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)

Secretion of growth hormone (GH) in adult male rats is characterized by high peak and undetectable trough levels, both of which are required for male-specific pattern of liver gene expression and GH-induced phosphorylation of STAT5. The present study suggests that regulation of GH receptor (GHR) levels in rat hepatoma cells by repeated GH stimulation determines GH responsiveness via the JAK2/STAT5 pathway. A short exposure to GH rapidly reduced GHR levels which resulted in an equal desensitization of the JAK2/STAT5 pathway. Recovery of GH-induced STAT5 phosphorylation correlated with the time-dependent recovery of GHR levels during incubation in the absence of GH. Acute GH also induced phosphorylation of ERK1/2 and Akt, and this induction was also inhibited by prior exposure to GH. However, unlike the JAK2/STAT5 pathway, the effect of GH to activate the MEK/ERK and phosphatidylinositol 3-kinase/Akt pathways did not recover following prolonged incubation in the absence of GH. Thus, GH administration desensitizes the JAK2/STAT5 pathway, possibly because of down-regulation of GHR, whereas an additional post-receptor mechanism is required for the prolonged refractoriness of the MEK/ERK and phosphatidylinositol 3-kinase/Akt pathways toward a second GH stimulation. Our study suggests that both receptor and post-receptor mechanisms are important in GH-induced homologous desensitization.
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PMID:Growth hormone-induced differential desensitization of STAT5, ERK, and Akt phosphorylation. 1216 50

The focal adhesion kinase (FAK) and epidermal growth factor receptor (EGFR) are protein-tyrosine kinases that are overexpressed and activated in human breast cancer. To determine the role of EGFR and FAK survival signaling in breast cancer, EGFR was stably overexpressed in BT474 breast cancer cells, and each signaling pathway was specifically targeted for inhibition. FAK and EGFR constitutively co-immunoprecipitated in EGFR-overexpressing BT474 cells. In low EGFR-expressing BT474-pcDNA3 vector control cells, inhibition of FAK by the FAK C-terminal domain caused detachment and apoptosis via pathways involving activation of caspase-3 and -8, cleavage of poly(ADP-ribose) polymerase, and caspase-3-dependent degradation of AKT. This apoptosis could be rescued by the dominant-negative Fas-associated death domain, indicating involvement of the death receptor pathway. EGFR overexpression did not inhibit detachment induced by the FAK C-terminal domain, but did suppress apoptosis, activating AKT and ERK1/2 survival pathways and inhibiting cleavage of FAK, caspase-3 and -8, and poly(ADP-ribose) polymerase. Furthermore, this protective effect of EGFR signaling was reversed by EGFR kinase inhibition with AG1478. In addition, inhibition of FAK and EGFR in another breast cancer cell line (BT20) endogenously overexpressing these kinases also induced apoptosis via the same mechanism as in the EGFR-overexpressing BT474 cells. The results of this study indicate that dual inhibition of FAK and EGFR signaling pathways can cooperatively enhance apoptosis in breast cancers.
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PMID:Dual inhibition of focal adhesion kinase and epidermal growth factor receptor pathways cooperatively induces death receptor-mediated apoptosis in human breast cancer cells. 1216 18

