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)

Lactogens [prolactin (Prl) and growth hormone] stimulate phosphorylation of the 40S ribosomal protein, S6, in Nb2 cells by mechanisms that do not involve participation of cAMP or protein kinase A, protein kinase C, or cGMP-dependent protein kinase. However, inhibition of tyrosine kinase (TK) abrogates Prl-mediated macromolecular biosynthesis. Inasmuch as lactogen signaling may involve sequential activation of protein kinases, the effect of Prl on the well-characterized mitogen-activated protein kinase (MAPK) and S6 kinase (S6K), the enzyme responsible for S6 phosphorylation in vivo, and their relationship to Nb2 macromolecular biosynthesis and mitogenesis were investigated. The results show that MAPK stimulation is transient (peak activity, 30 min) and precedes that of S6K, which reaches a maximum at 1.5-2 h, and slowly returns towards control levels at 6 h. Both staurosporine which inhibits GH receptor-associated kinase (JAK2) and genistein (GEN), an inhibitor of membrane-associated and cytoplasmic TKs, abrogate Prl-stimulated TK, MAPK, and S6K. Rapamycin (RAP), a specific inhibitor of p70S6K, completely blocks S6K but does not affect TK and MAPK. TK and MAPK activity correlates with Prl-stimulated anabolism, i.e., protein and DNA synthesis and mitogenesis. Thus, concentrations of STR and GEN which abrogate TK and MAPK inhibit anabolism virtually 100%. However, RAP, which inhibits S6K (ca. 100%) but not TK or MAPK, only delays Prl-mediated anabolism. These results indicate that Prl signaling in Nb2 cells involves a protein kinase cascade and that regulation of receptor-associated kinase, TK, and MAPK correlates with anabolism. The role of S6K (and S6 phosphorylation) appears to be ancillary.
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PMID:Stimulation of receptor-associated kinase, tyrosine kinase, and MAP kinase is required for prolactin-mediated macromolecular biosynthesis and mitogenesis in Nb2 lymphoma. 784 Jun 14

Aberrant function of protein kinases has been implicated in the development of melanoma. In an effort to define the molecular events involved in initiation and progression of this malignancy, we used RT-PCR to identify protein kinases in both normal and transformed melanocytes. Collectively, we identified seven clones corresponding to previously characterized protein kinases (JAK-1, TYK02, AXL/UFO, IGF1-R, KDR and FER) as well as the recently identified MLK-3/PTK1 protein kinase. Northern analysis was used to determine the expression pattern of each protein kinase in both normal melanocytes and a variety of melanoma cell lines. Relatively abundant levels of UFO/AXL and KDR mRNAs were observed in a subset of the melanoma cell lines whereas most of the remaining protein kinases were expressed at similar levels in both normal and transformed melanocytes.
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PMID:Protein kinases in normal and transformed melanocytes. 785 16

Interferons (IFNs) alpha/beta (type I) and gamma (type II) bind to distinct cell surface receptors, inducing transcription of overlapping sets of genes by intracellular pathways that have recently attracted much attention. Previous studies using cell lines selected for their inability to respond to IFN-alpha (ref. 4) have shown that the protein kinase Tyk2 plays a central role in the IFN alpha/beta response. Here we report the isolation of the cell line gamma 1A, selected for its inability to express IFN-gamma-inducible cell-surface markers, that is deficient in all aspects of the IFN-gamma response tested, but responds normally to IFNs alpha and beta. The mutant cells can be complemented by the expression of another member of the JAK family of protein tyrosine kinases, JAK2 (refs 6-9). Unlike IFNs alpha and beta, IFN-gamma induces rapid tyrosine phosphorylation of JAK2 in wild-type cells, and JAK2 immunoprecipitates from these cells show tyrosine kinase activity. These responses are absent in gamma 1A cells. JAK2 is therefore required for the response to IFN-gamma but not to IFNs alpha and beta.
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PMID:Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. 823 50

