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 effect of several interleukin-1 beta converting enzyme (ICE) inhibitors on apoptosis was examined. The ICE inhibitors tested were peptide aldehydes such as ethyloxycarbonyl-Ala-Tyr-Val-Ala-Asp-aldehyde (Etoco-AYVAD-CHO), acetyl-Tyr-Val-Ala-Asp-aldehyde (Ac-YVAD-CHO), benzyloxycarbonyl-Val-His-Asp-aldehyde (Z-VHD-CHO), a tetrapeptide chloromethylketone, acetyl-Tyr-Val-Ala-Asp-chloromethylketone (Ac-YVAD-Cmk) and their common intermediate benzyloxycarbonyl-Asp-(beta-tertier-butyl ester)-bromomethylketone (Z-D(OtBu)-Bmk). Apoptosis was induced with several chemical agents conventionally used for this purpose in THP-1, L929, NB-41A3 cell lines and mouse thymocytes. DNA fragmentation during apoptosis was measured by conventional gel electrophoresis and ELISA. The cell morphology was examined by hematoxylin/eosin staining method. Cell viability was also monitored by MTT assay. Contrary to expectations, the peptide aldehydes listed above and Ac-YVAD-Cmk, known as highly specific ICE inhibitors, did not inhibit the apoptosis of these cell types. However, Z-D(OtBu)-Bmk, which had no relevant inhibitory activity on ICE, potently blocked the DNA fragmentation in THP-1 cells and thymocytes whichever of the inducing agents was used. In the other two cell lines Z-D(OtBu)-Bmk was inactive. The apoptotic cell morphology was also inhibited by Z-D(OtBu)-Bmk. Nevertheless, Z-D(OtBu)-Bmk failed to prevent the loss of mitochondrial activity and the cell destruction in the late phase of apoptosis. These data suggest that ICE is not involved in the apoptotic cell death induced by chemical agents. Thus, Z-D(OtBu)-Bmk, a common intermediate of some ICE inhibitors, may be a useful antiapoptotic agent for studying the early events of apoptosis in some cell types.
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PMID:Antiapoptotic effect of benzyloxycarbonyl-aspartyl-(beta-tertier-butyl ester)-bromomethylketone (Z-D(OtBu)-Bmk), an intermediate of interleukin-1 beta converting enzyme inhibitors. 937 72

Many cell-surface and extracellular matrix proteins contain multiple modular domains known as fibronectin type III (FNIII) repeats. Cells adhere to the extracellular matrix proteins fibronectin and tenascin in part by the interaction of certain integrins with the Arg-Gly-Asp (RGD) sequence, displayed on specific FNIII repeats. We have found that, after experimental activation of beta1 integrins, a number of cell types adhere and spread on FNIII repeats lacking RGD, derived from extracellular matrix proteins and cytokine receptors. Interaction between individual FNIII domains and beta1 integrins mediates focal adhesion kinase phosphorylation and subsequent stress fiber and focal contact formation. These data suggest that many FNIII-containing proteins may bind and signal through activated beta1 integrins, dramatically expanding the potential for integrin-dependent intercellular and cell-matrix communication.
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PMID:Fibronectin type III repeats mediate RGD-independent adhesion and signaling through activated beta1 integrins. 939 78

