Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated levels of fibronectin (Fn) in articular cartilage have been linked to the progression of both rheumatoid and osteoarthritis. In this study, we examined intracellular events which follow ligation of Fn to its receptor, the integrin alpha5beta1. In addition, we examined the regulatory influence of nitric oxide on these events, since this free radical has been implicated in cartilage degradation. Exposure of chondrocytes to Fn-coated beads resulted in the circumferential clustering of the alpha5beta1 integrin receptor, which was accompanied by the subplasmalemmal assembly of a focal activation complex comprised of F-actin, the tyrosine kinase, focal adhesion kinase (FAK), the ras related G protein rho A, as well as tyrosine-phosphorylated proteins. Treatment with exogenous nitric oxide (NO) or catabolic cytokines which induce nitric oxide synthase blocked the assembly of F-actin, FAK, rho A and tyrosine-phosphorylated proteins while not affecting the total number of beads bound per cell nor the clustering of alpha5beta1 integrin. Use of a cGMP antagonist (Rp-8-Br cGMPS) or cGMP agonist (Sp-cGMPS) either abolished or mimicked the NO effect, respectively. Adherence of chondrocytes to fibronectin enhanced proteoglycan synthesis by twofold (vs. albumin). In addition, basic fibroblast growth factor (FGF) and insulin growth factor (IGF-1) induced proteoglycan synthesis in chondrocytes adherent to Fn but not albumin suggesting a costimulatory signal transduced by alpha5betal and the FGF receptor. Both constitutive and FGF stimulated proteoglycan synthesis were completely inhibited by nitric oxide. These data indicate that the ligation of alpha5beta1 in the chondrocyte induced the intracellular assembly of an activation complex comprised of the cytoplasmic tail of alpha5beta1 integrin, actin, and the signaling molecules rho A and FAK. We show that NO inhibits the assembly of the intracellular activation complex and the synthesis of proteoglycans, but has no effect on the extracellular aggregation of alpha5beta1 integrin. These observations provide a basis by which nitric oxide can interfere with chondrocyte functions by affecting chondrocyte-matrix interactions.
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PMID:Outside-in signaling in the chondrocyte. Nitric oxide disrupts fibronectin-induced assembly of a subplasmalemmal actin/rho A/focal adhesion kinase signaling complex. 931 79

In previous studies, we have shown that smooth muscle cells and myofibroblast subpopulations of the perivascular stem villous sheath of the human placenta contain focal adhesion plaques and talin immunoreactivity. The close association of these cells to elastic and collagen fibres have led to the assumption of a functional myofibroelastic unit within the perivascular stem villous sheath. Interactions between the extracellular matrix and smooth muscle cells depend on a variety of structural protein assemblies. In the present study, we examined, by immunocytochemistry, whether the molecular assembly of extracellular matrix proteins and molecules of focal adhesions, known to be essential for signal transduction in smooth muscle cells, are also found in smooth muscle cells of the perivascular stem villous sheath of the human placenta. Vascular and extravascular smooth muscle cells were immunoreactive for alpha-actinin, vinculin, paxillin and tensin, the integrin chains alpha1 and beta1, and the basement membrane components laminin and heparan/-chondroitin sulfate proteoglycan perlecan. pp125(FAK) did not react. In the extracellular matrix of blood vessel walls and the perivascular stem villous sheath, we found immunoreactivity of fibronectin and collagen types I, VI and undulin (collagen type XIV). From our data we conclude that within the perivascular stem villous sheath, there exists a system of signal transduction molecules, indicating a cross talk between the smooth muscle cells of this sheath and their surrounding extracellular matrix.
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PMID:Molecular anatomy of the perivascular sheath in human placental stem villi: the contractile apparatus and its association to the extracellular matrix. 936 35

Components of osteoarthritis include increases in pericellular fibronectin and in chondrocyte beta1 integrin expression. Events which follow ligation of fibronectin to its chondrocyte-receptor, the integrin alpha5beta1 include an assembly of a subplasmalemmal actin/rho A/focal adhesion kinase signaling complex. In addition, nitric oxide (NO), a potential mediator of cartilage pathophysiology disrupts the cytoskeletal signaling complex associated with integrin signaling. In these studies, we examined the relationship among integrin signaling, biosynthesis of S-35 sulfate containing proteoglycans and release of YKL-40 (a secretory glycoprotein) by comparing cell responses using cells plated on a fibronectin-coated or polyHEME coated surfaces. We report that the release of proteoglycan and glycoprotein require anchorage dependent signals by integrin costimulation. NO which disrupts the integrin signaling complex attenuates both cell responses. Taken together NO may serve as a nonspecific 'brake' to prevent anabolic and catabolic injury responses.
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PMID:Nitric oxide alters chondrocyte function by disrupting cytoskeletal signaling complexes. 1041 79

