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)

pp125FAK, a protein tyrosine kinase (PTK) co-localized with integrins in focal adhesion plaques, is known to transduce signals involved in the regulation of cell adhesion and motility as well as the anchorage-independent growth of transformed cells. We investigated whether pp125FAK could be part of a signalling pathway that contributes to the progression of human prostate carcinoma (PCa). Up-regulation of pp125FAK expression, its activation by phosphorylation on tyrosine and its association with paxillin and p50csk were preferentially observed in PCa tissues from patients with metastases, whereas normal and hyperplastic prostates and localized PCa tissues showed undetectable or low levels of both FAK mRNA and protein and an absence of pp125FAK signalling complexes. The increase in expression and activation of pp125FAK in metastatic PCa tissues was also corroborated by our findings in human PCa cell lines. Indeed, higher levels of pp125FAK and FAK mRNA were observed in highly tumorigenic PC-3 cells as was the presence of activated pp125FAK, as opposed to an inactive form in LNCaP cells, which have a lower tumorigenic ability. In addition, pp125FAK formed signalling complexes with both paxillin and p50csk in PC-3 cells as in metastatic PCa tissues. Together, our results show that an increase in FAK mRNA and protein, as well as pp125FAK activation and association with signalling proteins, correlates with progression and invasion in human PCa tissues and cells.
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PMID:Focal adhesion kinase (pp125FAK) expression, activation and association with paxillin and p50CSK in human metastatic prostate carcinoma. 890 Apr 22

Insulin signaling results in rapid changes to the cell cytoskeleton, and it has recently been shown that insulin stimulates the dephosphorylation of the cytoskeletal-associated tyrosine kinase, focal adhesion kinase (pp125(FAK)). We report here that mutation of two tryptic cleavage sites (Lys164 and Lys582 --> Asn; 2N) in the insulin receptor alpha-subunit results in a cell-line (CHO.2N-10) with altered morphology associated with an increase in cell size, a decrease in cell adhesiveness, and a decrease in pp125(FAK) tyrosine phosphorylation in the absence of insulin (45.2 +/- 9.7% compared to nontransfected Chinese hamster ovary (CHO) cells). In contrast to pp125(FAK), paxillin phosphorylation was similar in all cell lines despite lower levels (61.0 +/- 10.4% compared to CHO cells) of paxillin protein in CHO.2N-10 cells. We observed comparable protein levels of pp125(FAK) and the structural focal adhesion protein, vinculin, in all cell lines. Despite underphosphorylation of pp125(FAK) in the basal state, insulin stimulation of CHO.2N-10 cells still resulted in dephosphorylation of pp125(FAK). CHO.2N-10 and CHO.T (overexpress wild-type insulin receptor) cells have similar insulin binding characteristics, insulin-stimulated autokinase and peptide phosphorylation, and insulin-stimulated pp185/IRS-1 phosphorylation. Our results suggest that the insulin receptor may play an important role in cell-matrix interactions, such as modulating cell adhesion and inducing cell architecture changes.
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PMID:Reduced cell attachment and phosphorylation of focal adhesion kinase associated with expression of a mutant insulin receptor. 891 May 46

Paxillin is a 68-kD focal adhesion phosphoprotein that interacts with several proteins including members of the src family of tyrosine kinases, the transforming protein v-crk, and the cytoskeletal proteins vinculin and the tyrosine kinase, focal adhesion kinase (FAK). This suggests a function for paxillin as a molecular adaptor, responsible for the recruitment of structural and signaling molecules to focal adhesions. The current study defines the vinculin- and FAK-interaction domains on paxillin and identifies the principal paxillin focal adhesion targeting motif. Using truncation and deletion mutagenesis, we have localized the vinculin-binding site on paxillin to a contiguous stretch of 21 amino acids spanning residues 143-164. In contrast, maximal binding of FAK to paxillin requires, in addition to the region of paxillin spanning amino acids 143-164, a carboxyl-terminal domain encompassing residues 265-313. These data demonstrate the presence of a single binding site for vinculin, and at least two binding sites for FAK that are separated by an intervening stretch of 100 amino acids. Vinculin- and FAK-binding activities within amino acids 143-164 were separable since mutation of amino acid 151 from a negatively charged glutamic acid to the uncharged polar residue glutamine (E151Q) reduced binding of vinculin to paxillin by >90%, with no reduction in the binding capacity for FAK. The requirement for focal adhesion targeting of the vinculin- and FAK-binding regions within paxillin was determined by transfection into CHO.K1 fibroblasts. Significantly and surprisingly, paxillin constructs containing both deletion and point mutations that abrogate binding of FAK and/or vinculin were found to target effectively to focal adhesions. Additionally, expression of the amino-terminal 313 amino acids of paxillin containing intact vinculin- and FAK-binding domains failed to target to focal adhesions. This indicated other regions of paxillin were functioning as focal adhesion localization motifs. The carboxyl-terminal half of paxillin (amino acids 313-559) contains four contiguous double zinc finger LIM domains. Transfection analyses of sequential carboxyl-terminal truncations of the four individual LIM motifs and site-directed mutagenesis of LIM domains 1, 2, and 3, as well as deletion mutagenesis, revealed that the principal mechanism of targeting paxillin to focal adhesions is through LIM3. These data demonstrate that paxillin localizes to focal adhesions independent of interactions with vinculin and/or FAK, and represents the first definitive demonstration of LIM domains functioning as a primary determinant of protein subcellular localization to focal adhesions.
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PMID:Identification of LIM3 as the principal determinant of paxillin focal adhesion localization and characterization of a novel motif on paxillin directing vinculin and focal adhesion kinase binding. 892 90