Integrins and other adhesion receptors are essential components for outside-in and inside-out signaling through the cell membrane. The platelet glycoprotein IIb-IIIa (also known as fibrinogen receptor or integrin alpha IIb beta 3) is activated by platelet agonists, inhibited by cyclic-nucleotide-elevating agents, and is involved in the activation of protein tyrosine kinases including the 125-kDa focal adhesion kinase (pp125FAK). However, the molecular details of glycoprotein IIb-IIIa regulation are not well understood. Here we report that in ADP-activated human platelets cAMP- and cGMP-dependent protein-kinase-mediated phosphorylation of the focal adhesion vasodilator-stimulated phosphoprotein (VASP) at Ser157 correlates well with glycoprotein IIb-IIIa inhibition. Human platelets contain similar concentrations of glycoprotein IIb-IIIa complexes (fibrinogen binding sites) and VASP. Using gel-filtered platelets, cAMP-elevating agents [e.g. prostaglandin E1 and the forskolin analog 6-(3-dimethylaminopropionyl)forskolin (NKH 477)] caused VASP Ser157 phosphorylation and inhibited glycoprotein IIb-IIIa activation up to 70-100%. NO-generating, cGMP-elevating agents [e.g. 3-morpholinosydnonimine hydrochloride (SIN1) and sodium nitroprusside] stimulated VASP Ser157 phosphorylation and inhibited glycoprotein IIb-IIIa activation up to a maximal extent of 30-50%. The effects of cAMP- and cGMP-elevating agents on VASP phosphorylation and fibrinogen binding were reversible and could be mimicked by membrane-permeant selective activators of platelet cAMP- or cGMP-dependent protein kinase, respectively. Using threshold concentrations, the nitrovasodilator SIN 1 potentiated the effects of the forskolin analog NKH 477 with respect to inhibition of platelet aggregation, VASP phosphorylation and glycoprotein IIb-IIIa inhibition. It is proposed that the inhibition of glycoprotein IIb-IIIa induced by cyclic nucleotide involves cAMP-and cGMP-dependent protein-kinase-mediated VASP phosphorylation at Ser157.
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PMID:Phosphorylation of focal adhesion vasodilator-stimulated phosphoprotein at Ser157 in intact human platelets correlates with fibrinogen receptor inhibition. 792 40

The proliferation of normal hematopoietic cells is strictly factor dependent, while leukemic cell lines and primary leukemic cells are frequently factor independent. Although autocrine growth stimulation of human leukemias is occasionally observed in vitro, it is possible that mutations of signal-transduction or cell-cycle control genes may also be important in the development of factor independence. We have previously shown that the proto-oncogene Raf-1, a 70-kd serine/threonine protein kinase, is rapidly phosphorylated and activated by hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and Steel factor and is likely to be an important intermediate in mitogenic signal transduction pathways in hematopoietic cells. In an effort to better understand the possible role of abnormal signal transduction in the development of factor independence, we compared the state of phosphorylation and associated kinase activity of Raf-1 between a series of factor-dependent human and murine-myeloid normal cells or cell lines and a series of factor-independent myeloid cell lines. In factor-dependent myeloid cells (normal neutrophils; monocytes; and the cell lines MO7, 32Dc13, and FDC-P1), Raf-1 phosphorylation and associated kinase activity was strictly regulated by the supply of growth factor. In contrast, each of eight factor-independent leukemic cell lines examined, HL-60, KG-1, K562, U937, JOSK-S, JOSK-M, JOSK-K, and JOSK-I, expressed hyperphosphorylated Raf-1 with increased Raf-1 associated kinase activity in the absence of growth factor addition. To further explore the relationship of Raf-1 to factor-independent growth, factor-independent sublines were derived from two factor-dependent cell lines, MO7 and FDC-P1, by culture in CSF-deprived medium. Also, several factor-independent sublines were derived by transfection of a cDNA encoding p210BCR/ABL into three different cell lines: MO7, 32Dc13, and FDC-P1. In each case, the new sublines expressed constitutively hyperphosphorylated and activated Raf-1. The correlation of hyperphosphorylation of Raf-1 with factor independence was also observed with primary acute myeloblastic leukemia cells. The rate of "spontaneous" proliferation of primary acute myeloblastic leukemia (AML) cells in vitro correlated with the extent of Raf-1 phosphorylation. These results suggest that the evolution of myeloid leukemic cells to factor independence is associated with phosphorylation and activation of Raf-1, implicating Raf-1 and signal transduction pathways which activate RAf-1 in this process.
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PMID:Factor independence of human myeloid leukemia cell lines is associated with increased phosphorylation of the proto-oncogene Raf-1. 792 78