A role for alpha/beta interferon (IFN-alpha/beta) in the IFN-gamma antiviral response has long been suggested. Accordingly, possible roles for autocrine or double-stranded-RNA (dsRNA)-induced IFN-alpha/beta in the IFN-gamma response were investigated. Use was made of wild-type and a variety of mutant human fibrosarcoma cell lines, including mutant U5A cells, which lack a functional IFN-alpha/beta receptor and hence an IFN-alpha/beta response. IFN-gamma did not induce detectable levels of IFN-alpha/beta in any of the cell lines, nor was the IFN-gamma response per se dependent on autocrine IFN-alpha/beta. On the other hand, a number of responses to dsRNA [poly(I). poly(C)] and encephalomyocarditis virus were greatly enhanced by IFN-gamma pretreatment (priming) of wild-type cells or of mutant cells lacking an IFN-alpha/beta response; these include the primary induction of dsRNA-inducible mRNAs, including IFN-beta mRNA, and, to a lesser extent, the dsRNA-mediated activation of the p38 mitogen-activated protein (MAP) kinase(s). IFN-gamma priming of mRNA induction by dsRNA is dependent on JAK1 and shows biphasic kinetics, with an initial rapid (<30-min) response being followed by a more substantial effect on overnight incubation. The IFN-gamma-primed dsRNA responses appear to be subject to modulation through the p38, phosphatidylinositol 3-kinase, and ERK1/ERK2 MAP kinase pathways. It can be concluded that despite efficient priming of IFN-beta production, the IFN-alpha/beta pathways play no significant role in the primary IFN-gamma antiviral response in these cell-virus systems. The observed IFN-gamma priming of dsRNA responses, on the other hand, will likely play a significant role in combating virus infection in vivo.
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PMID:The antiviral response to gamma interferon. 1218 89

Neuronal cell membranes are particularly rich in gangliosides, which play important roles in brain physiology and pathology. Previously, we reported that gangliosides could act as microglial activators and are thus likely to participate in many neuronal diseases. In the present study we provide evidence that JAK-STAT inflammatory signaling mediates gangliosides-stimulated microglial activation. Both in rat primary microglia and murine BV2 microglial cells, gangliosides stimulated nuclear factor binding to GAS/ISRE elements, which are known to be STAT-binding sites. Consistent with this, gangliosides rapidly activated JAK1 and JAK2 and induced phosphorylation of STAT1 and STAT3. In addition, gangliosides increased transcription of the inflammation-associated genes inducible nitric-oxide synthase, ICAM-1, and MCP-1, which are reported to contain STAT-binding elements in their promoter regions. AG490, a JAK inhibitor, reduced induction of these genes, nuclear factor binding activity, and activation of STAT1 and -3 in gangliosides-treated microglia. AG490 also inhibited gangliosides-induced release of nitric oxide, an inflammation hallmark. Furthermore, AG490 markedly reduced activation of ERK1/2 MAPK, indicating that ERKs act downstream of JAK-STAT signaling during microglial activation. However, AG490 did not affect activation of p38 MAPK. We also report that the sialic acid residues present on gangliosides may be one of the essential components in activation of JAK-STAT signaling. The present study indicates that JAK-STAT signaling is an early event in gangliosides-induced brain inflammatory responses.
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PMID:JAK-STAT signaling mediates gangliosides-induced inflammatory responses in brain microglial cells. 1219 95

Phosphoinositide-3-kinase (PI3K) is a lipid kinase, which phosphorylates the D3 position of phosphoinositides, and is known to be activated by a host of protein tyrosine kinases. PI3K plays an important role in mitogenesis in several cell systems. However, whether parathyroid hormone (PTH) affects the activity and functional roles of PI3K in intestinal cells remain to be determined. The objective of this study was to identify and characterize the PI3K pathway, and its relation to other non-receptor tyrosine kinases in mediating PTH signal transduction in rat enterocytes. PTH dose- and time-dependently increased PI3K activity with a peak occurring at 2 min. The tyrosine kinase inhibitor genistein, c-Src inhibitor PP1 and two structurally different inhibitors of PI3K, LY294002 and wortmannin, suppressed PI3K activity dependent on PTH. Co-immunoprecipitation analysis showed a constitutive association between c-Src and PI3K, which was enhanced by PTH treatment, suggesting that the cytosolic tyrosine kinase forms an immunocomplex with PI3K probably via the N-SH2 domain of the p85alpha regulatory subunit. In response to PTH, tyrosine phosphorylation of p85alpha was enhanced, effect that was abolished by PP1, the inhibitor of c-Src kinase. PTH causes a rapid (0.5-5 min) phosphorylation of Akt/PKB, effect that was abrogated by PI3K inhibitors, indicating that in rat enterocytes, PI3K is an upstream mediator of Akt/PKB activation by PTH. We report here that PI3K is also required for PTH activation of the mitogen-activated protein kinases ERK1 and ERK2. Taken together, the present study demonstrate, for the first time, that PTH rapidly and transiently stimulates PI3K activity and its down effector Akt/PKB in rat enterocytes playing c-Src kinase a central role in PTH-dependent PI3K activation and that PI3K signaling pathway contributes to PTH-mediated MAPK activation.
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PMID:Involvement of PI3-kinase and its association with c-Src in PTH-stimulated rat enterocytes. 1221 Jul 43

