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)

The urokinase-type plasminogen activator (uPA) binds to cells via a specific receptor attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor. Despite the lack of a transmembrane domain, the urokinase receptor (uPAR) is capable of transducing extracellular signals affecting growth, migration, and adhesion. Several Tyr kinases of the src family as well as beta1, beta2, and beta3 integrins were found to be associated with the uPAR. We found that in the human kidney epithelial line TCL-598, also components of the JAK1/STAT1 signal transduction pathway including gp130, are associated with uPAR as revealed by coimmunoprecipitation and are co-localized in caveolae. Upon clustering of uPA.uPAR complex by a monoclonal antibody, JAK1 associates with uPAR, which in turn leads to STAT1 phosphorylation, dimerization, specific binding to DNA, and gene activation. To prove the dependence of STAT1 activation on the uPAR, TCL-598 cells were treated with sense and antisense uPAR oligonucleotides. In antisense-treated cells in which uPAR expression was reduced to less then one third, activation of STAT1 by the clustering antibody was abolished while STAT1 activation by interferon-gamma was unaffected. Therefore, in this cell line, uPA.uPAR also utilizes the JAK1/STAT1 pathway for signaling, and gp130 might be the transmembrane adapter for this signal transduction pathway.
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PMID:Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598. 935 20

Exposure of low-passage endothelial cells in culture to nonlethal amounts of asbestos, but not refractory ceramic fiber-1, increases cell motility and gene expression. These changes may be initiated by the fibers mimicking matrix proteins as ligands for receptors on the cell surface. In the present study, 1- to 3-hr exposures of endothelial cells to 5 mg/cm2 of chrysotile asbestos caused marked cell elongation and motility. However, little morphological change was seen when chrysotile was added to cells pretreated with either mannosamine to prevent assembly of glycophosphatidylinositol (GPI)-anchored receptors or with herbimycin A to inhibit tyrosine kinase activity. Affinity purification of GPI-anchored urokinase-type plasminogen activator receptor (uPAR) from chrysotile-exposed cells demonstrated that asbestos altered the profile of proteins and phosphoproteins complexed with this receptor. Tyrosine kinase activities in the complexes were also increased by asbestos. Immunoprecipitations with selective monoclonal antibodies demonstrated that both chrysotile and crocidolite asbestos increase kinase activities associated with p60 Src or p120 focal adhesion kinase (FAK). Further, chrysotile also changed the profile of proteins and phosphoproteins associated with FAK in intact cells. These data suggest that asbestos initiates endothelial cell phenotypic change through interactions with uPAR-containing complexes and that this change is mediated through tyrosine kinase cascades.
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PMID:Increased focal adhesion kinase- and urokinase-type plasminogen activator receptor-associated cell signaling in endothelial cells exposed to asbestos. 940 Jul 12

The assembly of signaling molecules surrounding the integrin family of adhesion receptors remains poorly understood. Recently, the membrane protein caveolin was found in complexes with beta1 integrins. Caveolin binds cholesterol and several signaling molecules potentially linked to integrin function, e.g., Src family kinases, although caveolin has not been directly implicated in integrin-dependent adhesion. Here we report that depletion of caveolin by antisense methodology in kidney 293 cells disrupts the association of Src kinases with beta1 integrins resulting in loss of focal adhesion sites, ligand-induced focal adhesion kinase (FAK) phosphorylation, and adhesion. The nonintegrin urokinase receptor (uPAR) associates with and stabilizes beta1 integrin/caveolin complexes. Depletion of caveolin in uPAR-expressing 293 cells also disrupts uPAR/integrin complexes and uPAR-dependent adhesion. Further, beta1 integrin/caveolin complexes could be disassociated by uPAR-binding peptides in both uPAR-transfected 293 cells and human vascular smooth muscle cells. Disruption of complexes by peptides in intact smooth muscle cells blocks the association of Src family kinases with beta1 integrins and markedly impairs their migration on fibronectin. We conclude that ligand-induced signaling necessary for normal beta1 integrin function requires caveolin and is regulated by uPAR. Caveolin and uPAR may operate within adhesion sites to organize kinase-rich lipid domains in proximity to integrins, promoting efficient signal transduction.
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PMID:A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. 1008 70

Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) participate in matrix degradation and cell migration by focusing proteolysis and functioning as a signaling ligand/receptor complex. uPAR, anchored by a lipid moiety in the membrane, is thought to require a transmembrane adapter to transduce signals into the cytoplasm. To study uPAR signaling, we transfected the prostate carcinoma cell line LNCaP, which does not express endogenous uPA or uPAR, with a uPAR encoding cDNA, resulting in high-level surface expression. We studied migration of these cells on fibronectin, which is mediated by the integrin alpha5beta1. Ligation of uPAR with uPA or its amino-terminal fragment enhanced haptotactic migration to fibronectin. In cells on fibronectin, but not on poly-l-lysine, ligation of uPAR also resulted in tyrosine phosphorylation of several proteins, including two proteins involved in integrin signaling, focal adhesion kinase and the crk-associated substrate p130(Cas). Furthermore, after uPAR ligation, uPAR was co-immunoprecipitated with beta1 integrins from the detergent-insoluble fraction of cell lysates. Thus, our data suggest that uPAR occupancy results in an interaction between uPAR and integrins and a potentiation of integrin-mediated signaling, which leads to enhanced cell migration.
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PMID:Urokinase-type plasminogen activator binding to its receptor stimulates tumor cell migration by enhancing integrin-mediated signal transduction. 1038 37

Liver regeneration after partial hepatectomy (PHx) of the liver serves as a model for studying normal growth factor signals that become aberrant in cancer. Growth factor signals that may play a role in initiating the proliferation of hepatocytes after 70% PHx in the rat were investigated immediately after surgical resection of the liver. Presumptive activity was evaluated by determining the tyrosine phosphorylation state of receptors for epidermal growth factor (EGF) and hepatocyte growth factor (HGF) in the liver after PHx and after sham operation as a control. Under these conditions, it was determined that the EGF receptor was constitutively phosphorylated. EGF receptor tyrosine phosphorylation, however, was increased over basal levels by 60 min after resection. The HGF receptor, c-Met, was minimally phosphorylated in control livers, but a biphasic increase in phosphorylation was observed at 1-5 min after PHx and 60 min postsurgery. A slight increase in c-Met phosphorylation was observed in the sham-operated livers, but the signal was significantly less when compared with that in resected livers. Furthermore, 1 min after PHx, but not sham operation, urokinase-type plasminogen activator (u-PA) and u-PA receptor were observed in the immunoprecipitates of c-Met. Signaling downstream of growth factor receptor activation was also examined. There were no discernible phosphorylation changes in focal adhesion kinase during the early events after surgery in PHx; however, a rapid and sustained increase in the tyrosine phosphorylation of paxillin beginning 1 min after PHx, and a gradual increase in the phosphorylation beginning 5 min postsham operation, were observed. Changes in the activated state of the small GTP-binding protein Rho A and its associated proteins were seen but only after 3 h after PHx. The results indicate that HGF-related signal transduction cascades, which contribute to hepatocyte proliferation, are initiated within one min after PHx.
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PMID:Growth factor signal transduction immediately after two-thirds partial hepatectomy in the rat. 1046 91