The rat L6 skeletal muscle cell line was used to study expression of the dystrophin-containing glycoprotein complex and its interaction with the integrin system involved in the cell-matrix adhesion reaction. A complex of dystrophin and its associated proteins was fully expressed in L6 myotubes, from which anti-dystrophin or anti-alpha-sarcoglycan co-precipitated integrin alpha 5 beta 1 and other focal adhesion-associated proteins vinculin, talin, paxillin, and focal adhesion kinase. Immunostaining and confocal microscopy revealed that dystrophin, alpha-sarcoglycan, integrin alpha 5 beta 1, and vinculin exhibited overlapping distribution in the sarcolemma, especially at focal adhesion-like, spotty structures. Adhesion of cells to fibronectin- or collagen type I-coated dishes resulted in induction of tyrosine phosphorylation of alpha- and gamma-sarcoglycans but not beta-sarcoglycan. The same proteins were also tyrosine-phosphorylated when L6 cells in suspension were exposed to Arg-Gly-Asp-Ser peptide. All of these tyrosine phosphorylations were inhibited by herbimycin A. On the other hand, treatment of L6 myotubes with alpha- and gamma-sarcoglycan antisense oligodeoxynucleotides resulted in complete disappearance of alpha- and gamma-sarcoglycans and in significant reduction of levels of the associated focal adhesion proteins, which caused about 50% reduction of cell adhesion. These results indicate the existence of bidirectional communication between the dystrophin-containing complex and the integrin adhesion system in cultured L6 myocytes.
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PMID:Bidirectional signaling between sarcoglycans and the integrin adhesion system in cultured L6 myocytes. 943 Jun 99

Klebsiella oxytoca strain HB60 is highly resistant to cefoperazone and aztreonam (MICs = 128 mg/L). It produces a chromosomally encoded beta-lactamase of pI 5.7 which was highly efficient against penicillins, first-generation cephalosporins and cefoperazone, a non-oxyimino third-generation cephalosporin. Aztreonam and oxyimino broad-spectrum cephalosporins were less good substrates. The beta-lactamase activity was susceptible to inhibition by clavulanic acid (IC50 = 1 microM). The enzyme purified to homogeneity had a specific activity towards benzylpenicillin of 3670 U/mg. The 263 amino acid residues of the protein were sequenced by Edman degradation of proteolytic peptides. The beta-lactamase was shown to belong to the OXY-2 group as it had only one amino acid substitution (Asn for Asp at ABL position 197) compared with the beta-lactamase (pI 5.2) from the aztreonam-susceptible K. oxytoca strain SL911 and two substitutions (Ala223 for Val and Asp255 for Asn) compared with the beta-lactamase (pI 6.4) from the aztreonam-resistant K. oxytoca strain D488. These three OXY-2-group enzymes behave in the same way towards beta-lactam antibiotics. The variability in the resistance of these K. oxytoca strains would thus seem to be due to variation in the level of production of the beta-lactamases rather than to structural alteration of the enzymes.
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PMID:Characterization and amino acid sequence of the OXY-2 group beta-lactamase of pI 5.7 isolated from aztreonam-resistant Klebsiella oxytoca strain HB60. 946 29

The human colon adenocarcinoma cell lines Colo 201 and Colo 205 lose adhevise capacity to the extracellular matrix (ECM) and take on a round and floating cell shape. Treatment of these cells with all-trans-retinoic acid (RA) results in inhibition of growth and in a marked increase in the production of carcinoembryonic antigen, thereby indicating that the cells undergo differentiation. This RA-induced differentiation was accompanied by a large increase in the degree of cell adhesion with localization of E-cadherin molecules at cell-cell contact sites. We examined several adhesion molecules involved in cell-cell and cell-ECM interaction by immunoblotting, but no change in E-cadherin, intercellular adhesion molecule-1, or CD44 was observed in RA-treated Colo 201 cells. Although the adhesion of Colo 201 cells to ECM depends on the Arg-Gly-Asp sequence, levels of integrins, alpha 2, alpha 3, alpha 5, alpha V, and beta 1 in differentiated adherent cells were similar to those in untreated cells. In contrast to equivalent amounts of cell surface adhesion molecules before and after differentiation, intracellular focal adhesion kinase (FAK) was markedly induced during RA treatment, and the increase in FAK resulted in elevation of tyrosine-phosphorylated FAK. These findings suggest a role for FAK in activation of cell adhesion of RA-induced differentiation of these colon cancer cells. This may serve as an appropriate model to examine the mode of activation of the adhesive capacity of cancer cells.
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PMID:Acquisition of cell adhesion and induction of focal adhesion kinase of human colon cancer Colo 201 cells by retinoic acid-induced differentiation. 956 10

