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)

In rat liver epithelial cell lines (WB or GN4), angiotensin II (Ang II) stimulates cytosolic tyrosine kinase activity, in part, through a calcium-dependent mechanism. In other cell types, selected hormones that activate Gi- or Gq-coupled receptors stimulate the soluble tyrosine kinase, p125FAK. Immunoprecipitation of p125FAK from Ang II-activated GN4 cells demonstrated a doubling of p125FAK kinase activity. However, an additional Ang II-activated tyrosine kinase (or kinases) representing the majority of the total activity was detected when the remaining cell lysate, immunodepleted of p125FAK, was reimmunoprecipitated with an anti-phosphotyrosine antibody. Cytochalasin D pretreatment blocks G-protein receptor-dependent tyrosine phosphorylation in Swiss 3T3 cells. While cytochalasin D decreased the Tyr(P) content of 65-75-kDa substrates in Ang II-treated GN4 cells, it did not diminish tyrosine phosphorylation of 115-130-kDa substrates, again suggesting activation of at least two tyrosine kinase pathways in GN4 cells. To search for additional Ang II-activated enzymes, we used molecular techniques to identify 20 tyrosine kinase sequences in these cell lines. None was the major cytosolic enzyme activated by Ang II. Specifically, JAK2, which had been shown by others to be stimulated by Ang II in smooth muscle cells, was not activated by Ang II in GN4 cells. Finally, we purified Tyr(P)-containing tyrosine kinases from Ang II-treated cells, using anti-Tyr(P) and ATP affinity resins; 80% of the tyrosine kinase activity migrated as a single 115-120-kDa tyrosine-phosphorylated protein immunologically distinct from p125FAK. In summary, Ang II activates at least two separate tyrosine kinases in rat liver epithelial cells; p125FAK and a presumably novel, cytosolic 115-120-kDa protein referred to as the calcium-dependent tyrosine kinase.
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PMID:Angiotensin II activates at least two tyrosine kinases in rat liver epithelial cells. Separation of the major calcium-regulated tyrosine kinase from p125FAK. 749 50

T cell-mediated immune responses are initiated by interaction of antigen bound to a glycoprotein encoded by the major histocompatibility complex with the T cell antigen receptor (TCR). These recognition and binding steps are followed by multiple intracellular biochemical events. The earliest event detected is an increase in intracellular protein tyrosine phosphorylation that involves a complex interaction of tyrosine kinases and phosphatases. Subsequently, one observes an increase in protein serine/threonine phosphorylation, phospholipid hydrolysis, and changes in intracellular Ca2+ levels. These and other biochemical changes lead to cell proliferation, differentiation, and acquisition of effector functions. While binding of extracellular growth factors to receptors containing cytoplasmic protein tyrosine kinase (PTK) domains induces direct activation of their kinase activity, the multichain TCR lacks an intrinsic kinase domain and therefore represents a distinct type of receptor. It transduces signals via the interaction with, and activation of, non-receptor PTKs. Recent efforts directed at defining the TCR-linked signaling pathways have provided insight into the regulatory role of three PTKs, and the functional importance of some unique protein motifs in both TCR subunits and PTKs, which mediate critical protein-protein interactions in this pathway.
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PMID:The role of tyrosine kinases and phosphotyrosine-containing recognition motifs in regulation of the T cell-antigen receptor-mediated signal transduction pathway. 750 72

Addition of 1-oleoyl-lysophosphatidic acid (LPA) induces tyrosine phosphorylation of multiple substrates in Swiss 3T3 cells including bands of M(r) 110,000-130,000 and M(r) 70,000-80,000. An increase in tyrosine phosphorylation of the M(r) 110,000-130,000 cluster of bands was detected as soon as 30 s after LPA stimulation reaching a maximum within 1 min. LPA stimulated tyrosine phosphorylation of all bands in a concentration-dependent fashion; a half-maximal effect occurred at 30 nM. Immunoprecipitation of lysates of LPA-treated cells with monoclonal antibodies that specifically recognize focal adhesion kinase (p125FAK), paxillin, and p130 revealed that these proteins are prominent substrates for LPA-stimulated tyrosine phosphorylation. Down-regulation of protein kinase C (PKC) by prolonged pretreatment with phorbol 12,13-dibutyrate, selective inhibition of PKC by GF109203X, or depletion of the intracellular Ca2+ pool by thapsigargin had no effect on LPA-stimulated tyrosine phosphorylation. Thus, protein tyrosine phosphorylation by LPA is largely independent of either the PKC or Ca2+ pathways. In contrast, pretreatment of the cells with cytochalasin D, which selectively disrupts the network of the actin filaments, completely inhibited LPA-induced tyrosine phosphorylation. Furthermore, tyrosine phosphorylation of p125FAK induced by LPA was completely prevented when cells were stimulated in the presence of platelet-derived growth factor at a concentration (30 ng/ml) that causes disruption of actin stress fibers. This suggests that the integrity of the actin cytoskeleton is essential for LPA-induced tyrosine phosphorylation and reveals a novel cross-talk between LPA and platelet-derived growth factor on p125FAK tyrosine phosphorylation.
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PMID:Lysophosphatidic acid stimulates tyrosine phosphorylation of focal adhesion kinase, paxillin, and p130. Signaling pathways and cross-talk with platelet-derived growth factor. 751 Jul 8