Plasminogen activator inhibitor 1 (PAI-1) is a major inhibitor of urokinase-type plasminogen activator (uPA). In this study, we explored the role of PAI-1 in cell signaling. In MCF-7 cells, PAI-1 did not directly activate the mitogen-activated protein (MAP) kinases, extracellular signal-regulated kinase (ERK) 1 and ERK2, but instead altered the response to uPA so that ERK phosphorylation was sustained. This effect required the cooperative function of uPAR and the very low density lipoprotein receptor (VLDLr). When MCF-7 cells were treated with uPA-PAI-1 complex in the presence of the VLDLr antagonist, receptor-associated protein, or with uPA-PAI-1(R76E) complex, which binds to the VLDLr with greatly decreased affinity, transient ERK phosphorylation (<5 min) was observed, mimicking the uPA response. ERK phosphorylation was not induced by tissue-type plasminogen activator-PAI-1 complex or by uPA-PAI-1 complex in the presence of antibodies that block uPA binding to uPAR. uPA-PAI-1 complex induced tyrosine phosphorylation of focal adhesion kinase and Shc and sustained association of Sos with Shc, whereas uPA caused transient association of Sos with Shc. By sustaining ERK phosphorylation, PAI-1 converted uPA into an MCF-7 cell mitogen. This activity was blocked by receptor-associated protein and not observed with uPA-PAI-1(R76E) complex, demonstrating the importance of the VLDLr. uPA promoted the growth of other cells in which ERK phosphorylation was sustained, including beta3 integrin overexpressing MCF-7 cells and HT 1080 cells. The MEK inhibitor, PD098059, blocked the growth-promoting activity of uPA and uPA-PAI-1 complex in these cells. Our results demonstrate that PAI-1 may regulate uPA-initiated cell signaling by a mechanism that requires VLDLr recruitment. The kinetics of ERK phosphorylation in response to uPAR ligation determine the function of uPA and uPA-PAI-1 complex as growth promoters.
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PMID:Plasminogen activator inhibitor 1 functions as a urokinase response modifier at the level of cell signaling and thereby promotes MCF-7 cell growth. 1126 65

The urokinase receptor (uPAR) is linked to cellular migration through its capacity to promote pericellular proteolysis, regulate integrin function, and mediate cell signaling in response to urokinase (uPA) binding. The mechanisms for these activities remain incompletely defined, although uPAR was recently identified as a cis-acting ligand for the beta2 integrin CD11b/CD18 (Mac-1). Here we show that a major beta1 integrin partner for uPAR/uPA signaling is alpha3. In uPAR-transfected 293 cells uPAR complexed (>90%) with alpha3beta1 and antibodies to alpha3 blocked uPAR-dependent vitronectin (Vn) adhesion. Soluble uPAR bound to recombinant alpha3beta1 in a uPA-dependent manner (K(d) < 20 nM) and binding was blocked by a 17-mer alpha3beta1 integrin peptide (alpha325) homologous to the CD11b uPAR-binding site. uPAR colocalized with alpha3beta1 in MDA-MB-231 cells and uPA (1 nM) enhanced spreading and focal adhesion kinase phosphorylation on fibronectin (Fn) or collagen type I (Col) in a pertussis toxin- and alpha325-sensitive manner. A critical role of alpha3beta1 in uPA signaling was verified by studies of epithelial cells from alpha3-deficient mice. Thus, uPAR preferentially complexes with alpha3beta1, promoting direct (Vn) and indirect (Fn, Col) pathways of cell adhesion, the latter a heterotrimeric G protein-dependent mechanism of signaling between alpha3beta1 and other beta1 integrins.
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PMID:Urokinase receptors promote beta1 integrin function through interactions with integrin alpha3beta1. 1159 85

Although the involvement of transforming growth factor-beta (TGF-beta) in inflammatory reactions has been extensively studied, its mode of action in the context of the extracellular matrix (ECM) is still not fully understood. We undertook this study in an attempt to reveal the putative roles of TGF-beta in T-cell adhesion and migration. We found that a 60-min treatment of T cells with TGF-beta regulates T-cell adhesion to fibronectin (FN), a prototype cell adhesion protein of the ECM, depending on the presence of other activators. At 5 pg/ml to 1 ng/ml, TGF-beta alone induced T-cell adhesion to FN in an integrin alpha4/beta1- and integrin alpha5/beta1-dependent manner. TGF-beta also attenuated T-cell migration on the stromal cell-derived factor (SDF)-1alpha gradients. These effects of TGF-beta were not accompanied by alteration in the expression of very-late activation antigen type 4 (VLA-4) and VLA-5, nor were they mediated by the cyclo-oxygenase pathway. The cellular mechanism underlying the adhesion-regulating activities of TGF-beta involves adhesion-associated cytoskeletal elements. TGF-beta induced the phosphorylation of focal adhesion kinase Pyk2, but not extracellular signal-regulated kinase (ERK), and this effect was markedly increased in the presence of immobilized FN, suggesting a collaborative role for FN-specific integrins. Indeed, TGF-beta-induced Pyk2 phosphorylation was inhibited by monoclonal antibodies against VLA-4, VLA-5 and CD29. Thus, TGF-beta, which may appear at extravascular sites during inflammation, affects the adhesion of T cells to ECM glycoproteins and their migration by its ability to differentially induce or inhibit the phosphorylation of Pyk2.
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PMID:Regulation of T-cell interaction with fibronectin by transforming growth factor-beta is associated with altered Pyk2 phosphorylation. 1168 54

