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)

Integrins from normal human renal cortex epithelial cells (RCEC) and from four renal carcinoma lines (metastatic Caki-1, non-metastatic Caki-2, metastatic ACHN, and non-metastatic 769-P) were compared by immunoprecipitation with specific anti-integrin antibodies. Integrin alpha 2 was present in normal RCEC, but absent in all four tumor lines. There was a 2.0-3.0 fold decrease of alpha 3 and beta 1 in localized tumor lines, and a further 5.0-7.0 fold decrease in metastatic lines over their expression in normal renal cells. No alpha V was detected in Caki-1 cells. The greatest adhesion of all cells occurred in the presence of a stimulatory anti-alpha 3 antibody, mediated by specific matrix proteins employed as substrates, while anti-beta 1 treatment dramatically inhibited cell attachment on collagen IV, plasma fibronectin, laminin and merosin substrates. In addition, the mRNA expression of focal adhesion kinase (p125FAK) and paxillin were up-regulated (2.0-2.5 fold increase) in the metastatic Caki-1 cells over normal RCEC. The alteration of integrin subunits alpha 2, alpha 3, alpha V, beta 1, as well as p125FAK and paxillin may contribute to the pathogenicity and/or metastatic propensity of renal epithelial tumors. The up-regulation of paxillin independently or in concert with p125FAK as shown in this study indicates its significant role as a potential marker of metastasis in renal carcinoma cells.
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PMID:Integrin expression on cell adhesion function and up-regulation of P125FAK and paxillin in metastatic renal carcinoma cells. 902 46

The focal adhesion kinase (FAK), a protein-tyrosine kinase (PTK), associates with integrin receptors and is activated by cell binding to extracellular matrix proteins, such as fibronectin (FN). FAK autophosphorylation at Tyr-397 promotes Src homology 2 (SH2) domain binding of Src family PTKs, and c-Src phosphorylation of FAK at Tyr-925 creates an SH2 binding site for the Grb2 SH2-SH3 adaptor protein. FN-stimulated Grb2 binding to FAK may facilitate intracellular signaling to targets such as ERK2-mitogen-activated protein kinase. We examined FN-stimulated signaling to ERK2 and found that ERK2 activation was reduced 10-fold in Src- fibroblasts, compared to that of Src- fibroblasts stably reexpressing wild-type c-Src. FN-stimulated FAK phosphotyrosine (P.Tyr) and Grb2 binding to FAK were reduced, whereas the tyrosine phosphorylation of another signaling protein, p130cas, was not detected in the Src- cells. Stable expression of residues 1 to 298 of Src (Src 1-298, which encompass the SH3 and SH2 domains of c-Src) in the Src- cells blocked Grb2 binding to FAK; but surprisingly, Src 1-298 expression also resulted in elevated p130cas P.Tyr levels and a two- to threefold increase in FN-stimulated ERK2 activity compared to levels in Src- cells. Src 1-298 bound to both FAK and p130cas and promoted FAK association with p130cas in vivo. FAK was observed to phosphorylate p130cas in vitro and could thus phosphorylate p130cas upon FN stimulation of the Src 1-298-expressing cells. FAK-induced phosphorylation of p130cas in the Src 1-298 cells promoted the SH2 domain-dependent binding of the Nck adaptor protein to p130cas, which may facilitate signaling to ERK2. These results show that there are additional FN-stimulated pathways to ERK2 that do not involve Grb2 binding to FAK.
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PMID:Fibronectin-stimulated signaling from a focal adhesion kinase-c-Src complex: involvement of the Grb2, p130cas, and Nck adaptor proteins. 903 97

