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)

Beta-amyloid1-42 (Abeta) is a naturally occuring peptide whose accumulation in the brain is putatively coupled to Alzheimer's disease pathogenesis. Deleterious effects of Abeta on neurons have been linked to the inappropriate activation of signaling pathways within the cell (reviewed in Yankner, 1996), including tyrosine phosphorylation of focal adhesion kinase (FAK) (Zhang et al., 1994, 1996a,b). Here we have investigated the effects of Abeta on paxillin in a neural cell line. Paxillin, a substrate for FAK, is thought to act as a signal "integrator," functioning to link other proteins into multi-molecular signaling complexes (reviewed in Turner, 1994). Treatment of the rat central nervous system B103 cell line with aggregates of Abeta was found to induce the tyrosine phosphorylation of paxillin within 30 min, nearly 24 hr prior to significant cell death. Particularly striking was a subsequent "mobilization" of paxillin to the cytoskeleton in Abeta-treated cells. The amount of paxillin associated with the cytoskeleton in Abeta-treated cells was increased 10-fold over controls. The Abeta-induced paxillin accumulation could be visualized immunocytochemically, with an increase in number and size of paxillin-labeled focal contacts upon treatment with Abeta. This effect was specific, in that vinculin, another focal contact protein, was unaffected by Abeta. Disruption of f-actin, which inhibits both Abeta-induced neurotoxicity (Furukawa and Mattson, 1995) and focal contact signaling in B103 cells (Zhang et al., 1996b) was found to block the cytoskeletal paxillin accumulation. The rapid tyrosine phosphorylation and cytoskeletal mobilization of paxillin links Abeta to the activation of focal contact signaling events that may influence neuronal cytoskeletal architecture, gene expression, synaptic plasticity and cell viability.
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PMID:Rapid impact of beta-amyloid on paxillin in a neural cell line. 945 12

Normal endothelial and epithelial cells undergo apoptosis when cell adhesion and spreading are prevented, implying a requirement for antiapoptotic signals from the extracellular matrix for cell survival. We investigated some of the molecular changes occurring in focal adhesions during growth factor deprivation-induced apoptosis in confluent monolayers of human umbilical vein endothelial cells. Among the first morphologic changes after initiation of the apoptotic process are membrane blebbing, loss of focal adhesion sites, and retraction from the matrix followed by detachment. We observe a specific proteolytic cleavage of focal adhesion kinase (pp125FAK), an important component of the focal adhesion complex, and identify pp125FAK as a novel substrate for caspase-3 and caspase-3-like apoptotic caspases. The initial cleavage precedes detachment, and coincides with loss of pp125FAK and paxillin from focal adhesion sites and their redistribution into the characteristic membrane blebs of apoptotically dying cells. Cleavage of pp125FAK differentially affects its association with signaling and cytoskeletal components of the focal adhesion complex; binding of paxillin, but not pp130(Cas) (Cas, Crk-associated substrate) and vinculin, to the COOH terminally truncated pp125FAK is abolished. Therefore, caspase-mediated cleavage of pp125FAK may be participating in the disassembly of the focal adhesion complex and actively interrupting survival signals from the extracellular matrix, thus propagating the cell death program.
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PMID:Caspase-mediated cleavage of focal adhesion kinase pp125FAK and disassembly of focal adhesions in human endothelial cell apoptosis. 946 8

We have found that the E6 oncoprotein of Bovine Papillomavirus Type 1 (BE6) as well as the E6 protein of the cancer associated HPV-16 (16E6) interact with the focal adhesion protein paxillin. Mutational analysis of paxillin revealed that BE6 binds paxillin through small protein interaction motifs called LD motifs that have been previously identified as important in regulating association of paxillin with vinculin and focal adhesion kinase (FAK), and that BE6 can interact with at least two separate binding sites on paxillin. The LD motifs of paxillin that bind BE6 share homology with the E6 binding site of E6-AP, a ubiquitin ligase that together with 16E6 targets the degradation of the p53 tumor suppressor. Paxillin binding to BE6 excludes simultaneous binding to E6-AP. Mutational analysis of BE6 can distinguish the interaction of BE6 with E6-AP compared to paxillin and revealed that the interaction of BE6 with paxillin may be necessary for the induction of anchorage independent growth of cells by BE6.
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PMID:Association of Bovine Papillomavirus Type 1 E6 oncoprotein with the focal adhesion protein paxillin through a conserved protein interaction motif. 946 41