Signaling events involving angiotensin IV (ANG IV)-mediated pulmonary artery endothelial cell (PAEC) proliferation were examined. ANG IV significantly increased upstream phosphatidylinositide (PI) 3-kinase (PI3K), PI-dependent kinase-1 (PDK-1), extracellular signal-related kinases (ERK1/2), and protein kinase B-alpha/Akt (PKB-alpha) activities, as well as downstream p70 ribosomal S6 kinase (p70S6K) activities and/or phosphorylation of these proteins. ANG IV also significantly increased 5-bromo-2'-deoxy-uridine incorporation into newly synthesized DNA in a concentration- and time-dependent manner. Pretreatment of cells with wortmannin and LY-294002, inhibitors of PI3K, or rapamycin, an inhibitor of the mammalian target of rapamycin kinase and p70S6K, diminished the ANG IV-mediated activation of PDK-1 and PKB-alpha as well as phosphorylation of p70S6K. Although an inhibitor of mitogen-activated protein kinase kinase, PD-98059, but not rapamycin, blocked ANG IV-induced phosphorylation of ERK1/2, both PD-98059 and rapamycin independently caused partial reduction in ANG IV-mediated cell proliferation. However, simultaneous treatment with PD-98059 and rapamycin resulted in total inhibition of ANG IV-induced cell proliferation. These results demonstrate that ANG IV-induced DNA synthesis is regulated in a coordinated fashion involving multiple signaling modules in PAEC.
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PMID:Activation of multiple signaling modules is critical in angiotensin IV-induced lung endothelial cell proliferation. 1222 47

Adhesive interactions of cells are critical to tissue integrity. We show that infection with Porphyromonas gingivalis, a major pathogen in the periodontal disease periodontitis, interferes with both cell-matrix and cell-cell adhesion in the oral keratinocyte cell line HOK-16. Thus, infected cells showed reduced adhesion to extracellular matrix, changes in morphology from spread to rounded, and impaired motility on purified matrices in Transwell migration assays and scratch assays. Western blot analysis of P. gingivalis-challenged HOK-16 cells revealed proteolysis of focal contact components (e.g., focal adhesion kinase), adherens junction proteins (e.g., catenins), and adhesion signaling molecules (e.g., the tyrosine kinase SRC). Proteolysis was selective, since important components of adherens junctions (E-cadherin) or signaling molecules (extracellular signal-regulated kinases ERK1/2) were not degraded. The virulence factors gingipains, cysteine proteinases expressed by P. gingivalis, are likely responsible for this proteolytic attack, since they directly digested specific proteins in pull-down experiments, and their proteolytic activity was blocked by the cysteine proteinase inhibitor N-alpha-p-tosyl-L-lysine chloromethyl ketone and also by a caspase inhibitor. Proteolysis was strain dependent, such that ATCC 33277 and 381 had high proteolytic potential, whereas W50 showed almost no proteolytic activity. These findings may help explain the formation of gingival pockets between cementum and periodontal epithelium, a hallmark of periodontitis. Furthermore, they illustrate a new pathogenetic paradigm of infection whereby bacteria may disrupt the integrity of epithelia.
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PMID:Discrete proteolysis of focal contact and adherens junction components in Porphyromonas gingivalis-infected oral keratinocytes: a strategy for cell adhesion and migration disabling. 1222 16