Intact fibronectin (FN) protects cells from apoptosis. When FN is fragmented, specific domains induce proteinase expression in fibroblasts. However, it is not known whether specific domains of FN can also regulate apoptosis. We exposed fibroblasts to four recombinant FN fragments and then assayed for apoptosis using criteria of cellular shape change, condensed nuclear morphology, and DNA fragmentation. The fragments extended from the RGD-containing repeat III10 to III15; they included (V(+)) or excluded (V(-)) the alternatively spliced V region and contained either a mutated (H(-)) or an unmutated (H(+)) heparin binding domain. Only the V(+)H(-) fragment triggered decreases in pp125(FAK) levels and apoptosis, which was rescued by intact FN and inhibitors of caspase-1 and caspase-3. This apoptotic mechanism was mediated by a chondroitin sulfate proteoglycan, since treating cells with chondroitin sulfate or chondroitinase reversed the apoptotic cell shape changes. The alpha4 integrin receptor may also be involved, since using a blocking antibody to alpha4 alone induced apoptotic cell shape changes, whereas co-treatment with this antibody plus V(+)H(+) reversed these effects. These results demonstrate that the V and heparin binding domains of FN modulate pp125(FAK) levels and regulate apoptosis through a chondroitin sulfate proteoglycan- and possibly alpha4 integrin-mediated pathway, which triggers a caspase cascade.
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PMID:Mutations in the heparin binding domain of fibronectin in cooperation with the V region induce decreases in pp125(FAK) levels plus proteoglycan-mediated apoptosis via caspases. 1052 84

Transcription of specific skeletal muscle genes requires the expression of the muscle regulatory factor myogenin. To assess the role of the extracellular matrix (ECM) in skeletal muscle differentiation, the specific inhibitors of proteoglycan synthesis, sodium chlorate and beta-D-xyloside, were used. Treatment of cultured skeletal muscle cells with each inhibitor substantially abolished the expression of creatine kinase and alpha-dystroglycan. This inhibition was totally reversed by the addition of exogenous ECM. Myoblast treatment with each inhibitor affected the deposition and assembly of the ECM constituents glypican, fibronectin, and laminin. These treatments did not affect MyoD, MEF2A, and myogenin expression and nuclear localization. Differentiated myoblast treatment with RGDS peptides completely inhibited myogenesis without affecting the expression or nuclear localization of myogenin. Integrin-mediated signaling of focal adhesion kinase was partially inhibited by chlorate and beta-D-xyloside, an effect reversed by the addition of exogenous ECM gel. These results suggested that the expression of myogenin is not sufficient to successfully drive skeletal muscle formation and that ECM is required to complete the skeletal muscle differentiation process.
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PMID:ECM is required for skeletal muscle differentiation independently of muscle regulatory factor expression. 1178 50

Integrins are cell-surface glycoproteins that mediate cell activities, including tissue morphogenesis, development, immune response, and cancer, through interaction with extracellular proteins. Here we report a novel means by which integrin signaling and functions are regulated. In pull-down assays and immunoprecipitation, beta(1)-integrin bound to the C-terminal domain of PG-M/versican, an extracellular chondroitin sulfate proteoglycan. This was confirmed by cell-surface binding assays. Binding was calcium- and manganese-dependent. Upon native gel electrophoresis, beta(1)-integrin comigrated with the C-terminal domain of PG-M/versican. The interaction of beta(1)-integrin with the C-terminal domain of PG-M/versican activated focal adhesion kinase, enhanced integrin expression, and promoted cell adhesion. As a result, cells expressing the C-terminal domain of PG-M/versican were resistant to free radical-induced apoptosis. As the PG-M/versican peptide used in this study does not contain the RGD consensus-binding motif for integrins, the mechanism of the observed binding represents an entirely new function.
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PMID:beta 1-Integrin-mediated glioma cell adhesion and free radical-induced apoptosis are regulated by binding to a C-terminal domain of PG-M/versican. 1180 2

Ac-SYN is the core protein of a cell surface proteoglycan of the sea urchin Anthocidaris crassispina. To examine the functions of Ac-SYN, embryos were cultured in the presence of affinity-purified antibody against Ac-SYN. At the late pluteus stage, severe inhibition of elongation of the postoral arms was seen in treated embryos compared with control embryos. Blastocoeleic microinjection of the antibody did not affect morphogenesis. The relationship between the number of cells in the postoral arms and the length of the postoral rods was investigated in normal embryos. This showed that postoral arm elongation has two phases: the first phase accompanies the increase in cell numbers while the second does not. The syndecan antibody inhibited the increase in cell numbers in the postoral arms. Furthermore, in the treated embryos, cell numbers continued to increase normally until 31 h post fertilization (hpf), while cell division stopped after 31 hpf. These results suggest that Ac-SYN participates in postoral arm formation via cell division in sea urchin embryos.
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PMID:Role of syndecan in the elongation of postoral arms in sea urchin larvae. 1186 91