Apoptosis is an important process maintaining cell number and tissue structure. To determine whether cell-extracellular matrix (ECM) and cell-cell interactions modulate apoptosis in bronchial epithelium, we cultured human bronchial epithelial cells in different conditions and evaluated the cells for apoptosis. We found that plating cells in conditions that prevent cell-ECM adhesion induced apoptosis. Plating cells on type I collagen, fibronectin, and biosynthesized matrix prevented apoptosis, due at least in part to integrin-mediated adhesion. When cells were cultured at high density but under conditions preventing cell-substratum adhesion, aggregation occurred. Apoptosis was inversely correlated with aggregation. Cell-cell adhesion in these conditions was mediated at least partly by integrins containing alpha v. Cell aggregation was not associated with activation of a signaling pathway that is usually activated by cell-ECM adhesion, phosphorylation of focal adhesion kinase, but was associated with Bcl-2 protein expression, consistent with the concept that Bcl-2 protects against apoptosis. We conclude that both cell-ECM and cell-cell interactions, likely mediated in part by integrins, modulate apoptosis in bronchial epithelium.
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PMID:Cell-matrix and cell-cell interactions modulate apoptosis of bronchial epithelial cells. 903 99

The ninth and tenth type III domains of fibronectin each contain specific cell binding sequences, RGD in FIII10 and PHSRN in FIII9, that act synergistically in mediating cell adhesion. We investigated the relationship between domain-domain orientation and synergistic adhesive activity of the FIII9 and FIII10 pair of domains. The interdomain interaction of the FIII9-10 pair was perturbed by introduction of short flexible linkers between the FIII9 and FIII10 domains. Incremental extensions of the interdomain link between FIII9 and FIII10 reduced the initial cell attachment, but had a much more pronounced effect on the downstream cell adhesion events of spreading and phosphorylation of focal adhesion kinase. The extent of disruption of cell adhesion depended upon the length of the interdomain linker. Nuclear magnetic resonance spectroscopy of the wild type and mutant FIII9-10 proteins demonstrated that the structure of the RGD-containing loop is unaffected by domain-domain interactions. We conclude that integrin-mediated cell adhesion to the central cell binding domain of fibronectin depends not only upon specific interaction sites, but also on the relative orientation of these sites. These data have implications for the molecular mechanisms by which integrin-ligand interactions are achieved.
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PMID:Structural requirements for biological activity of the ninth and tenth FIII domains of human fibronectin. 904 28

We investigated the role of integrin-fibronectin (FN) interactions in tumor cell adhesion. Two cloned tumor cell lines designated OV-LM (low-metastatic) and OV-HM (high-metastatic) were isolated from a murine ovarian carcinoma, OV2944. OV-LM and OV-HM cells exhibited high and low RGDS-sequence-dependent adhesiveness to FN, respectively. Both lines expressed comparable levels of alpha5 and alpha v integrins, which are capable of reacting with RGDS on FN. To compare the functions of these integrins between the two tumor lines, the signaling mechanism following FN stimulation was examined. Significant levels of phosphorylation of focal adhesion kinase (FAK) were detected in both OV-LM and OV-HM cells before FN stimulation. Whereas the level of FAK phosphorylation was appreciably enhanced in OV-LM cells stimulated with FN, stimulation of OV-HM cells with FN induced a reduction in the FAK phosphorylation in association with a significant decrease in the amount of FAK protein in the soluble compartment of cell lysates. A difference in the deposition of FN on the cell surface was also observed between the two types of tumor lines; OV-HM cells had an appreciably smaller amount of FN than OV-LM. Consistent with the functional abnormality of the integrin-FAK system and the smaller amount of FN on OV-HM, this clone exhibited a reduced cell-cell adhesion in the in vitro cell aggregation assay. Namely, OV-LM cells displayed a time-dependent increase in the formation of cell aggregates, whereas most OV-HM cells remained single. The formation of aggregates by OV-LM cells was inhibited by addition of RGDS peptide. These results indicate that the highly metastatic clone, OV-HM, exhibits a decreased capacity of cell-cell adhesion mediated by integrin-FN interactions and suggest that this defect is mainly due to the dysfunction of integrins/FAK rather than a decrease in the amount of integrins expressed on tumor cells.
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PMID:A defect in cell-to-cell adhesion via integrin-fibronectin interactions in a highly metastatic tumor cell line. 904 98