FAK is a focal adhesion kinase that is phosphorylated on tyrosine in activated platelets. Induction of FAK phosphorylation requires both fibrinogen binding to integrin alpha IIb beta 3 and post-occupancy events during agonist-induced platelet aggregation or platelet spreading on a fibrinogen matrix. To identify the signaling pathways necessary for tyrosine phosphorylation of FAK, we have examined the conditions that stimulate or inhibit this phosphorylation in platelets in which fibrinogen binding to alpha IIb beta 3 and platelet aggregation were induced directly with an anti-beta 3 Fab fragment (anti-LIBS6). Apyrase was added to prevent effects of the endogenous platelet agonist, ADP. Under these conditions, neither fibrinogen binding nor primary platelet aggregation was sufficient to induce FAK phosphorylation, suggesting that a second "costimulatory" event was required. Indeed, when epinephrine was added with fibrinogen and anti-LIBS6, large platelet aggregates formed and FAK phosphorylation occurred. This response was prevented by blockade of cyclooxygenase with indomethacin or thromboxane A2 receptors with SQ 30,741. A stable thromboxane A2 analogue (U46619) could substitute for epinephrine as the costimulus. Epinephrine costimulation of FAK phosphorylation was also prevented by chelation of intracellular Ca2+ with BAPTA or selective inhibition of protein kinase C (PKC) with bisindolylmaleimide, indicating that Ca2+ and PKC are necessary for FAK phosphorylation under these conditions. Epinephrine also promoted FAK phosphorylation and adhesive spreading of apyrase-treated platelets on a fibrinogen matrix. Cytochalasin D, an inhibitor of actin polymerization, blocked FAK phosphorylation under all these conditions. Thus, tyrosine phosphorylation of FAK in platelets requires coordinated signaling through occupied integrin and agonist receptors. These separate pathways may converge to increase free Ca2+ and activate PKC and thus promote the cytoskeletal reorganization required for activation of FAK.
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PMID:Tyrosine phosphorylation of pp125FAK in platelets requires coordinated signaling through integrin and agonist receptors. 751 81

To define the T-cell receptor signal transduction motif, we have transfected human and murine T-cell lines with a chimeric receptor consisting of the extracellular and transmembrane domains of human CD8 alpha and the membrane-proximal portion of CD3 zeta containing at its C terminus either an 18-amino acid segment (NQLYNELNLGRREEYDVL) or alanine-scanning point mutant derivatives. Crosslinking of the extracellular domain of the chimera is sufficient to initiate Ca2+ flux, interleukin 2 production, and tyrosine phosphorylation of cellular proteins including the chimera. Subsequently, the chimera becomes associated with several tyrosine-phosphorylated proteins, among them the 70-kDa protein tyrosine kinase ZAP70. Mutational data identify the T-cell activation motif as Y(X)2L(X)7Y(X)2L and show that each of the four designated residues is necessary for the above activation events. Recombinant protein containing the two tandem SH2 domains derived from ZAP70 binds to a synthetic peptide corresponding to the above 18-amino acid motif but only when both tyrosines are phosphorylated; in contrast, little or no binding is observed to monophosphorylated or nonphosphorylated analogues. These results imply that after receptor crosslinking in T cells, and by inference also in B cells and mast cells, the motif is phosphorylated on both tyrosine residues, thereafter serving as a docking site for protein tyrosine kinases containing tandem SH2 domains.
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PMID:Delineation of a T-cell activation motif required for binding of protein tyrosine kinases containing tandem SH2 domains. 751 60

The protein tyrosine kinase PYK2, which is highly expressed in the central nervous system, is rapidly phosphorylated on tyrosine residues in response to various stimuli that elevate the intracellular calcium concentration, as well as by protein kinase C activation. Activation of PYK2 leads to modulation of ion channel function and activation of the MAP kinase signalling pathway. PYK2 activation may provide a mechanism for a variety of short- and long-term calcium-dependent signalling events in the nervous system.
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PMID:Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. 765 31

A variant nonkiller (K-) T-cell clone derived from the MHC nonrestricted killer (K+) cell line TALL-103/2 (CD3/TCR gamma delta +) was studied to determine whether its lytic defects were at the tumor-binding or post-binding level. The two TALL-103/2 clones were found to display similar mRNA expression of TCR/CD3 complex epsilon, zeta, gamma, and delta chains, and the same mRNA and protein levels of SRC-like protein tyrosine kinase and kinase activity. However, the K- cells express much less surface CD45 RA and contain smaller intracytoplasmatic cytotoxic granules with a lower expression of the TIA-1 protein. Although the K- cells do not undergo granule exocytosis upon contact with a susceptible (K562) target, they can be triggered to degranulate and display redirected killing by activation of the CD3 receptor. Moreover, OKT3 induces PPI turnover and Ca2+ mobilization in both the K+ and K- cells, whereas K562 cells induces PPI turnover only in the K+ clone. The overall data indicate that, although the K- cells have significant post-binding defects that prevent them from killing MHC nonrestricted targets, they can fully utilize their lytic machinery upon specific activation of the CD3 pathway.
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PMID:A revertant TCR gamma delta + cell clone which has lost MHC nonrestricted cytotoxic activity but retains redirected killing upon stimulation of the CD3 receptor. 755 90

