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 focal adhesion kinase (FAK) has been implicated in integrin-mediated signaling events and in the mechanism of cell transformation by the v-Src and v-Crk oncoproteins. To gain further insight into FAK signaling pathways, we used a two-hybrid screen to identify proteins that interact with mouse FAK. The screen identified two proteins that interact with FAK via their Src homology 3 (SH3) domains: a v-Crk-associated tyrosine kinase substrate (Cas), p130Cas, and a still uncharacterized protein, FIPSH3-2, which contains an SH3 domain closely related to that of p130Cas. These SH3 domains bind to the same proline-rich region of FAK (APPKPSR) encompassing residues 711-717. The mouse p130Cas amino acid sequence was deduced from cDNA clones, revealing an overall high degree of similarity to the recently reported rat sequence. Coimmunoprecipitation experiments confirmed that p130Cas and FAK are associated in mouse fibroblasts. The stable interaction between p130Cas and FAK emerges as a likely key element in integrin-mediated signal transduction and further represents a direct molecular link between the v-Src and v-Crk oncoproteins. The Src family kinase Fyn, whose Src homology 2 (SH2) domain binds to the major FAK autophosphorylation site (tyrosine 397), was also identified in the two-hybrid screen.
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PMID:Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130Cas. 747 64

Growth factor-binding protein 2 (Grb2) is an adaptor protein that links tyrosine kinases to Ras. BCR-ABL is a tyrosine kinase oncoprotein that is implicated in the pathogenesis of Philadelphia chromosome (Ph1)-positive leukemias. Grb2 forms a complex with BCR-ABL and the nucleotide exchange factor Sos that leads to the activation of the Ras protooncogene. In this report we demonstrate that Grb2 mutant proteins lacking amino- or carboxyl-terminal src homology SH3 domains suppress BCR-ABL-induced Ras activation and reverse the oncogenic phenotype. The Grb2 SH3-deletion mutant proteins bind to BCR-ABL and do not impair tyrosine kinase activity. Expression of the Grb2 SH3-deletion mutant proteins in BCR-ABL-transformed Rat-1 fibroblasts and in the human Ph1-positive leukemic cell line K562 inhibits their ability to grow as foci in soft agar and form tumors in nude mice. Furthermore, expression of the Grb2 SH3-deletion mutants in K562 cells induced their differentiation. Because Ras plays an important role in signaling by receptor and nonreceptor tyrosine kinases, the use of interfering mutant Grb2 proteins may be applied to block the proliferation of other cancers that depend in part on activated tyrosine kinases for growth.
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PMID:Mutant forms of growth factor-binding protein-2 reverse BCR-ABL-induced transformation. 747 4

Reconstitution with mouse interleukin-2 (IL-2) receptor subunits demonstrated that the mouse IL-2 receptor complex was different from the human complex in the alpha chain requirement for the functional mouse receptor complex. The heterotrimeric complex of the mouse exogenous alpha and beta chains and the endogenous gamma chain on mouse lymphoid BW5147 cells showed the ability to bind IL-2 with high affinity, resulting in IL-2-induced tyrosine phosphorylation of a cytosolic tyrosine kinase, JAK3, which is involved in IL-2-dependent signals. Exogenous introduction of the beta chain with the endogenous gamma chain, however, could neither confer appreciable IL-2 binding nor IL-2-induced signal transduction on BW5147 cells, unlike the human beta gamma heterodimer. Mouse spleen CD8+ cells, not having the alpha chain initially, showed IL-2-dependent cell proliferation only when expression of the alpha chain was induced. Collectively, these results illustrate that the functional mouse IL-2 receptor complex necessarily includes the alpha chain, and that the regulation of CD8+ T cell growth during immune reaction depends upon alpha chain expression.
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PMID:Differences in the interleukin-2 (IL-2) receptor system in human and mouse: alpha chain is required for formation of the functional mouse IL-2 receptor. 748 34