To investigate the in vivo role of hepatocyte growth factor/scatter factor (HGF/SF) in liver function, we generated transgenic mice using a mouse HGF/SF cDNA under the control of the mouse metallothionein gene promoter and 5'/3' flanking sequences. In adult HGF/SF transgenic mice, liver weight as a percentage of total body weight was at least twice that of wild-type mice. Comparison of transgenic and control liver morphology revealed dramatic heterogeneity in the size and appearance of hepatocytes as a distinctive feature of HGF/SF overexpression. Transgenic livers exhibited a significant increase in the number of small hepatocytes with a 2N DNA content, accounting for the observed increase in liver mass. The DNA labeling index of hepatocytes increased 11-fold at 4 weeks of age, when liver enlargement first became apparent, and was still elevated about 5-fold in adult HGF/SF transgenic mice. Moreover, hepatocytes isolated by perfusion of transgenic livers doubled every 2 days in culture, whereas little or no growth was observed with isolated control hepatocytes. The mechanistic basis of hepatocyte proliferation was elucidated as the chronic activation of the c-met proto-oncogene product. Met and substrates such as phosphatidylinositol 3-kinase, Src homology and collagen-like, pp60c-src, focal adhesion kinase p125FAK, and paxillin were associated with tyrosine-phosphorylated complexes in a hepatocyte cell line established from the transgenic liver. This proliferative stimulus triggered the formation of hepatocellular adenomas and/or carcinomas in most transgenic mice > or = 1.5 years of age. Finally, the rate of transgenic mouse liver regeneration was increased 3-fold over control livers following partial hepatectomy.
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PMID:Hepatocyte growth factor/scatter factor overexpression induces growth, abnormal development, and tumor formation in transgenic mouse livers. 893 Apr 1

Related adhesion focal tyrosine kinase (RAFTK), also known as proline-rich tyrosine kinase 2 and cellular adhesion kinase beta, has been recently cloned and characterized as a member of the focal adhesion kinase (FAK) subfamily. RAFTK has an overall 48% amino acid homology to p125(FAK) and contains a kinase domain but lacks a transmembrane region, myristylation sites, and Src homology region 2 and 3 domains. By Northern blot analysis, RAFTK is expressed in myeloid, lymphoid, and megakaryocytic hematopoietic cells. Like p125(FAK), we found that RAFTK interacts with the focal adhesion protein paxillin. In the lymphoid cell line BaF3 and the myeloid cell line 32Dcl3, RAFTK coprecipitates with paxillin. Using in vitro binding assays, RAFTK and paxillin were shown to bind directly, through a segment of paxillin that required amino acids 100-227 and a domain in the C terminus of RAFTK. In vitro, RAFTK could phosphorylate paxillin on tyrosine residues. These results suggest that RAFTK, as well as p125(FAK), may be important in phosphotyrosine-signaling events within the focal adhesion.
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PMID:The related adhesion focal tyrosine kinase forms a complex with paxillin in hematopoietic cells. 894 Jan 24

