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)

The interactions of osteoblasts with their surrounding extracellular matrix (ECM) are essential for skeletal development, homeostasis, and maintenance of the mature osteoblastic phenotype. Integrins are the principal transducers of ECM signals that regulate this process of osteoblast commitment and differentiation. Several studies indicate that the alpha(2)beta(1) integrin interaction with type I collagen is a crucial signal for the induction of osteoblastic differentiation and matrix mineralization. Integrin alpha(2)beta(1) recognizes the Gly-Phe-Hyp-Gly-Glu-Arg (GFOGER) motif in residues 502-507 of the alpha(1)[I] chain of type I collagen. This study demonstrates that an alpha(2)beta(1) integrin-specific GFOGER peptide triggers the activation of focal adhesion kinase and alkaline phosphatase in MC3T3-E1 murine immature osteoblast-like cells, two events that have been implicated in the osteoblastic differentiation pathway. These GFOGER-peptide surfaces also support the expression of multiple osteoblast-specific genes, including osteocalcin and bone sialoprotein, and induce matrix mineralization in a manner similar to type I collagen. This triple-helical peptide represents a promising surface modification strategy for the design of collagen-mimetic bioadhesive surfaces that support osteoblastic differentiation.
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PMID:Alpha2beta1 integrin-specific collagen-mimetic surfaces supporting osteoblastic differentiation. 1516

The streptococcal collagen-like proteins Scl1 and Scl2 are prokaryotic members of a large protein family with domains containing the repeating amino acid sequence (Gly-Xaa-Yaa)(n) that form a collagen-like triple-helical structure. Here, we test the hypothesis that Scl variant might interact with mammalian collagen-binding integrins. We show that the recombinant Scl protein p176 promotes adhesion and spreading of human lung fibroblast cells through an alpha2beta1 integrin-mediated interaction as shown in cell adhesion inhibition assays using anti-alpha2beta1 and anti-beta1 integrins monoclonal antibodies. Accordingly, C2C12 cells stably expressing alpha2beta1 integrin as the only collagen-binding integrin show productive cell adhesion activities on p176 that can be blocked by an anti-alpha2beta1 integrin antibody. In addition, p176 promotes tyrosine phosphorylation of p125(FAK) of C2C12 cells expressing alpha2beta1 integrin, whereas parental cells do not. Furthermore, C2C12 adhesion of human lung fibroblast cells to p176 induces phosphorylation of p125FAK, p130CAS, and p68Paxillin proteins. In a domain swapping experiment, we show that integrin binds to the collagenous domain of the Scl protein. Moreover, the recombinant inserted domain of the alpha2 integrin interacts with p176 with a relatively high affinity (K(D) = 17 nm). Attempts to identify the integrin sites in p176 suggest that more than one site may be involved. These studies, for the first time, suggest that the collagen-like proteins of prokaryotes retained not only structural but also functional characteristics of their eukaryotic counterparts.
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PMID:A streptococcal collagen-like protein interacts with the alpha2beta1 integrin and induces intracellular signaling. 1564 74

The cannabinoid CB1 receptor allows endocannabinoids to act as intercellular and retrograde messengers in the central nervous system. Endocannabinoid actions have been implicated in both synaptic plasticity and neuroprotection. Here, cannabinergic activation of extracellular signal regulated-kinase (ERK) and focal adhesion kinase (FAK) occurred correspondingly in long-term hippocampal slice cultures. The stable endocannabinoid analogue R-methanandamide activated ERK1/ERK2 subtypes of mitogen-activated protein kinase (MAPK) through the upstream activator MAPK kinase (MEK). R-methanandamide also promoted FAK signaling, but in a MEK-independent manner. Both events of ERK and FAK activation were selectively blocked by N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281), a cannabinoid CB1 receptor antagonist, and the blockage was associated with a gradual decline in synaptic markers. Interestingly, the integrin antagonist Gly-Arg-Gly-Asp-Ser-Pro also caused the disruption of R-methanandamide-mediated ERK and FAK responses and upset the integrity of excitatory synapses. These results suggest that the endocannabinoid system supports synaptic maintenance through linkages with MAPK pathways and integrin-related FAK signaling.
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PMID:Blocking cannabinoid activation of FAK and ERK1/2 compromises synaptic integrity in hippocampus. 1568 Feb 53

