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 provide evidence for both matrix-dependent and pp60v-src tyrosine kinase-dependent modulation of cell migration via tyrosine phosphorylation of pp125FAK, a focal adhesion kinase, thought to be involved in integrin-mediated signaling. Enhanced pp125FAK tyrosine phosphorylation and cell spreading was associated with decreased migration. Cells plated on type I collagen were less spread and exhibited lower levels of pp125FAK tyrosine phosphorylation and faster migration rates compared with cells on fibronectin that were well spread, which exhibited enhanced levels of pp125FAK tyrosine phosphorylation and slower migration rates. Inside-out signaling via expression of pp60v-src or its kinase-negative mutant caused a decrease in cell migration by changing the extent of pp125FAK tyrosine phosphorylation to above or below the levels obtained with control cells plated on fibronectin. Hence, pp125FAK tyrosine phosphorylation appears to play a role in the signaling cascade pathway involved in regulation of extracellular matrix-modulated, integrin-mediated cell migration.
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PMID:Modulation of cell spreading and migration by pp125FAK phosphorylation. 767 74

Dystrophin and alpha- and gamma-sarcoglycans were newly expressed in BC3H1 cells during differentiation induced by serum withdrawal. These proteins formed a tight complex with other dystophin-associated proteins (DAPs), as detected by immunoprecipitation with anti-dystrophin antibody. Integrins beta 1 and beta 3, vinculin, and focal adhesion kinase were also detected in the same immunoprecipitate. In a cell adhesion assay, differentiated BC3H1 cells attached more efficiently to type I collagen-coated dishes than nondifferentiated cells and loss of alpha-sarcoglycan induced by antisense ODN in differentiated cells resulted in significant inhibition of cell adhesion. Thus dystrophin and DAPs, at least partly, form a complex with the focal adhesion proteins in differentiated BC3H1 cells and alpha-sarcoglycan seems to modulate the function of the focal adhesion complex in these cells.
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PMID:Expression of a dystrophin-sarcoglycan complex in serum-deprived BC3H1 cells and involvement of alpha-sarcoglycan in substrate attachment. 876 87

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

Interaction of type I collagen (COL(I)) with alpha2beta1 integrin causes differentiation and transforming growth factor (TGF)-beta receptor down-regulation in osteoblastic cells (Takeuchi, Y., Nakayama, K., and Matsumoto, T. (1996) J. Biol. Chem. 271, 3938-3644). The TGF-beta receptor down-regulation enables cells to escape from the inhibition of differentiation by TGF-beta. To clarify how the cell-matrix interaction regulates these phenotypic changes, signaling pathways were examined in murine MC3T3-E1 cells. Attachment of cells to COL(I) stimulated tyrosine phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), a mitogen-activated protein kinase (MAPK), and enhanced MAPK activity. Inhibition of tyrosine kinase by herbimycin A, destruction of focal adhesion by cytochalasin D, or overexpression of antisense FAK mRNA prevented the activation of ERK/MAPK and the increase in alkaline phosphatase (ALP) activity. Transient expression of a MAPK-specific phosphatase, CL100, also suppressed the elevation of ALP activity. In addition, introduction of a constitutively active MAPK kinase enhanced ALP activity in the absence of collagen production. TGF-beta receptor down-regulation was abrogated by treatments that inactivate FAK, whereas the expression of CL100 had no effect. These results demonstrate that COL(I)-alpha2beta1 integrin interaction facilitates differentiation and down-regulates TGF-beta receptors via the activation of FAK and its diverse downstream signals. These signaling pathways may play an important role in the sequential differentiation of osteoblasts during bone formation.
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PMID:Differentiation and transforming growth factor-beta receptor down-regulation by collagen-alpha2beta1 integrin interaction is mediated by focal adhesion kinase and its downstream signals in murine osteoblastic cells. 936 Oct 11