HOE 901 is a new biosynthetic long-acting human insulin analog (GLY[A21]ARG[B31]ARG[B32]). We compared HOE 901 with normal human insulin and the insulin analog Asp(B10), which is known to have increased mitogenic activity at least partially mediated through the insulin receptor. We have analyzed receptor binding, insulin-induced receptor autophosphorylation and phosphorylation of receptor substrates in rat-1 fibroblasts overexpressing human insulin receptor isoform A (HIR A) or B (HIR B). In HIR A expressing cells, insulin and its analogs showed no significant differences in receptor association while clearly different dissociation kinetics were observed. In HIR B expressing cells, no significant differences in association and dissociation kinetics were observed. All insulins induced rapid autophosphorylation of the insulin receptor reaching a maximum after 10 min of stimulation. Asp(B10)insulin induced a prolonged phosphorylation state (over 60 minutes) of the 95 kDa receptor beta-subunit and of the substrates IRS-1/IRS-2 and Shc in contrast to normal human insulin and to HOE 901. In addition, we observed an increased and prolonged tyrosine phosphorylation of an unidentified protein with Asp(B10)insulin at about 60 kDa. Insulin-dependent dephosphorylation of the focal adhesion kinase (p125FAK) was equally induced by all these ligands. With respect to [3H]thymidine incorporation into DNA, HOE 901 had similar effects as normal human insulin, while Asp(B10)insulin showed increased [3H]thymidine incorporation. In summary, the data show that the increased mitogenic activity of Asp(B10)insulin may be explained with a prolonged kinetics of tyrosine phosphorylation of the insulin receptor and of insulin signalling elements together with the preferential phosphorylation of an yet unidentified 60 kDa protein. HOE 901 behaves with respect to insulin receptor binding, receptor autophosphorylation, phosphorylation of signalling elements and promotion of mitogenesis like regular human insulin.
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PMID:The long acting human insulin analog HOE 901: characteristics of insulin signalling in comparison to Asp(B10) and regular insulin. 956 52

We have previously reported that non-activated platelets can be induced by morphological changes from the recombinant fusion protein of GST-rhodostomin [GST-RHO(RGD)], a member of disintegrin with an arginine-glycine-aspartic acid (RGD) motif. In this study, we further characterized the factors involved in platelet shape changes induced by rhodostomin. From less to full-spreading, four cell spreading indexes, p1, p2, s1 and s2, were designated to the platelet shape based on the scanning electron micrographs. Results of peptide competition and antibody blocking confirmed that interaction between the RGD of rhodostomin and the alpha(IIb)beta3 integrins of platelets was required for induction of a higher percentage of s2 cells. When platelets were pretreated with calphostin C, herbimycin A and cytochalasin B, respectively, the percentage of p1 and p2 cells on rhodostomin-coated plates was increased and, concomitantly, the percentage of s1 and s2 cells was decreased. Biochemical analyses indicated that the focal adhesion kinase (FAK or pp125FAK) in platelets that adhered to GST-RHO(RGD) was phosphorylated in contrast to little or no phosphorylation of FAK in cells adhered to fibrinogen or non-activated cells. Furthermore, the degree of FAK phosphorylation was consistently correlated with morphological changes in platelets treated with various drugs. Taking all the results together, we suggested that rhodostomin could directly bind to integrins of platelets and then trigger signal transduction leading to FAK phosphorylation and actin polymerization and finally resulting in platelet full-spreading.
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PMID:Full-spreading platelets induced by the recombinant rhodostomin are via binding to integrins and correlated with FAK phosphorylation. 969 Jul 77