The human placenta is an invasive structure in which highly proliferative, migratory, and invasive extravillous trophoblast (EVT) cells migrate and invade the uterus and its vasculature. Using in vitro propagated normal first-trimester EVT cells and immortalized EVT cells, which share all of the phenotypic and functional characteristics of the normal EVT cells, it has been shown that migration/invasion of human EVT cells is stringently regulated by many growth factors, their binding proteins, extracellular matrix (ECM) components, and some adhesion molecules in an autocrine/paracrine manner at the fetal-maternal interface in human pregnancy. Transforming growth factor beta (TGF-beta), decorin (a proteoglycan in the ECM), and melanoma cell adhesion molecule (Mel-CAM) inhibit, and insulin-like growth factor II (IGF-II), IGF-binding protein 1 (IGFBP-1), and endothelin 1 (ET-1) stimulate EVT cell migration/invasion. Inhibition of EVT cell migration by TGF-beta has been suggested to be due to upregulation of integrins, which make the cells more adhesive to the ECM. Its antiinvasive action is due to an upregulation of tissue inhibitor of matrix metalloprotease 1 (TIMP-1) and plasminogen activator inhibitor (PAI-1) and a downregulation of urokinase-type plasminogen activator (uPA). Molecular mechanisms of inhibition of migration/invasion of EVT cells by decorin and Mel-CAM remain to be identified. IGF-II action has been shown to be mediated by IGF type I receptors (IGF-RII) independently of IGF type I receptors (IGF-RI) and IGFBPs. This action of IGF-II appears to involve inhibitory G proteins and phosphorylation of mitogen-activated protein kinase (MAPK) (extracellular signal-regulated protein kinases 1 and 2 (ERK-1 and ERK-2)). IGFBP-1 stimulation of EVT cell migration appears to occur by binding its Arg-Gly-Asp (RGD) domain to alpha5beta1 integrin, leading to phosphorylation of focal adhesion kinase (FAK) and MAPK (ERK-1 and ERK-2). These studies may improve our understanding of diseases related to abnormal placentation, viz. hypoinvasiveness in preeclampsia and hyperinvasiveness in trophoblastic neoplasms.
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PMID:Regulation of human trophoblast migration and invasiveness. 1193 54

Syndecan-4 is a ubiquitous transmembrane proteoglycan that localizes to the focal adhesions of adherent cells and binds to a range of extracellular ligands, including growth factors and extracellular-matrix proteins. Engagement of syndecan-4 is essential for adhesion formation in cells adhering via certain integrins, and for cell proliferation and migration in response to growth factors. The cytoplasmic domain of syndecan-4 interacts with a number of signalling and structural proteins, and both extracellular and cytoplasmic domains are necessary for regulated activation of associated transmembrane receptors. PDZ domain-containing scaffold proteins (syntenin and CASK) bind to the C-terminus of the syndecan-4 cytoplasmic domain and co-ordinate clustering of receptors and connection to the actin cytoskeleton. Syndecan-4 also binds and activates protein kinase Calpha in the presence of phosphatidylinositol 4,5-bisphosphate, and regulates signalling by Rho-family GTPases and focal adhesion kinase. This review discusses the cytoplasmic interactions of syndecan-4 and how they affect cell behaviour as a consequence of the interaction with extracellular ligands. These conclusions also offer an insight into the role of syndecan-4 in vivo, and are consistent with phenotypes generated as a consequence of abnormal syndecan-4 expression in pathologies and gene disruption studies.
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PMID:Cytoplasmic interactions of syndecan-4 orchestrate adhesion receptor and growth factor receptor signalling. 1224 28

Tenascin-C is an adhesion-modulatory extracellular matrix protein that is predominantly expressed during embryonic development, wound healing and in tumor stroma. Here we report that anchorage-dependent human, rat and mouse fibroblasts adhere poorly and fail to proliferate on pure tenascin-C. This was due to a significant reduction of cyclin-dependent kinase 2 (cdk2) activity, resulting from elevated expression and association of the cdk inhibitors (CKIs) p21Cip1 and p27Kip1. To analyse the effect of tenascin-C on fibronectin-mediated adhesion, cells were plated on a mixed fibronectin/tenascin-C substratum. Compared to fibronectin alone, cell spreading and adhesion signaling were compromised, as determined by delayed phosphorylation kinetics of focal adhesion kinase (FAK). Despite the presence of growth factors, these cells remained arrested in the G1 phase of the cell cycle. In contrast to cells plated on pure tenascin-C, cdk2 activity appeared to be inhibited independently of CKIs. Interestingly, overexpression of the transmembrane proteoglycan syndecan-4 restored cell spreading, adhesion signaling and DNA replication on the fibronectin/tenascin-C substratum. A similar rescue was observed using a recombinant peptide that spans the syndecan-4-binding site in fibronectin. This indicates that tenascin-C causes cell cycle arrest and cdk2 inactivation by interfering with fibronectin-syndecan-4 interactions. We therefore propose that syndecan-4 signaling plays a central role in the control of cellular proliferation of anchorage-dependent fibroblasts.
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PMID:Tenascin-C blocks cell-cycle progression of anchorage-dependent fibroblasts on fibronectin through inhibition of syndecan-4. 1281 65


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