Cell adhesion to the extracellular matrix (ECM) has been implicated in apoptosis in anchorage-dependent cell types. We recently found that a peptide derived from fibronectin (termed III14-2) inhibits the integrin-mediated cell adhesion to ECM. Using this antiadhesive peptide and a variety of ECM proteins, we show here a critical role of the integrin-ECM protein interaction in apoptotic regulation of human umbilical vein endothelial cells (HUVEC). HUVEC in suspension underwent apoptosis under the serum-free conditions, as judged by nuclear and DNA fragmentations. This apoptosis was suppressed to varying degrees when alpha 5 beta 1, alpha v beta 3, and alpha 2 beta 1 integrins were occupied with either soluble or immobilized ECM proteins such as fibronectin, vitronectin, and type I collagen, respectively. Peptide III14-2, which had no effect by itself on the HUVEC apoptosis, disrupted the ligation of alpha 5 beta 1 and alpha v beta 3 but no alpha 2 beta 1 and ultimately led the cells to apoptosis, indicating that this antiadhesive peptide indirectly induces apoptosis by blocking cell survival signal delivered from alpha 5 beta 1 and alpha v beta 3 integrins. Genistein, a protein tyrosine kinase inhibitor, slightly reduced the rescuing effect of fibronectin, whereas sodium orthovanadate and bombesin, which increase in the level of protein tyrosine phosphorylation, made HUVEC less susceptible to apoptosis and blocked the effect of peptide III14-2. HUVEC adhesion to fibronectin substrate raised the tyrosine phosphorylation level of focal adhesion kinase and the expression of cytoprotective Bcl-2 protein, both of which were reversed by the antiadhesive effect of peptide III14-2. Thus, the opposing effects of ECM proteins, including fibronectin and vitronectin, and peptide III14-2 on HUVEC apoptosis appear to be due to the opposing effects of these factors on the signaling pathway which includes tyrosine phosphorylation of FAK and Bcl-2 expression.
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PMID:Modulation of apoptotic cell death by extracellular matrix proteins and a fibronectin-derived antiadhesive peptide. 966 6

The interaction of endothelial cells with their basement membrane and local stroma is highly regulated. The observation that CAI, an inhibitor of Ca++ influx, inhibited human umbilical vein endothelial cell (HUVEC) adhesion suggested that Ca++ influx was a regulator of HUVEC-matrix interaction. Exposure of HUVEC cells to CAI or SK&F 96365, another Ca++ influx inhibitor, selectively blocked spreading but not attachment on type IV collagen but not type I collagen. Ca++ influx blockade also prevented spreading-induced FAK phosphorylation and kinase activity and secondary paxillin phosphorylation. No inhibitory effect was observed when the cells spread on type I collagen. The inhibitory effect of CAI on spreading and spreading-associated FAK phosphorylation and kinase activity was reversible. These data indicate that HUVEC cells have a selective requirement for Ca++ influx for spreading and downstream signaling on basement membrane type IV collagen.
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PMID:Endothelial cell spreading on type IV collagen and spreading-induced FAK phosphorylation is regulated by Ca2+ influx. 970 78

The tight-skin (Tsk/+) mutant mouse, a putative murine model of scleroderma, is characterized primarily by the excessive deposition of collagen and other extracellular matrix molecules in the dermis, and also by a developmentally acquired defect in pulmonary architecture. Passive transfer experiments have suggested an etiologic role for the immune system in Tsk/+ dermal pathology. In addition, CD4+ T lymphocytes have been shown to be required for the excessive accumulation of dermal collagen in these mice. As IL-4, a product of differentiated CD4+ T cells, is capable of regulating the synthesis of various matrix molecules (including type I collagen) by fibroblasts in vitro, we investigated the potential role of IL-4 in mediating Tsk/+ dermal fibrosis. Confirming that Tsk/+ cells are capable of responding to IL-4, we found receptors for this cytokine on Tsk/+ embryonic fibroblasts and a dermal fibroblast cell line derived from these mice. Furthermore, IL-4 receptors on Tsk/+ fibroblasts were functional since IL-4 stimulation in vitro increased type I collagen secretion from these cells. These results demonstrated the potential for IL-4 to be directly involved in the excessive deposition of dermal collagen in Tsk/+ mice. Critical insight into the role played by IL-4 in mediating the dermal phenotype, however, was obtained following the administration of neutralizing anti-lL-4 antibodies to Tsk/+ mice. This treatment prevented the development of dermal fibrosis, leading to normalization of dermal collagen content. Given the requirement for CD4+ T cells in Tsk/+ dermal fibrosis, our results suggest that Th2 cells and/or factors elaborated by this T cell subset may play a key role in regulating dermal collagen content in this strain.
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PMID:Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. 975 50