The vinculin gene codes for a cytoskeletal protein, found in focal adhesion plaques and in cell-cell adherens junctions. Vinculin was inactivated by homologous recombination using a targeting vector in embryonic stem (ES) cells. The heterozygous ES cells were introduced into mice by established procedures to produce heterozygous animals that were normal and fertile. No homozygous vinculin-/- embryos were born and analyses during the gestational period showed that the vinculin null embryos were small and abnormal from day E8 but some survived until E10. The most prominent defect was lack of midline fusion of the rostral neural tube, producing a cranial bilobular appearance and attenuation of cranial and spinal nerve development. Heart development was curtailed at E9.5, with severely reduced and akinetic myocardial and endocardial structures. Mutant embryos were 30-40% smaller, somites and limbs were retarded and ectodermal tissues were sparse and fragile. Fibroblasts (MEF) isolated from mutant embryos were shown to have reduced adhesion to fibronectin, vitronectin, laminin and collagen compared to wild-type levels. In addition, migration rates over these substrata were two-fold higher and the level of focal adhesion kinase (FAK) activity was three-fold higher. We conclude that vinculin is necessary for normal embryonic development, probably because of its role in the regulation of cell adhesion and locomotion, cell behaviors essential for normal embryonic morphogenesis, although specific roles in neural and cardiac development cannot be ruled out.
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PMID:Vinculin knockout results in heart and brain defects during embryonic development. 948 5

Balb/c 3T3 cell adhesion on substrata coated with fibronectin's (FN) alternatively-spliced EDb, implicated in some tumor cell systems, and its neighboring type III repeats (III7 and III8) induced intracellular signaling coincident with morphological responses. These events were analysed using minigene-expressed proteins containing various permutations of type III repeats of FN. Cells adherent to the tri-repeat protein 7-EDb-8 were compared to those attached to the tri-repeat 8-9-10 which can interact with integrins through RGD and its synergistic sequences. Cell adhesion to 7-EDb-8 generated rapid tyrosine phosphorylation of several intracellular proteins (particularly the complex at 120-130 kD), with the overall phosphorylation level and its sensitivity to tyrosine kinase inhibitors similar to responses on the 8-9-10 tri-repeat. This similarity contrasted with the differential morphological responses of cells mediated by these proteins. Further analysis of the kinetics of phosphorylation through immunoblotting of two focal adhesion proteins, p125FAK and pl30cas, revealed a profile for Balb/c 3T3 adhesion to 7-EDb-8 distinct from that on 8-9-10. EDb mono-repeat was also more potent for inducing both limited cell spreading and FAK tyrosine phosphorylation than its neighboring repeats III7 or III8. Examination of cellular localization of FAK and vinculin showed that cells spread on the 7-EDb-8 substratum displayed vinculin-positive focal complex-like structures at the cell periphery, in contrast to the classical focal adhesions seen in 8-9-10-adherent cells. These results suggest that EDb induces cell signaling events, leading to tyrosine phosphorylation of focal adhesion proteins, through a mechanism different from that mediated by integrins recognizing sequences in III8-9-10. EDb-dependent signaling may have special significance in some tumor systems.
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PMID:Adhesion to fibronectin's EDb domain induces tyrosine phosphorylation of focal adhesion proteins in Balb/c 3T3 cells. 950 75