The erythropoietin receptor (EpoR) belongs to the cytokine receptor family, members of which lack a tyrosine kinase domain. Recent studies, however, have shown that a cytoplasmic tyrosine kinase, JAK2, interacts with the cytoplasmic domain of the EpoR and becomes activated upon binding of Epo to the receptor. Epo has also been shown to stimulate activation of Ras and Raf-1. The present studies were undertaken to examine the possible involvement of Epo-induced tyrosine phosphorylation in activation of the Ras/mitogen-activated protein kinase (MAP kinase) pathway and to determine its significance on the growth signaling from the EpoR. In an interleukin (IL)-3-dependent cell line expressing the transfected wild-type EpoR, Epo, or IL-3 induced tyrosine phosphorylation of Shc and its association with Grb2. These cytokines also induced tyrosine phosphorylation and activation of MAP kinase isoforms ERK1 and ERK2. A mutant EpoR with a carboxyl-terminal deletion of 108 amino acids (H mutant), which is mitogenically functional but lacks tyrosine phosphorylation sites in the carboxyl-terminal region, showed markedly diminished abilities to induce tyrosine phosphorylation of Shc and to phosphorylate and activate MAP kinases. A mutant receptor (PM4 mutant) inactivated by a point mutation, Trp282 to Arg, which abrogates the interaction with JAK2, failed to induce any effect on Shc or MAP kinases. In cells expressing a mutant EpoR that is constitutively activated by a point mutation, Arg129 to Cys, in the extracellular portion of the receptor, neither tyrosine phosphorylation of Shc nor activation of MAP kinases by phosphorylation was detectable without stimulation with Epo or IL-3. These results suggest that the carboxyl-terminal region of EpoR may play a crucial role in activation of MAP kinases through the Ras signaling pathway which may be activated by tyrosine phosphorylation of Shc and its association with Grb2. The activation of MAP kinases, however, failed to correlate with the mitogenic activity of mutant EpoRs and thus may not be required for growth signaling from the EpoR.
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PMID:Activation of the mitogen-activated protein kinase pathway by the erythropoietin receptor. 796 95

We have previously shown that the IL-6R in a growth-responsive B cell line, AF10, induces activation of mitogen-activated protein (MAP) kinase. Here we demonstrate the activation of Raf-1 and MEK-1, which act as a MAP kinase kinase kinase and a MAP kinase kinase, respectively, in the MAP kinase cascade induced by IL-6 in AF10 cells. IL-6 also induced tyrosine phosphorylation of the signaling transducing subunit of the IL-6R in AF10 cells, along with tyrosine phosphorylation of the gp130-associated tyrosine protein kinase JAK1 and the adaptor molecule p52shc. Although induction of tyrosine phosphorylation and activation of MAP kinase by IL-6 in a differentiation-responsive B cell line, SKW 6.4, were below the limits of detection, the phorbol ester PMA did activate Raf-1, MEK-1, and MAP kinase without inducing the phosphorylation of gp130, JAKs, or p52shc. These results suggest that JAK kinase family members associated with the IL-6R may participate in the activation of MAP kinase in AF10 cells by way of an adaptor protein and Ras-dependent kinase cascade.
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PMID:Involvement of Janus kinases, p52shc, Raf-1, and MEK-1 in the IL-6-induced mitogen-activated protein kinase cascade of a growth-responsive B cell line. 796 20

The high-affinity receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF) consists of a unique alpha chain and a beta c subunit that is shared with the receptors for interleukin-3 (IL-3) and IL-5. Two regions of the beta c chain have been defined; these include a membrane-proximal region of the cytoplasmic domain that is required for mitogenesis and a membrane-distal region that is required for activation of Ras, Raf-1, mitogen-activated protein kinase, and S6 kinase. Recent studies have implicated the cytoplasmic protein tyrosine kinase JAK2 in signalling through a number of the cytokine receptors, including the IL-3 and erythropoietin receptors. In the studies described here, we demonstrate that GM-CSF stimulation of cells induces the tyrosine phosphorylation of JAK2 and activates its in vitro kinase activity. Mutational analysis of the beta c chain demonstrates that only the membrane-proximal 62 amino acids of the cytosolic domain are required for JAK2 activation. Thus, JAK2 activation is correlated with induction of mitogenesis but does not, alone, activate the Ras pathway. Carboxyl truncations of the alpha chain, which inactivate the receptor for mitogenesis, are unable to mediate GM-CSF-induced JAK2 activation. Using baculovirus-expressed proteins, we further demonstrate that JAK2 physically associates with the beta c chain but not with the alpha chain. Together, the results further support the hypothesis that the JAK family of kinase are critical to coupling cytokine binding to tyrosine phosphorylation and ultimately mitogenesis.
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PMID:JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. 800 42