Cyclic strain has been shown to modulate endothelial cell (EC) morphology, proliferation, and function. We have recently reported that the focal adhesion proteins focal adhesion kinase (pp125FAK) and paxillin, are tyrosine phosphorylated in EC exposed to strain and these events regulate the morphological change and migration induced by cyclic strain. Integrins are also localized on focal adhesion sites and have been reported to induce by tyrosine phosphorylation of pp125FAK under a variety of stimuli. To study the involvement of different integrins in signaling induced by cyclic strain, we first observed the redistribution of alpha and beta integrins in EC subjects to 4 h cyclic strain. Human umbilical vein endothelial cells (HUVEC) seeded on either fibronectin or collagen surfaces were subjected to 10% average strain at a frequency 60 cycles/min. Confocal microscopy revealed that beta 1 integrin reorganized in a linear pattern parallel with the long axis of the elongated cells creating a fusion of focal adhesion plaques in EC plated on either fibronectin (a ligand for alpha 5 beta 1) or collagen (a ligand for alpha 2 beta 1) coated after 4 h exposure to cyclic strain. beta 3 integrin, which is a vitronectin receptor, did not redistribute in EC exposed to cyclic strain. Cyclic strain also led to a reorganization of alpha 5 and alpha 2 integrins in a linear pattern in HUVEC seeded on fibronectin or collagen, respectively. The expression of integrins alpha 5, alpha 2, and beta 1 did not change even after 24 h exposure to strain when assessed by immunoprecipitation of these integrins. Cyclic strain-induced tyrosine phosphorylation of pp125FAK occurred concomitant with the reorganization of beta 1 integrin. We concluded that alpha 5 beta 1 and alpha 2 beta 1 integrins play an important role in transducing mechanical stimuli into intracellular signals.
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PMID:Cyclic strain induces reorganization of integrin alpha 5 beta 1 and alpha 2 beta 1 in human umbilical vein endothelial cells. 905 8

Morphogenetic processes during development, including cell migration, depend on signals from both the extracellular matrix (ECM) and soluble signaling factors. Extensive evidence has shown that the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), is activated in response to both kind of signal. The most definitive evidence that FAK is directly downstream of signals initiated by the ECM comes from comparing the phenotypes of mice deficient for FAK and the ECM molecule, fibronectin: in both cases embryos die at about E8.5 and display almost identical severe vascular and other mesodermal defects. It is now clear that there are additional FAK-like proteins, indicating the existence of a FAK family. Furthermore, FAK is not located at adhesive sites in all cells where it is expressed. This, plus extensive data indicating that FAK becomes activated in response to several soluble signaling factors, suggests that the FAK family may be at the crossroads of multiple signaling pathways that affect cell and developmental processes.
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PMID:Focal adhesion kinase: at the crossroads of signal transduction. 906 92