We have isolated a cDNA encoding a novel human intracytoplasmic tyrosine kinase, termed RAFTK (for a related adhesion focal tyrosine kinase). In addition, we have cloned and characterized the murine homolog of the human RAFTK cDNA. Comparison of the deduced amino acid sequences of human RAFTK and murine Raftk cDNAs revealed 95% homology, indicating that RAFTK is highly conserved between these species. The RAFTK cDNA clone, encoding a polypeptide of 1009 amino acids, has closest homology (48% identity, 65% similarity) to the focal adhesion kinase (pp125FAK). Comparison of the deduced amino acid sequences also indicates that RAFTK, like pp125FAK, lacks a transmembrane region, myristylation sites, and SH2 and SH3 domains. In addition, like pp125FAK, RAFTK contains a kinase domain flanked by large N-terminal (426 residues) and C-terminal (331 residues) domains, and the C-terminal region contains a predicted proline-rich stretch of residues. In fetal tissues, RAFTK expression was abundant in brain, and low levels were observed in lung and liver. In adult tissues, it was less restricted, indicating that RAFTK expression is developmentally up-regulated. Expression of RAFTK was also observed in human CD34+ marrow cells, primary bone marrow megakaryocytes, platelets, and various areas of brain. The human RAFTK gene was assigned to human chromosome 8 using genomic DNAs from human/rodent somatic cell hybrid lines. The mouse Raftk gene was mapped to chromosome 14, closely linked to gonadotropin-releasing hormone. Using specific antibodies for RAFTK, a approximately 123-kDa protein from the human megakaryocytic CMK cell line was immunoprecipitated. Treatment of the megakaryocytic CMK cells with thrombin caused a rapid induction of tyrosine phosphorylation of RAFTK protein. The structural features of RAFTK suggest that it is a member of the focal adhesion kinase gene family and may participate in signal transduction in human megakaryocytes and brain as well as in other cell types.
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PMID:Identification and characterization of a novel related adhesion focal tyrosine kinase (RAFTK) from megakaryocytes and brain. 749 42

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

The tyrosine kinase JAK2 is an integral part of the signal transduction pathways of a number of cytokines and growth factors, including IFN-gamma. Previously, we identified a species-nonspecific binding site for the C terminus of IFN-gamma, encompassed by IFN-gamma peptide IFN-gamma(95-133), on the membrane proximal region of the cytoplasmic domain of the IFN-gamma R alpha-chain. Using both a radioligand binding assay and coimmunoprecipitation with antireceptor antiserum, we were able to demonstrate specific interaction of JAK2 with the murine IFN-gamma R(MIR) alpha-chain. Furthermore, this interaction is increased by the addition of murine IFN-gamma or its C-terminal peptide, muIFN-gamma(95-133). We also identified two regions of the cytoplasmic domain of the receptor that interact with JAK2 using synthetic peptides of the MIR alpha-chain in receptor competition studies. These regions are encompassed by receptor peptide MIR(283-309), which is adjacent to the membrane proximal region at which the C terminus of IFN-gamma binds, and receptor peptide MIR(404-432), which lies near the C terminus of the receptor, encompassing a potentially important phosphorylation site. These data show site-specific interaction between JAK2 and IFN-gamma with the IFN-gamma R and have broader implications for the role of the IFN-gamma ligand in the IFN-gamma signal transduction pathway. Furthermore, the data support previous studies that demonstrated that intracellular IFN-gamma plays a role in cell activation.
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PMID:Identification of IFN-gamma receptor binding sites for JAK2 and enhancement of binding by IFN-gamma and its C-terminal peptide IFN-gamma(95-133). 749 45

Transformation of hematopoietic cells by the p210bcr/abl tyrosine kinase appears to require the expression of a functional MYC protein, suggesting that simultaneous targeting of BCR-ABL and c-myc might be a rational strategy for attempting treatment of Phil-adelphia leukemia. To test this hypothesis, severe combined immunodeficiency mice injected with Philadelphia leukemic cells were treated systemically with equal doses of bcr-abl or c-myc antisense oligodeoxynucleotides (ODNs) or with both ODNs in combination. Compared with the mice treated with individual agents, the disease process was much slower in the group treated with both ODNs, as revealed by flow cytometry, clonogenic assay, and reverse transcriptase-polymerase chain reaction analysis to detect leukemic cells in mouse tissue cell suspensions, and by enumeration of liver metastases. The retardation of the disease process was positively correlated with a markedly increased survival of leukemic mice treated with both ODNs. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.
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PMID:Leukemia treatment in severe combined immunodeficiency mice by antisense oligodeoxynucleotides targeting cooperating oncogenes. 750 9