During capillary formation, endothelial cell migration and organization are critically dependent on surrounding basement membrane proteins. These proteins serve as a physical support and are likely to provide signals which regulate migration and organization of the cells. In this study the possible involvement of tyrosine kinase signalling pathways in basement membrane-induced organization of human endothelial cells is examined. Interaction of endothelial cells with reconstituted basement membrane Matrigel activates tyrosine phosphorylation of several proteins including focal adhesion kinase. Inhibition of this pathway with tyrosine kinase inhibitors impairs localization of paxillin to focal adhesions and organization of actin filaments, decreases motility and elongation of endothelial cells, and prevents their organization into cords or tubes on basement membrane. These data demonstrate that basement membrane-induced modulation of endothelial cell motility, shape, and organization is critically dependent on tyrosine kinase signalling pathway(s) involving cytoskeletal proteins.
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PMID:Involvement of protein tyrosine kinases in regulation of endothelial cell organization by basement membrane proteins. 895 7

Short cytoplasmic domains of integrin heterodimers are crucial for transduction of signals generated by adhesion of cells to the extracellular matrix. Here, we describe the use of peptides mimicking the intracellular tails of integrin alpha5beta1 to assay in vitro associations with cytoskeletal proteins. Our results suggest that the focal adhesion protein, paxillin, may interact directly with the intracellular region of the integrin beta1 subunit. Paxillin is known to form stable complexes with several signaling molecules, including focal adhesion kinase. Physical interaction between paxillin and the beta1 cytoplasmic domain suggests a model in which paxillin may function as a key intermediary in integrin-mediated signal transduction.
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PMID:Paxillin association in vitro with integrin cytoplasmic domain peptides. 898 Jan 18

Lymphocyte binding to endothelial surface adhesion molecules is an important early step in inflammation, which is mediated initially by P-selectin and E-selectin. We tested the hypothesis that lymphocyte binding to the selectin adhesion molecules induces intracellular signaling by tyrosine phosphorylation. We used an adhesion assay, which relied on cell binding to chimeric proteins consisting of the extracellular domains for P-selectin and E-selectin. Tyrosine phosphorylation was determined using anti-phosphotyrosine Abs by confocal microscopy and Western blot. Binding to P-selectin induced a significant increase in anti-phosphotyrosine immunoreactivity. The P-selectin effect was time dependent with an early response after 10 min and a maximum effect at 30 min. Western blot showed a time-dependent phosphorylation of two distinct 68- and 125-kDa proteins. These proteins were pp125 focal adhesion kinase (FAK) and paxillin, as shown by immunoprecipitation and colocalization. Phosphorylation of pp125 FAK was time dependent reaching a maximum after 30 min. Incubation with the tyrosine kinase inhibitor genistein, and, to a lesser extent, with the protein kinase C inhibitor staurosporine, resulted in decreased pp125 FAK phosphorylation. Our results are the first to demonstrate that lymphocyte binding to P-selectin induces tyrosine phosphorylation of distinct proteins. Thus, lymphocyte activation may occur already at the initial contact with surface adhesion molecules.
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PMID:T cell adhesion to P-selectin induces tyrosine phosphorylation of pp125 focal adhesion kinase and other substrates. 901 43

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

Integrins are important receptors for neuronal adhesion to laminin, which is one of the best promoters of neurite outgrowth. The present study was carried out to understand some of the intracellular mechanisms which allow integrin-mediated neurite extension on laminin. In chicken retinal neurons, integrin-mediated adhesion to laminin and antibody-induced integrin clustering caused an increase in tyrosine phosphorylation of paxillin and focal adhesion kinase. The kinetics of phosphorylation and dephosphorylation of these proteins were different in neurons plated on laminin, compared to neurons in which the receptors were clustered with anti-integrin antibodies. Analysis of sucrose velocity gradients could not show any association of paxillin and focal adhesion kinase with the integrin receptors. On the other hand, by using digitonin and milder extraction conditions, we found an enrichment of the tyrosine-phosphorylated polypeptides in the cytoskeletal, digitonin-insoluble fraction. Furthermore, neuronal adhesion induced a dramatic increase in the fraction of tyrosine-phosphorylated paxillin recovered with the digitonin-insoluble fraction, suggesting redistribution of this protein following adhesion of neurons to laminin. Localization studies on the detergent-insoluble fraction showed codistribution of both paxillin and focal adhesion kinase with integrins. We also found that paxillin tyrosine phosphorylation, but not paxillin expression, is developmentally regulated in the retina. Our results show that integrin-mediated neuronal adhesion leads to the accumulation of a pool of highly phosphorylated proteins at adhesion sites. There they may be responsible for the reorganization of the cytoskeleton, which underlies the process of neurite extension.
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PMID:Integrin-mediated tyrosine phosphorylation and redistribution of paxillin during neuronal adhesion. 902 82


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