We have identified a novel cytoplasmic protein, leupaxin, that is preferentially expressed in hematopoietic cells and is most homologous to the focal adhesion protein, paxillin. Leupaxin possesses two types of protein interaction domains. There are four carboxyl-terminal LIM domains in leupaxin that share 70% amino acid identity and 80% similarity with those in paxillin. Paxillin LIM domains mediate localization to focal contacts. In the amino-terminal region of leupaxin there are three short stretches of approximately 13 amino acids that share 70-90% similarity with paxillin LD motifs. Paxillin LD motifs have been implicated in focal adhesion kinase (FAK) and vinculin binding resulting in the localization of FAK to focal adhesions. Leupaxin is expressed in cell types, such as macrophage, that lack FAK. We demonstrate here that leupaxin associates with a second FAK family member, PYK2. As leupaxin and PYK2 are both preferentially expressed in leukocytes they may therefore form a cell type-specific signaling complex. We also demonstrate that leupaxin is a substrate for a tyrosine kinase in lymphoid cells and thus may function in and be regulated by tyrosine kinase activity. Leupaxin is thus a phosphotyrosine protein with LD and LIM binding motifs most homologous to paxillin that may assemble and regulate PYK2 signaling complexes in leukocytes.
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PMID:Leupaxin is a novel LIM domain protein that forms a complex with PYK2. 956 92

Ceramide induces cell rounding and subsequent apoptotic cell death in trigeminal neurinoma 476-16 cells. A protein tyrosine phosphatase inhibitor, orthovanadate, inhibits cell rounding and subsequent apoptotic death, while a serine/threonine phosphatase inhibitor, calyculin A, stimulates cell rounding but inhibits apoptosis (reference 11). In an attempt to determine critical cellular changes associated with cell rounding during the induction of apoptosis, focal adhesion and cytoskeletal proteins in apoptotic round cells induced by ceramide were examined by immunoblotting and compared with those of non-apoptotic round cells and adherent cells. As compared with adherent cells, tyrosine phosphorylation of a group of proteins between 110-125 KDa, including p125 focal adhesion kinase (FAK) is reduced in the apoptotic round cells as well as in non-apoptotic round cells induced by calyculin A and metaphase cells in mitosis. However, a concerted decrease of vinculin, paxillin and FAK, preceding the changes of whole cellular proteins, is seen in the apoptotic round cells but not in the non-apoptotic round cells. The inhibition of ceramide-induced apoptosis by orthovanadate is accompanied by a prevention of such a decrease in focal adhesion proteins. It thus appears that these focal adhesion proteins are degraded during the cell rounding occurring during apoptosis. Proteolysis of focal adhesion components may not only irreversibly disrupt cell adhesion but also impede transduction of growth and survival signals, and may play a critical role in the initiation and execution of apoptosis.
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PMID:Alterations in focal adhesion and cytoskeletal proteins during apoptosis. 956 94

Cultured fibroblasts from the cutaneous tissue of 16 schizophrenic patients were compared with 16 control cultured fibroblasts from the healthy subjects. The fibroblasts from the schizophrenic patients showed a decreased adhesion efficiency within 30 min after plating compared to that of the control subjects. However, after 90 min, there was no significant difference between the groups, where more than 90% of the cells from both groups had adhesed to the plate. By immunohistochemistry and western blotting using the antibodies against integrin (VLA5), talin, vinculin, fodrin, vimentin, ankyrin, plectin, fibronectin, and focal adhesion kinase (FAK), there was no significant difference in localization and amount between the groups. The amount of fibronectin released into the medium in which the fibroblast had already kept confluency showed no significant difference between the groups. However, the fibronectin content in cell lysate within 48 h after plating was significantly lower in the schizophrenic group.
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PMID:Altered adhesion efficiency and fibronectin content in fibroblasts from schizophrenic patients. 968 89