Dictyostelium discoideum cells harbor two annexin VII isoforms of 47 and 51 kDa which are present throughout development. In immunofluorescence and cell fractionation studies annexin VII was found in the cytoplasm and on the plasma membrane. In gene disruption mutants lacking both annexin VII isoforms growth, pinocytosis, phagocytosis, chemotaxis and motility were not significantly impaired under routine laboratory conditions, and the cells were able to complete the developmental cycle on bacterial plates. On non-nutrient agar plates development was delayed by three to four hours and a significant number of aggregates was no longer able to form fruiting bodies. Exocytosis as determined by measuring extracellular cAMP phosphodiesterase, alpha-fucosidase and alpha-mannosidase activity was unaltered, the total amounts of these enzymes were however lower in the mutant than in the wild type. The mutant cells were markedly impaired when they were exposed to low Ca2+ concentrations by adding EGTA to the nutrient medium. Under these conditions growth, motility and chemotaxis were severely affected. The Ca2+ concentrations were similar in mutant and wild-type cells both under normal and Ca2+ limiting conditions; however, the distribution was altered under low Ca2+ conditions in SYN-cells. The data suggest that annexin VII is not required for membrane fusion events but rather contributes to proper Ca2+ homeostasis in the cell.
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PMID:The in vivo role of annexin VII (synexin): characterization of an annexin VII-deficient Dictyostelium mutant indicates an involvement in Ca(2+)-regulated processes. 765 24

Treatment of quiescent Swiss 3T3 cells with 20 microM ([(3,4,5-trihydroxyphenyl)methylene]propanedinitrile) (tyrphostin) caused a 76% reduction in the tyrosine phosphorylation of the M(r) 110,000-130,000 band induced by bombesin. This was accompanied by a 48% reduction in the tyrosine phosphorylation of the cytosolic tyrosine kinase p125 focal adhesion kinase. Preincubation with 20 microM tyrphostin did not inhibit either protein kinase A activation by forskolin or protein kinase C (PKC) activation by phorbol 12,13-dibutyrate in intact Swiss 3T3 cells. Similarly, 20 microM tyrphostin neither interfered with binding of bombesin to its receptor nor prevented bombesin-stimulated Ca2+ mobilization or PKC activation. Thus tyrphostin selectively inhibits tyrosine phosphorylation induced by bombesin in intact Swiss 3T3 cells. Consequently, we examined the contribution of this tyrosine phosphorylation pathway to the subsequent induction of c-fos and stimulation of mitogenesis by bombesin. Tyrphostin prevented both c-fos mRNA expression and DNA synthesis induced by bombesin. The incorporation of [3H] thymidine was inhibited by tyrphostin in a dose-dependent manner (IC50 = 20 microM), and this effect was not reversed even at high concentrations of bombesin. These results provide evidence that tyrosine phosphorylation is a mitogenic signal for bombesin.
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PMID:Tyrphostin inhibits bombesin stimulation of tyrosine phosphorylation, c-fos expression, and DNA synthesis in Swiss 3T3 cells. 768 55

The biological effects of growth hormone (GH) are initiated by its binding to the GH receptor (GHR) followed by association and activation of the tyrosine kinase JAK2. Here we report that GH can stimulate an increase in intracellular free Ca2+ concentration ([Ca2+]i) in cells expressing wild-type GHRs and receptor mutants lacking up to 132 amino acids of the C terminus, whereas GHRs lacking a further 52 amino acids in the C terminus are unable to induce Ca2+ signaling. The GH-induced rise in [Ca2+]i was dependent upon extracellular Ca2+ and the response consisted of GH-induced Ca2+ oscillations of varying frequency and amplitude. GH-induced transcription of the serine protease inhibitor 2.1 gene required the same C-terminal 52-amino acid domain of the receptor as for Ca2+ signaling. Mutation of the four proline residues in the conserved box 1 region of the GHR, which is responsible for binding and activation of JAK2 kinase, completely abolished GH-induced gene transcription but did not affect the GH-induced rise in [Ca2+]i. The Ca2+ channel blocker verapamil prevented GH-induced Ca2+ signaling as well as GH-induced gene transcription in cells expressing endogenous GHRs. These findings indicate that the GHR can initiate two independent signaling pathways, one requiring the box 1 region and the other requiring the region between amino acids 454 and 506, and suggest that both of these pathways are required for GH-induced gene transcription.
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PMID:Growth hormone receptor C-terminal domains required for growth hormone-induced intracellular free Ca2+ oscillations and gene transcription. 770 14


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