MTI/G-Gly mice and hGAS mice, overexpressing glycine-extended gastrin (G-Gly) and progastrin, respectively, display colonic mucosa hyperplasia, hyperproliferation, and an increased susceptibility to intestinal neoplasia. Here, we have used these transgenic mice to analyze in vivo the modulation of intracellular signaling pathways that may be responsible for the proliferative effects of gastrin precursors. The expression, activation, and localization of signaling and cell-to-cell adhesion molecules were studied using immunofluorescence and Western blot techniques on colonic tissues derived from MTI/G-Gly, hGAS, or wild-type FVB/N mice. These analyses revealed an up-regulation of Src tyrosine kinase and related signaling pathways [phosphatidyl inositol 3'-kinase (PI3K)/Akt, Janus-activated kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3, and extracellular-signal regulated kinases (ERK)] in both MTI/G-Gly and hGAS mice compared with the wild-type control animals as well as an overexpression of transforming growth factor-alpha (TGF-alpha). In contrast, overexpression of the gastrin precursors did not affect the activation status of STAT1 nor the expression and the distribution of adhesion proteins (focal adhesion kinase, cadherins, and catenins). We report for the first time that the transition from a normal colonic epithelium to a hyperproliferative epithelium in MTI/G-Gly and hGAS mice may be a consequence of the up-regulation of Src, PI3K/Akt, JAK2, STAT3, ERKs, and TGF-alpha. Deregulation of cell adhesion, a late event in tumor progression, does not occur in these transgenic models.
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PMID:Signaling pathways associated with colonic mucosa hyperproliferation in mice overexpressing gastrin precursors. 1580 77

Integrin class adhesion proteins are concentrated at adult brain synapses. Whether synaptic integrins engage kinase signaling cascades has not been determined, but is a question of importance to ideas about integrin involvement in functional synaptic plasticity. Accordingly, synaptoneurosomes from adult rat brain were used to test if matrix ligands activate integrin-associated tyrosine kinases, and if integrin signaling targets include NMDA-class glutamate neurotransmitter receptors. The integrin ligand peptide Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) induced rapid (within 5 min) and robust increases in tyrosine phosphorylation of focal adhesion kinase, proline-rich tyrosine kinase 2 and Src family kinases. Increases were similarly induced by the native ligand fibronectin, blocked with neutralizing antibodies to beta1 integrin, and not obtained with control peptides, indicating that kinase activation was integrin-mediated. Both GRGDSP and fibronectin caused rapid Src kinase-dependent increases in tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B in synaptoneurosomes and acute hippocampal slices. Tests of the physiological significance of the latter result showed that ligand treatment caused a rapid and beta1 integrin-dependent increase in NMDA receptor-mediated synaptic responses. These results provide the first evidence that, in adult brain, synaptic integrins activate local kinase cascades with potent effects on the operation of nearby neurotransmitter receptors implicated in synaptic plasticity.
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PMID:Integrin signaling cascades are operational in adult hippocampal synapses and modulate NMDA receptor physiology. 1585 87

Heterozygous mutations of COL2A1 create several clinical entities collectively termed type II collagenopathies. These disorders not only impair skeletal growth but also cause ocular and otolaryngological abnormalities. The classical phenotypes include the spondyloepiphyseal dysplasia (SED) spectrum with variable severity, Stickler dysplasia type I (STD-I), and Kniest dysplasia (KND). Most COL2A1 mutations occur in the triple helical region of alpha 1(II) chains: the SED spectrum is mostly attributed to missense mutations that substitute bulky amino acids for glycine residues, STD-I to haploinsufficiency of truncation mutations, and KND to exon skipping due to splice-site mutations. To further elucidate the genotype-phenotype relationship of type II collagenopathies, we examined COL2A1 mutations in 56 families that were suspected of having type II collagenopathies, and found 38 mutations in 41 families. Phenotypes for all 22 missense mutations and one in-frame deletion in the triple helical region fell along the SED spectrum. Glycine to serine substitutions resulted in alternating zones that produce severer and milder skeletal phenotypes. Glycine to nonserine residue substitutions exclusively created more severe phenotypes. The gradient of the SED spectrum did not necessarily correlate with the occurrence of extraskeletal manifestations. All nine truncation or splice-site mutations in the triple helical or N-propeptide region caused STD-I or KND, and extraskeletal changes were inevitable in both phenotypes. All six C-propeptide mutations produced a range of atypical skeletal phenotypes and created ocular, but not otolaryngological, changes.
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PMID:The phenotypic spectrum of COL2A1 mutations. 1589 62

Lipid phosphate phosphohydrolase-3 (LPP3) is a cell surface protein that exhibits ectoenzyme activity. Previously, we identified human LPP3 in a functional assay of angiogenesis and showed that the Arg-Gly-Asp (RGD) motif in the proposed second extracellular domain interacts with a subset of integrins to mediate cell-cell adhesion. In contrast to the RGD domain of human LPP3, murine Lpp3 contains a variant sequence, Arg-Gly-Glu (RGE). Whether the RGE motif of murine Lpp3 mediates cell-cell interaction has not been studied. In this report, we test the hypothesis that the cell adhesion function of the LPP3 protein is conserved across mouse and human. A glutathione S-transferase (GST) fusion protein of the proposed second extracellular loop of the murine Lpp3 sequence (GST-mLpp3-RGE) promoted attachment of cells in a long-term cell adhesion assay. GST-mLpp3-RGE interacted with alpha(5)beta(1) and alpha(v)beta(3) integrins in a solid-phase ELISA, while a mutant control, GST-hLPP3-RAD, did not. Long-term adhesion of endothelial cells to GST-mLpp3-RGE induced phosphorylation of FAK, SHC, and CAS, whereas adhesion to GST-hLPP3-RAD failed to do so. Upon long-term adhesion both the GST-hLPP3-RGD and GST-mLpp3-RGE substrates bound to the alpha(5)beta(1) integrin of FRT-alpha(5)(+) cells, an interaction that was inhibited by an anti-alpha(5) integrin antibody. In addition, a cell aggregation assay showed that the intact mLpp3-RGE protein interacts with alpha(5)beta(1) and alpha(v)beta(3) integrins expressed by adjacent cells, an interaction that can be blocked by GRGDSP peptides and anti-LPP3-RGD antibodies. These data, together with the known importance of integrins in angiogenesis, provide a mechanism for the function of LPP3 in cell-cell interactions in both human and mouse.
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PMID:Murine lipid phosphate phosphohydrolase-3 acts as a cell-associated integrin ligand. 1609 22