The Legionnaires' disease bacterium, Legionella pneumophila, is a facultative intracellular pathogen that invades and replicates within two evolutionarily distant hosts, free living protozoa and mammalian cells. Invasion and intracellular replication within protozoa are thought to be major factors in the transmission of Legionnaires' disease. We have recently reported the identification of a galactose/N-acetyl-D-galactosamine (Gal/GalNAc) lectin in the protozoan host Hartmannella vermiformis as a receptor for attachment and invasion by L. pneumophila (Venkataraman, C., B.J. Haack, S. Bondada, and Y.A. Kwaik. 1997. J. Exp. Med. 186:537-547). In this report, we extended our studies to the effects of bacterial attachment and invasion on the cytoskeletal proteins of H. vermiformis. We first identified the presence of many protozoan cytoskeletal proteins that were putative homologues to their mammalian counterparts, including actin, pp125(FAK), paxillin, and vinculin, all of which were basally tyrosine phosphorylated in resting H. vermiformis. In addition to L. pneumophila-induced tyrosine dephosphorylation of the lectin, bacterial attachment and invasion was associated with tyrosine dephosphorylation of paxillin, pp125(FAK), and vinculin, whereas actin was minimally affected. Inhibition of bacterial attachment to H. vermiformis by Gal or GalNAc monomers blocked bacteria-induced tyrosine dephosphorylation of detergent-insoluble proteins. In contrast, inhibition of bacterial invasion but not attachment failed to block bacteria-induced tyrosine dephosphorylation of H. vermiformis proteins. This was further supported by the observation that 10 mutants of L. pneumophila that were defective in invasion of H. vermiformis were capable of inducing tyrosine dephosphorylation of H. vermiformis proteins. Entry of L. pneumophila into H. vermiformis was predominantly mediated by noncoated receptor-mediated endocytosis (93%) but coiling phagocytosis was infrequently observed (7%). We conclude that attachment but not invasion by L. pneumophila into H. vermiformis was sufficient and essential to induce protein tyrosine dephosphorylation in H. vermiformis. These manipulations of host cell processes were associated with, or followed by, entry of the bacteria by a noncoated receptor-mediated endocytosis. A model for attachment and entry of L. pneumophila into H. vermiformis is proposed.
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PMID:Identification of putative cytoskeletal protein homologues in the protozoan host Hartmannella vermiformis as substrates for induced tyrosine phosphatase activity upon attachment to the Legionnaires' disease bacterium, Legionella pneumophila. 968 28

The ubiquitously expressed Na-H exchanger NHE1 functions in regulating intracellular pH and cell volume. NHE1 activity is stimulated by hormones, growth factors, and activation of integrin receptors. We recently determined that NHE1 activity is also stimulated by activation of the low molecular weight GTPase RhoA and that increases in NHE1 activity are necessary for RhoA-induced formation of actin stress fibers. We now show that NHE1 acts downstream of RhoA to modulate initial steps in integrin signaling for the assembly of focal adhesions. Adhesion of CCL39 fibroblasts on fibronectin was markedly delayed in the presence of the NHE inhibitor ethylisopropylamiloride. In mutant PS120 cells, derived from CCL39 fibroblasts but lacking NHE1, adhesion was also delayed but was rescued in PS120 cells stably expressing NHE1. In the absence of NHE1 activity, cell spreading was inhibited, and the accumulation of integrins, paxillin, and vinculin at focal contacts was impaired. Additionally, tyrosine phosphorylation of p125(FAK) induced by integrin clustering was also impaired. Inactivation of RhoA with C3 transferase and inhibition of the Rho-kinase p160ROCK with the pyridine derivative Y-27632 completely abolished activation of NHE1 by integrins but not by platelet-derived growth factor. These findings indicate that NHE1 acts downstream of RhoA to contribute a previously unrecognized critical signal to proximal events in integrin-induced cytoskeletal reorganization.
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PMID:Na-H exchange acts downstream of RhoA to regulate integrin-induced cell adhesion and spreading. 969 82


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