Caspases, a family of cysteine proteases, are the key effector proteins of apoptosis. These proteases cleave cellular proteins and are responsible for the destruction of the cell body during apoptosis. They are also involved in the activation of other proteins, such as cytokines. In this study, we demonstrate a novel function for these proteases. Z-Asp-CH2-DCB (Z-Asp), a general caspase inhibitor, blocked cell spreading on collagen-coated plates in a dose-dependent manner but did not affect cell viability. Caspase 3-like activity but not caspase 1-like activity was detected in adherent cells on both collagen-coated and poly-L-lysine-coated plates but not in suspended cells. The caspase 3-like activity was significantly inhibited by Z-Asp. However, only Z-Asp, not specific caspase inhibitors (Z-DEVD for caspase 3, Z-YVAD for caspase 1), was effective in the suppression of cell spreading. The inhibitory effect of Z-Asp was blocked by a phosphokinase C activator, PMA, and a Rho activator, lysophosphatidic acid (LPA), while neither a Rac activator, bradykinin, nor a Cdc42 activator, sphingosine-1 -phosphate, was effective. Immunoprecipitation demonstrated that Z-Asp downregulated the expression of focal adhesion kinase (FAK) protein, downstream of Rho signaling, in adherent cells. Our results suggest that not caspase 1 or 3 but another yet unknown caspase(s) plays an important role in the maintenance of cytoskeleton integrity via FAK protein expression, implying a new function for caspases.
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PMID:Possible involvement of caspase-like family in maintenance of cytoskeleton integrity. 1008 31

Interaction of epithelial cells with the extracellular matrix is mediated through integrin receptors, which transmit signals regulating cell growth, differentiation and death. Occupation of these receptors, via Arg-Gly-Asp (RGD) recognition sequences, leads to activation of focal adhesion kinase (FAK). We treated human breast cancer cell lines with RGD-containing peptides, which can disrupt integrin attachment, and investigated alterations in FAK phosphorylation, cell detachment and death. Cells grown in vitro were treated with insulin-like growth factor-binding protein-1 (IGFBP-1) and a small, synthetic RGD-containing peptide (Gly-Arg-Gly-Asp-Thr-Pro) and its negative control peptide RGE (Arg-Gly-Glu-Ser) for either 30 min followed by immunoprecipitation of cell lysates with anti-phosphotyrosine and Western immunoblotting with anti-FAK or for 24 h followed by cell counting, immunocytochemistry and flow cytometry. Both IGFBP-1 (0-800 ng/ml) and the synthetic RGD-containing peptide (1-100 microg/ml) caused significant dephosphorylation of FAK. Furthermore, after 24 h both peptides caused detachment from the matrix and the induction of apoptosis. We conclude from these data that IGFBP-1 can interact with integrin receptors to induce FAK dephosphorylation and subsequently influence attachment and cell death.
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PMID:Effect of insulin-like growth factor binding protein-1 on integrin signalling and the induction of apoptosis in human breast cancer cells. 1019 17

We have previously shown that overexpression of focal adhesion kinase (FAK) in Chinese hamster ovary (CHO) cells promoted their migration on fibronectin. This effect was dependent on the phosphorylation of FAK at Tyr-397. This residue was known to serve as a binding site for both Src and phosphatidylinositol 3-kinase (PI3K), implying that either one or both are required for FAK to promote cell migration. In this study, we have examined the role of PI3K in FAK-promoted cell migration. We have demonstrated that the PI3K inhibitors, wortmannin and LY294002, were able to inhibit FAK-promoted migration in a dose-dependent manner. Furthermore, a FAK mutant capable of binding Src but not PI3K was generated by a substitution of Asp residue 395 with Ala. When overexpressed in CHO cells, this differential binding mutant failed to promote cell migration although its association with Src was retained. Together, these results strongly suggest that PI3K binding is required for FAK to promote cell migration and that the binding of Src and p130(Cas) to FAK may not be sufficient for this event.
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PMID:Requirement of phosphatidylinositol 3-kinase in focal adhesion kinase-promoted cell migration. 1021 7


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