Extracellular matrix proteins and cell adhesion receptors (integrins) play essential roles in the regulation of cell adhesion and migration. Interactions of integrins with the extracellular matrix proteins lead to phosphorylation of several intracellular proteins such as focal adhesion kinase, activating different signaling pathways responsible for the regulation of a variety of cell functions, including cytoskeleton mobilization. Once leukocytes are guided to sites of infection, inflammation, or antigen presentation, integrins can participate in the initiation, maintenance, or termination of the immune and inflammatory responses. The modulation of neutrophil activation through integrin-mediated pathways is important in the homeostatic control of the resolution of inflammatory states. In addition, during recirculation, T lymphocyte movement through distinct microenvironments is mediated by integrins, which are critical for cell cycle, differentiation and gene expression. Disintegrins are a family of low-molecular weight, cysteine-rich peptides first identified in snake venom, usually containing an RGD (Arg-Gly-Asp) motif, which confers the ability to selectively bind to integrins, inhibiting integrin-related functions in different cell systems. In this review we show that, depending on the cell type and the microenvironment, disintegrins are able to antagonize the effects of integrins or to act agonistically by activating integrin-mediated signaling. Disintegrins have proven useful as tools to improve the understanding of the molecular events regulated by integrin signaling in leukocytes and prototypes in order to design therapies able to interfere with integrin-mediated effects.
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PMID:Disintegrins: integrin selective ligands which activate integrin-coupled signaling and modulate leukocyte functions. 1617 44

The myocardial stretch-induced increase in intracellular [Ca(2+)] ([Ca(2+)](i)) is considered to be caused by integrin stimulation. Myocardial stretch is also associated with increased nitric oxide (NO) formation. We hypothesised that NO is implicated in calcium signalling following integrin stimulation. Integrins of neonatal rat cardiomyocytes were stimulated with a pentapeptide containing the Arg-Gly-Asp (RGD) sequence. [Ca(2+)](i) was measured with Fura2, [NO](i) was measured with DAF2 and phosphorylation of focal adhesion kinase (FAK) was monitored with immunofluorescence techniques. Integrin stimulation increased both [NO](i) and [Ca(2+)](i), the latter response being inhibited by ryanodine receptor-2 (RyR2) blockers and by N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NOS, but resistant to GdCl(3), diltiazem and wortmannin. Integrin-induced intracellular Ca(2+) release thus appears to be independent of the influx of extracellular Ca(2+) and phosphatidylinositol-3 kinase activity. In addition, integrin stimulation induced phosphorylation of FAK. Our results provide evidence for an integrin-induced Ca(2+) release from RyR2 which is mediated by NO formation, probably via FAK-induced NOS activation.
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PMID:Integrin stimulation induces calcium signalling in rat cardiomyocytes by a NO-dependent mechanism. 1628 42

Junctional adhesion molecule-A (JAM-A) is a member of the immunoglobulin superfamily, and is mainly expressed in the tight junctions of both epithelial and endothelial cells. We have recently shown that JAM-A is involved in basic fibroblast growth factor (bFGF)-induced angiogenesis. Here, we show that, when ectopically expressed in human umbilical vein endothelial cells (HUVECs), JAM-A induced enhanced cell migration on vitronectin, but had no effect on fibronectin. Use of antibodies that block integrin function indicated that the migration on vitronectin is specific to integrin alpha(v)beta(3) and not to integrin alpha(v)beta(5). JAM-A-induced migration was inhibited by anti-JAM-A antibody. Additionally, overexpression of a JAM-A cytoplasmic domain deletion mutant failed to induce HUVEC migration. Addition of phosphoinositide 3-kinase and protein kinase C inhibitors blocked JAM-A-induced migration, suggesting that these kinases act downstream of JAM-A. Immunoprecipitation analysis showed that JAM-A interacts with integrin alpha(v)beta(3), and this association was increased by engagement of the ligand-binding site of the integrin by Arg-Gly-Asp-Ser (RGDS) peptide. Furthermore, activation of both focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK) on vitronectin was enhanced by JAM-A overexpression but not by its cytoplasmic domain deletion mutant. Taken together, these results suggest that signaling through JAM-A is necessary for alpha(v)beta(3)-dependent HUVEC migration and implicate JAM-A in the regulation of vascular function.
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PMID:Junctional adhesion molecule-A-induced endothelial cell migration on vitronectin is integrin alpha v beta 3 specific. 1641 18


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