Integrin-mediated cell adhesion causes activation of MAP kinases and increased tyrosine phosphorylation of focal adhesion kinase (FAK). Autophosphorylation of FAK leads to the binding of SH2-domain proteins including Src-family kinases and the Grb2-Sos complex. Since Grb2-Sos is a key regulator of the Ras signal transduction pathway, one plausible hypothesis has been that integrin-mediated tyrosine phosphorylation of FAK leads to activation of the Ras cascade and ultimately to mitogen activated protein (MAP) kinase activation. Thus, in this scenario FAK would serve as an upstream regulator of MAP kinase activity. However, in this report we present several lines of evidence showing that integrin-mediated MAP kinase activity in fibroblasts is independent of FAK. First, a beta1 integrin subunit deletion mutant affecting the putative FAK binding site supports activation of MAP kinase in adhering fibroblasts but not tyrosine phosphorylation of FAK. Second, fibroblast adhesion to bacterially expressed fragments of fibronectin demonstrates that robust activation of MAP kinase can precede tyrosine phosphorylation of FAK. Finally, we have used FRNK, the noncatalytic COOH-terminal domain of FAK, as a dominant negative inhibitor of FAK autophosphorylation and of tyrosine phosphorylation of focal contacts. Using retroviral infection, we demonstrate that levels of FRNK expression sufficient to completely block FAK tyrosine phosphorylation were without effect on integrin-mediated activation of MAP kinase. These results strongly suggest that integrin-mediated activation of MAP kinase is independent of FAK and indicate the probable existence of at least two distinct integrin signaling pathways in fibroblasts.
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PMID:Integrin-mediated activation of MAP kinase is independent of FAK: evidence for dual integrin signaling pathways in fibroblasts. 908 51

Adhesion molecules include ligands and receptors. Together they provide cells with anchorage and traction for migration, and the receptors also mediate signals that control cell polarity, survival, growth, differentiation and gene expression. Integrins are a major group of versatile adhesion receptors that serve both adhesive and signaling functions. They possess shared and unique specifics both outside and inside the cell. Many of the integrins share an affinity toward the RGD recognition sequence in their extracellular matrix ligands, but are still capable of distinguishing different RGD-containing proteins. The shared signaling pathways are likely to include changes in intracellular Ca2+ and PIP2 concentrations, and the activation of protein kinase C and focal adhesion kinase. Examples of integrin-specific signaling include that the alpha v beta 3 integrin (vitronectin receptor) can potentiate the effects of insulin and certain other growth factors and that the alpha 5 beta 1 integrin (fibronectin receptor) supports cell survival in serum-free cultures by up-regulating the anti-apoptosis protein Bcl-2. Another integrin function is that some integrins, in particular alpha 5 beta 1, are necessary for fibronectin matrix formation. Overexpression of alpha 5 beta 1, which results in the assembly of additional fibronectin matrix, reduces tumorigenicity of cultured tumor cells. Systemic treatment of tumor-bearing mice with an artificially generated fibronectin matrix suppresses metastasis. These and other findings indicate that the ligand binding and signaling functions of integrins offer targets for new therapeutic approaches.
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PMID:Integrins as signaling molecules and targets for tumor therapy. 915 Apr 52

Focal adhesion kinase (pp125(FAK)) is a protein tyrosine kinase that is localized to focal adhesions in many cell types and which undergoes tyrosine phosphorylation after integrin binding to extracellular matrix. In some cells the C-terminal non-catalytic domain of pp125(FAK) is expressed as a separate protein referred to as FRNK (FAK-related, non-kinase). We have previously shown that overexpression of FRNK inhibits tyrosine phosphorylation of pp125(FAK) and its substrates as well as inhibiting cell spreading on fibronectin. In this report we identify Ser148 and Ser151 as residues in FRNK that are phosphorylated after tyrosine phosphorylation of pp125(FAK) and in response to integrin binding to fibronectin. Tyrosine phosphorylation of pp125(FAK) appears to be an early event after integrin occupancy, and serine phosphorylation of FRNK occurs significantly later. Treatment of fibroblasts with a series of protein kinase A inhibitors delayed serine phosphorylation of FRNK as well as cell spreading on fibronectin and tyrosine phosphorylation of pp125(FAK). However, these PKA inhibitors are unlikely to delay cell spreading simply by preventing serine phosphorylation of FRNK, as overexpression of FRNK containing mutations of Ser148 and Ser151 either singly or jointly to either alanine or glutamate residues did not significantly alter the ability of FRNK to act as an inhibitor of pp125(FAK).
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PMID:Identification of integrin-stimulated sites of serine phosphorylation in FRNK, the separately expressed C-terminal domain of focal adhesion kinase: a potential role for protein kinase A. 916 50


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