The c-kit receptor tyrosine kinase is highly expressed by about 10% of the neurons in the dorsal root ganglia (DRGs) of mouse embryos. We investigated the in vitro effect of stem cell factor (SCF), the ligand for c-kit receptor, on DRGs. Recombinant murine SCF (rmSCF) induced the outgrowth of c-kit-positive neurites from DRGs of normal (+/+) embryos. The effect of SCF was dose dependent and completely abolished by anti-c-kit ACK2 monoclonal antibody (mAb). Some neurites whose outgrowth was induced by nerve growth factor (NGF) were c-kit-positive, but anti-NGF mAb did not inhibit the rmSCF-induced neurite outgrowth. rmSCF did not induce neurite outgrowth from DRGs of W/W embryos that did not express c-kit receptors on the cell surface and of W42/W42 mutant embryos that expressed c-kit receptors without tyrosine kinase activity. rmSCF also had a trophic effect on c-kit-positive neurons in the culture of dissociated DRG cells. Most c-kit-positive neurons appeared to respond to NGF as well, and the SCF-responsive subpopulation represented about 10% of NGF-responsive neurons. rmSCF did not support the survival of DRG neurons from embryos of W/W and W42/W42 genotypes. These results suggest that the stimulus through the c-kit receptor tyrosine kinase has an important role in development of the peripheral nervous system.
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PMID:Stem cell factor induces outgrowth of c-kit-positive neurites and supports the survival of c-kit-positive neurons in dorsal root ganglia of mouse embryos. 750 40

JAK family tyrosine kinases have recently been implicated in intracellular signal transduction by transmembrane cytokine receptors of the interferon (IFN) and hematopoietin receptor families. Using the prolactin (PRL)-dependent rat pre-T cell line Nb2, a PRL receptor-associated, candidate tyrosine kinase of 120-130 kDa was recently characterized (1). In the present work this protein is identified as JAK2, based upon reciprocal anti-JAK2 and anti-phosphotyrosine immunoprecipitation and immunoblotting. JAK2 underwent rapid and transient tyrosine phosphorylation in response to receptor activation, reaching peak levels within 5 min of exposure to 100 nM PRL at 37 degrees C. In vitro tyrosine kinase assays using either [gamma-32P]ATP and autoradiography or unlabeled ATP combined with anti-phosphotyrosine immunoblotting, demonstrated that the activity of JAK2 was stimulated by PRL. Phosphoamino acid analysis of JAK2 after in vitro tyrosine kinase assay revealed that the majority of phosphate was incorporated into tyrosine residues. Furthermore, JAK2 was associated with PRL receptors to a comparable extent before and after PRL binding, as demonstrated by anti-receptor immunoprecipitation and subsequent anti-JAK2 immunoblotting. We propose that binding of ligand to the PRL receptor activates preassociated JAK2, and that this enzyme generates the initial signal in the intracellular communication cascade.
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PMID:Activation of receptor-associated tyrosine kinase JAK2 by prolactin. 750 35

We report the cloning of a novel tyrosine kinase (TyK)-encoding gene (TYK) from the human hepatoma cell line Hep3B. Using the polymerase chain reaction (PCR) and oligodeoxyribonucleotide primers based on conserved TYK motifs, a 180-bp fragment was cloned and used to obtain full-length cDNA clones of 2.9 kb, with an open reading frame of 505 amino acids (aa). Restricted expression was detected by Northern blotting or reverse-transcribed PCR in a broad range of cell lines. The predicted aa sequence contains characteristic TyK motifs without a transmembrane region, suggesting an intracellular localization. There was 49% aa sequence identity with human FYN product and 47% with human SRC product; however, several structural differences distinguish this clone from other SRC subfamily members. This clone, FYN-related kinase or FRK, is a novel member of the intracellular TYK gene family.
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PMID:Cloning of FRK, a novel human intracellular SRC-like tyrosine kinase-encoding gene. 751 Feb 61


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