Activation of focal adhesion kinase (FAK), overexpressed in several human cancers, induces survival, proliferation and motility of cells in culture, but its functional importance in human tumor growth in vivo has not been elucidated. I explored the role of FAK in regulating tumorigenicity of human carcinoma cells, HEp3. These cells overexpress urokinase receptor (uPAR) which, by activating alpha5beta1 integrin, initiates an intracellular signal through FAK and Src leading to ERK activation and tumorigenicity in vivo. Down regulation of uPAR in these cells led to an approximately 3-5-fold reduction in FAK phosphorylation and association with Src and dormancy in vivo. Both FAK phosphorylation and ability to grow in vivo were restored by re-expression of uPAR. The FAK signaling pathway in T-HEp3 cells, measured by FAK phosphorylation, GTP-loaded Ras and ERK activation, was inhibited by transient or stable transfection of FAK related non-kinase (FRNK), known to have a dominant negative function, but not by a FRNK mutant version (S1034-FRNK). Most importantly, while vector- and mutant-S1034-FRNK transfected cells inoculated onto chicken embryo CAMs formed progressively growing tumors, the HA-FRNK-expressing T-HEp3 cells did not proliferate in vivo and remained dormant for at least 6 weeks. Both cell types had similar rate of apoptosis in vivo and the p38(SAPK) or PI3K-Akt signaling pathways were unaffected by FRNK. FRNK induced dormancy could be reverted by expression of an active-R4F-Mek1 mutant. These results show that active FAK is an important mediator of uPAR-regulated tumorigenicity of HEp3 cells and that interruption of FAK mitogenic signaling either through down-regulation of uPAR or by expression of FRNK can force human carcinoma cells into dormancy.
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PMID:Inhibition of FAK signaling activated by urokinase receptor induces dormancy in human carcinoma cells in vivo. 1197 Nov 86

Kaposi's sarcoma-associated herpes virus (KSHV) infects B cells and microvascular endothelium,and is linked to both lymphoid and endothelial neoplasms. KSHV encodes a G protein-coupled receptor (v-GPCR) that can bind several CC and CXC chemokines but is able to signal in the absence of known ligands. This signaling can transform cultured fibroblasts, promote angiogenesis in vitro and in vivo, and activate the mitogen-activated protein kinase, c-Jun-NH(2)-terminal kinase, and p38 pathways. To assess the potential impact of v-GPCR signaling on host cell biology we have examined cellular gene expression in v-GPCR-transfected cells using DNA microarrays. v-GPCR expression up-regulated numerous cellular transcripts in both BJAB B cells and SLK endothelial cells, but with a remarkable degree of cell-type specificity. Among the most highly regulated genes in endothelial cells were the cytokines interleukin 6 and GRO alpha; several genes affecting endothelial/vascular growth and remodeling were also induced, including plasminogen, thrombomodulin, the urokinase-type plasminogen activator receptor, and to a modest extent vascular endothelial growth factor C. By contrast, the most highly regulated genes in B cells were the CC chemokines macrophage inflammatory protein 1 alpha and macrophage inflammatory protein 1 beta. No genes other than members of the dual-specificity phosphatase family were induced in both cell lines. The results indicate that the effects of KSHV GPCR expression in these two target cell types differ considerably and suggest that signaling by this molecule may make different contributions to the pathogenesis of KSHV-related endothelial and lymphoproliferative lesions.
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PMID:Modulation of host gene expression by the constitutively active G protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus. 1215 65


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