Differentiation of endothelial cells, i.e., formation of a vessel lumen, is a prerequisite for angiogenesis. The underlying molecular mechanisms are ill defined. We have studied a brain capillary endothelial cell line (IBEC) established from H-2Kb-tsA58 transgenic mice. These cells form hollow tubes in three-dimensional type I collagen gels in response to fibroblast growth factor-2 (FGF-2). Culture of IBEC on collagen gels in the presence of FGF-2 protected cells from apoptosis and allowed tube formation (i.e., differentiation) but not growth of the cells. FGF-induced differentiation, but not cell survival, was inhibited by treatment of the cells with an anti-beta1-integrin IgG. Changes in integrin expression in the collagen-gel cultures could not be detected. Rather, cell-matrix interactions critical for endothelial cell differentiation were created during the culture, as indicated by the gradual increase in tyrosine phosphorylation of focal adhesion kinase in the collagen-gel cultures. Inclusion of laminin in the collagen gels led to FGF-2-independent formation of tube structures, but cells were not protected from apoptosis. These data indicate that FGF receptor-1 signal transduction in this cell model results in cell survival. Through mechanisms dependent on cell-matrix interactions, possibly involving the alpha3beta1-integrin and laminin produced by the collagen-cultured IBE cells, FGF stimulation also leads to differentiation of the cells.
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PMID:Signaling via fibroblast growth factor receptor-1 is dependent on extracellular matrix in capillary endothelial cell differentiation. 1009 27

Hepatic stellate cells are now recognized as the major source of extracellular matrix in hepatic fibrosis. Following liver injury the hepatic stellate cell changes from a quiescent to an activated cell. The activation process includes an increased proliferation rate, a phenotypic change to a myofibroblast-like cell, loss of vitamin A stores, increased extra-cellular matrix protein synthesis and contractility. Furthermore, hepatic stellate cells have been implicated in hepatic inflammation through their ability to secrete cytokines and chemokines. Here, we review the literature on the molecular pathogenesis of hepatic stellate cells activation with emphasis on the most recent findings. The reviewed topics include transcriptional and post-transcriptional regulation of the genes encoding type I collagen in hepatic stellate cells; the role of the transcription factor nuclear factor Kappa B in the hepatic stellate cell activation; focal adhesion kinase and integrin-mediated signal transduction in hepatic stellate cell, and apoptosis in hepatic stellate cells. New insight into hepatic stellate cell activation and death may lead to the development of novel therapies for hepatic fibrosis.
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PMID:Gene regulation in hepatic stellate cell. 1036 3

We have shown that nonvoltage-operated Ca(2+) entry regulates human umbilical vein endothelial cell adhesion, migration, and proliferation on type IV collagen. We now demonstrate a requirement for Ca(2+) influx for activation of the RhoA pathway during endothelial cell spreading on type IV collagen. Reorganization of actin into stress fibers was complete when the cells where fully spread at 90 minutes. No actin organization into stress fibers was seen in endothelial cells plated on type I collagen, indicating a permissive effect of type IV collagen. CAI, a blocker of nonvoltage-operated Ca(2+) channels, prevented development of stress fiber formation in endothelial cells on type IV collagen. This permissive effect was augmented by Ca(2+) influx, as stimulated by 0. 5 microM thapsigargin or 0.1 microM ionomycin, yielding faster development of actin stress fibers. Ca(2+) influx and actin rearrangement in response to thapsigargin and ionomycin were abrogated by CAI. Activated, membrane-bound RhoA is a substrate for C3 exoenzyme which ADP-ribosylates and inactivates RhoA, preventing actin stress fiber formation. Pretreatment of endothelial cells with C3 exoenzyme prevented basal and thapsigargin-augmented stress fiber formation. While regulation of Ca(2+) influx did not alter RhoA translocation, it reduced in vitro ADP-ribosylation of RhoA (P(2)<0. 05), suggesting Ca(2+) influx is needed for RhoA activation during spreading on type IV collagen; no Ca(2+) regulated change in RhoA was seen in HUVECs spreading on type I collagen matrix. Blockade of Ca(2+) influx of HUVEC spread on type IV collagen also reduced tyrosine phosphorylation of p190Rho-GAP and blocked thapsigargin-enhanced binding of p190Rho-GAP to focal adhesion kinase. Thus, Ca(2+) influx is necessary for RhoA activation and for linkage of the RhoA/stress fiber cascade to the focal adhesion/focal adhesion kinase pathway during human umbilical vein endothelial cell spreading on type IV collagen.
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PMID:Regulation of the RhoA pathway in human endothelial cell spreading on type IV collagen: role of calcium influx. 1050 26


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