In this report we demonstrate that soluble peptides, elastin degradation products stimulate proliferation of arterial smooth muscle cells. We show that these effects are due to generation of intracellular signals transduced through the cell surface elastin receptor, which consists of peripheral 67-kDa elastin-binding protein (EBP) (spliced variant of beta-galactosidase), immobilized to the transmembrane sialidase and the protective protein. We found that elastin receptor-transduced signaling triggers activation of G proteins, opening of l-type calcium channels, and a sequential activation of tyrosine kinases: FAK, c-Src, platelet-derived growth factor-receptor kinase and then Ras-Raf-MEK1/2-ERK1/2 phosphorylation cascade. This, in turn, causes an increase in expression of cyclins and cyclin-dependent kinases, and a consequent increase in cellular proliferation. The EBP-transduced signals also induce tyrosine kinase-dependent phosphorylation of beta-tubulin, LC3, microtubule-associated protein 1, and alpha-actin and troponin-T, which could be linked to reorganization of cytoskeleton. We have also disclosed that induction of these signals can be abolished by anti-EBP antibody or by galactosugars, which cause shedding of EBP from the cell surface. Moreover, elastin-derived peptides did not induce proliferation of EBP-deficient cells derived from patients bearing a nonsense mutation of the beta-galactosidase gene or sialidase-deficient cells from patients with congenital sialidosis.
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PMID:Signaling pathways transduced through the elastin receptor facilitate proliferation of arterial smooth muscle cells. 1224 48

Cell proliferation, survival, and differentiation are carefully orchestrated processes during nephrogenesis that become aberrant during renal cyst formation. Signaling through focal adhesion kinase (FAK) impacts these processes, although its role during nephrogenesis requires further delineation. We previously demonstrated that phosphorylation of FAK and paxillin is not downregulated in cystic kidneys from B cell lymphoma/leukemia-2 (bcl-2) -/- mice. Here we examine whether FAK downstream signaling pathways are affected in these cystic kidneys. Cystic kidneys from bcl-2 -/- mice exhibited sustained phosphorylation of Src and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK, ERK1). However, similar levels of expression were noted for phosphorylated c-Jun NH(2)-terminal kinase, phosphatidylinositol-3-kinase, and its target protein kinase B/ATP-dependent tyrosine kinase in kidneys from postnatal day 20 bcl-2 +/+ and bcl-2 -/- mice. We also examined expression of the adapter protein Shc, implicated in growth and apoptosis. Expression of p66(Shc) decreases to low levels in postnatal kidneys, whereas p52/p46(Shc) was constitutively expressed during nephrogenesis. Shc expression was similar in normal and cystic kidneys. Therefore, sustained activation of MAPK/ERKs through the Src/FAK pathway may contribute to the hyperproliferation observed in cystic kidneys from bcl-2 -/- mice.
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PMID:Sustained activation of MAPK/ERKs signaling pathway in cystic kidneys from bcl-2 -/- mice. 1237 84

Insulin plays an important role in muscle cell survival and proliferation. However, there is no report showing the role of insulin in spreading of muscle cells. In the present report, we showed that insulin enhances muscle cell spreading concomitant with enhanced tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin. Moreover, insulin can stimulate the cell spreading even in presence of integrin alpha5 blockers although to a lesser extent as compared to control. Cell adhesion was not dependent on insulin and serum, and decreased in presence of integrin blockers. We found direct association of FAK with affinity purified insulin receptors using in vitro kinase assay. The increase in FAK tyrosine phosphorylation was associated with increase in its kinase activity and further supported by increased phosphotyrosine accumulation on focal adhesions and increased membrane localization of FAK after stimulation by insulin. Moreover, insulin-mediated muscle cell spreading was dependent upon phosphatidylinositol 3-kinase (PI 3-kinase) activity. PI 3-kinase activity was found to be associated with FAK and the FAK associated PI 3-kinase activity enhanced when cells were plated in presence of insulin. We also observed activation of MAP kinases, i.e., ERK-1/-2 during insulin mediated muscle cell spreading. In conclusion, FAK, PI 3-kinase, and MAP kinase are important components of pathway(s) that regulate insulin stimulated muscle cell spreading.
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PMID:Insulin stimulates spreading of skeletal muscle cells involving the activation of focal adhesion kinase, phosphatidylinositol 3-kinase and extracellular signal regulated kinases. 1238 96


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