROS) play an important role in the pathogenesis of many human diseases, including the acute respiratory distress syndrome, Parkinson's disease, pulmonary fibrosis, and Alzheimer's disease. In mammalian cells, several genes known to be induced during the immediate early response to growth factors, including the protooncogenes c-fos and c-myc, have also been shown to be induced by ROS. We show that members of the STAT family of transcription factors, including STAT1 and STAT3, are activated in fibroblasts and A-431 carcinoma cells in response to H2O2. This activation occurs within 5 min, can be inhibited by antioxidants, and does not require protein synthesis. STAT activation in these cell lines is oxidant specific and does not occur in response to superoxide- or nitric oxide-generating stimuli. Buthionine sulfoximine, which depletes intracellular glutathione, also activates the STAT pathway. Moreover, H2O2 stimulates the activity of the known STAT kinases JAK2 and TYK2. Activation of STATs by platelet-derived growth factor (PDGF) is significantly inhibited by N-acetyl-L-cysteine and diphenylene iodonium, indicating that ROS production contributes to STAT activation in response to PDGF. These findings indicate that the JAK-STAT pathway responds to intracellular ROS and that PDGF uses ROS as a second messenger to regulate STAT activation.
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PMID:Activation of the JAK-STAT pathway by reactive oxygen species. 984 26

In this review, the signal events regulated by angiotensin II (AngII) in vascular smooth muscle are analyzed based on activation of specific tyrosine kinases. AngII has been shown to play a critical role in the pathogenesis of hypertension, inflammation, atherosclerosis, and congestive heart failure. The expanding role of AngII indicates that multiple signal transduction pathways are likely to be activated in a tissue-specific manner. Although at least three AngII receptors have been characterized, it seems that the AngII type I receptor (AT1R) is physiologically most important since pharmacologic inhibitors of the AT1R block most AngII signal events and have beneficial effects on cardiovascular disease. The AT1R is a seven transmembrane-spanning G protein-coupled receptor that regulates intracellular signal events by activation of Gq and Gi. However, many recent data indicate that activation of tyrosine kinases by several different mechanisms contributes to AngII effects in target tissues. Tyrosine kinases activated by AngII include c-Src, focal adhesion kinase (FAK), Pyk2 (CADTK), Janus kinases (JAK2 and TYK2), and the receptor tyrosine kinases Ax1, epidermal growth factor, and platelet-derived growth factor. Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of paxillin, Shc, Raf, and phospholipase C-gamma after AngII stimulation. These AngII-regulated tyrosine kinases seem to be required for AngII effects such as vasoconstriction, proto-oncogene expression, and protein synthesis based on studies with tyrosine kinase inhibitors. Thus, understanding AngII-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases.
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PMID:Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. 989 42

Phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) has been proposed to act as a second messenger to recruit regulatory proteins to the plasma membrane via their pleckstrin homology (PH) domains. The PH domain of Bruton's tyrosine kinase (Btk), which is mutated in the human disease X-linked agammaglobulinemia, has been shown to interact with PI(3,4,5)P3 in vitro. In this study, a fusion protein containing the PH domain of Btk and the enhanced green fluorescent protein (BtkPH-GFP) was constructed and utilized to study the ability of this PH domain to interact with membrane inositol phospholipids inside living cells. The localization of expressed BtkPH-GFP in quiescent NIH 3T3 cells was indistinguishable from that of GFP alone, both being cytosolic as assessed by confocal microscopy. In NIH 3T3 cells coexpressing BtkPH-GFP and the epidermal growth factor receptor, activation of epidermal growth factor or endogenous platelet-derived growth factor receptors caused a rapid (<3 min) translocation of the cytosolic fluorescence to ruffle-like membrane structures. This response was not observed in cells expressing GFP only and was completely inhibited by treatment with the PI 3-kinase inhibitors wortmannin and LY 292004. Membrane-targeted PI 3-kinase also caused membrane localization of BtkPH-GFP that was slowly reversed by wortmannin. When the R28C mutation of the Btk PH domain, which causes X-linked agammaglobulinemia, was introduced into the fluorescent construct, no translocation was observed after stimulation. In contrast, the E41K mutation, which confers transforming activity to native Btk, caused significant membrane localization of BtkPH-GFP with characteristics indicating its possible binding to PI(4,5)P2. This mutant, but not wild-type BtkPH-GFP, interfered with agonist-induced PI(4,5)P2 hydrolysis in COS-7 cells. These results show in intact cells that the PH domain of Btk binds selectively to 3-phosphorylated lipids after activation of PI 3-kinase enzymes and that losing such binding ability or specificity results in gross abnormalities in the function of the enzyme. Therefore, the interaction with PI(3,4,5)P3 is likely to be an important determinant of the physiological regulation of Btk and can be utilized to visualize the dynamics and spatiotemporal organization of changes in this phospholipid in living cells.
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PMID:Phosphatidylinositol 3-kinase-dependent membrane association of the Bruton's tyrosine kinase pleckstrin homology domain visualized in single living cells. 1019 79

Src family kinases (SFKs) have been implicated as important regulators of ligand-induced cellular responses including proliferation, survival, adhesion and migration. Analysis of SFK function has been impeded by extensive redundancy between family members. We have generated mouse embryos harboring functional null mutations of the ubiquitously expressed SFKs Src, Yes and Fyn. This triple mutation leads to severe developmental defects and lethality by E9.5. To elucidate the molecular mechanisms underlying this phenotype, SYF cells (deficient for Src, Yes and Fyn) were derived and tested for their ability to respond to growth factors or plating on extracellular matrix. Our studies reveal that while Src, Yes and Fyn are largely dispensable for platelet-derived growth factor (PDGF)-induced signaling, they are absolutely required to mediate specific functions regulated by extracellular matrix proteins. Fibronectin-induced tyrosine phosphorylation of focal adhesion proteins, including the focal adhesion kinase FAK, was nearly eliminated in the absence of Src, Yes and Fyn. Furthermore, consistent with previous reports demonstrating the importance of FAK for cell migration, SYF cells displayed reduced motility in vitro. These results demonstrate that SFK activity is essential during embryogenesis and suggest that defects observed in SYF triple mutant embryos may be linked to deficiencies in signaling by extracellular matrix-coupled receptors.
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PMID:Src family kinases are required for integrin but not PDGFR signal transduction. 1022 60

Pathological fibrogenesis in the liver is mediated by activated stellate cells. These cells have a myofibroblastic phenotype with the ability to proliferate and synthesize large quantities of extracellular matrix components. A number of factors have been proposed to initiate and perpetuate the fibrogenic process in stellate cells, including inflammatory cytokines, alterations in the extracellular matrix, growth factors, and oxidative stress. Some recent research has focused on the intracellular signaling pathways that are stimulated by these factors in stellate cells, including mitogen-activated protein kinases, phosphatidylinositol 3-kinase, focal adhesion kinase, and protein kinase C. This paper will summarize the experimental evidence that implicates these pathways in stellate cell activation, focusing on the effects of exposure to platelet-derived growth factor, tumor necrosis factor-alpha, and fibronectin. Implications for alcohol-induced hepatic fibrosis and future directions for research will also be discussed.
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PMID:Intracellular signaling pathways in stellate cell activation. 1037 15


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