Previously, we characterized the prostaglandin (PG) F2 alpha receptor linked to phospholipase C activation and DNA synthesis in NIH-3T3 cells (Nakao, A., Watanabe, T., Taniguchi, S., Nakamura, M., Honda, Z-I., Shimizu, T., and Kurokawa, K. (1993) J. Cell. Physiol. 155, 257-264). To elucidate intracellular events evoked via this receptor, we examined changes caused by PGF2 alpha stimulation in the phosphotyrosine composition of cellular proteins. The addition of PGF2 alpha to cells in quiescent culture rapidly increased the levels of phosphotyrosine in cellular proteins with Mr values of 70,000 (pp70), 85,000 (pp85), 92,000 (pp92), 100,000 (pp100), and 125,000 (pp125); the latter was immunologically identified as p125 focal adhesion kinase. The PGF2 alpha-induced changes in the level of intracellular Ca2+ ([Ca2+]i) elevation, formation of inositol phosphates, and [3H]thymidine incorporation followed a similar dose dependence as PGF2 alpha-induced tyrosine phosphorylation. This tyrosine phosphorylation was independent of extracellular Ca2+, while a [Ca2+]i chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (50 microM), completely inhibited the PGF2 alpha-induced elevation of [Ca2+]i, tyrosine phosphorylation, and [3H]thymidine incorporation. Ionomycin (0.1 microM), which induced [Ca2+]i elevation without formation of inositol phosphates, mimicked the PGF2 alpha-induced tyrosine phosphorylation. 12-O-Tetradecanoylphorbol-13-acetate (TPA) also induced [3H]thymidine incorporation in a dose-dependent manner but had no significant effect on tyrosine phosphorylation. The PGF2 alpha-induced tyrosine phosphorylation could be observed even in the cells pretreated with TPA (5 microM, 24 h). PGF2 alpha exhibited an additive effect on TPA-induced [3H]thymidine incorporation but had no effect on the 32P-phosphorylation of a known 80-kDa protein kinase (PK) C substrate. Both staurosporine and H-7 inhibited the PGF2 alpha-induced increase in [3H]thymidine incorporation and tyrosine phosphorylation in a similar dose-dependent manner whether or not cells were pretreated with TPA (5 microM, 24 h). However, W-7 and KN-62 had no effect on these cellular responses even at the concentration for the almost complete inhibition of Ca2+/calmodulin-dependent PKs (20 microM). These results, taken together, indicate that PGF2 alpha receptor-mediated tyrosine phosphorylation is evoked by a [Ca2+]i-dependent mechanism that is sensitive to staurosporine and H-7 but which is independent of PKC or Ca2+/calmodulin PKs. Finally, the data suggest that this PGF2 alpha-induced signaling pathway is linked to the proliferation of cells.
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PMID:Prostaglandin F2 alpha enhances tyrosine phosphorylation and DNA synthesis through phospholipase C-coupled receptor via Ca(2+)-dependent intracellular pathway in NIH-3T3 cells. 802 Dec 71

Fertilization results in the tyrosine phosphorylation of several egg proteins within minutes of sperm-egg binding, although the identity of the kinase(s) involved and the mechanism of regulation is not known. In the present study, we have used site-directed antibodies based on the predicted amino acid sequence of a sea urchin egg transcript that shares significant homology with members of the ABL family of protein tyrosine kinases. These antibodies identified a 220-kDa protein kinase, highly enriched in the egg cortex, where it is tightly associated with detergent-insoluble cytoskeletal elements. The enzyme is capable of phosphorylating synthetic peptide substrates which were used to characterize the kinase activity in an immune-complex assay. Measurement of the protein tyrosine kinase activity immunoprecipitated at different times after fertilization revealed that the level of kinase activity is transiently elevated during the first few minutes postinsemination. Western blot analysis indicated that the amount of the 220-kDa protein did not increase significantly during this period, so the increased kinase activity probably results from activation of the enzyme. These in vitro studies indicate that the 220-kDa abl-related kinase is one of the protein kinases activated during fertilization and suggest that it may play a role in the egg activation process.
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PMID:Identification of an abl-related protein tyrosine kinase in the cortex of the sea urchin egg: possible role at fertilization. 804 47


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