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)

Growth hormone (GH) plays a central role in regulating growth and intermediary metabolism in vertebrates, although the mechanisms by which GH initiates these actions are largely unknown. The GH receptor, a member of the cytokine receptor superfamily, does not demonstrate homology with any known tyrosine kinases. However, addition of GH to cells in vitro has been shown to stimulate tyrosine phosphorylation of various intracellular proteins including mitogen-activated protein kinases (MAP kinases) and the newly described Janus kinase, JAK2. Subsequent steps in GH-mediated signal transduction have not been delineated. In the present study, we have examined early events in GH action in vivo. Hypophysectomized juvenile male rats were treated with GH for 15, 30, or 60 min. Rat liver whole cell and nuclear extracts were prepared and analyzed via SDS-polyacrylamide gel electrophoresis and Western blotting techniques. GH rapidly stimulated the tyrosine phosphorylation of at least 8 nuclear proteins of 205, 91, 83, 80, 65, 53, 44, and 42 kDa, and caused the dephosphorylation of a single approximately 149-kDa protein. Using specific antibodies, we have identified three of these nuclear phosphoproteins as 42- and 44-kDa MAP kinases, and as STAT91, a 91-kDa component of the interferon-stimulated gene factor-3 protein complex. One consequence of the activation of STAT91 in the nucleus is the appearance of GH-stimulated DNA binding activity, as assessed by gel-mobility shift assay using an oligonucleotide containing a c-sis-inducible element from the c-fos promoter. These results show that nuclear protein tyrosine phosphorylation is a prominent early event in GH action in vivo and demonstrate a link between GH-stimulated signal transduction and target gene expression.
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PMID:Rapid changes in nuclear protein tyrosine phosphorylation after growth hormone treatment in vivo. Identification of phosphorylated mitogen-activated protein kinase and STAT91. 751 Jun 76

The intracellular pathways by which the binding of growth hormone (GH) to its receptor elicits its diverse effects have eluded investigators for many years. Studies showing that GH rapidly stimulates tyrosyl phosphorylation of cellular proteins, and that tyrosine kinase activity co-purifies with GH-GH receptor complexes, led us to hypothesize that activation by GH of a receptor-associated tyrosine kinase is an important early, and perhaps, initiating step in signal transduction by GH. Here, we review the work identifying JAK2 as a GH receptor-associated tyrosine kinase that is rapidly activated by ligand binding.
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PMID:The identification of JAK2 tyrosine kinase as a signaling molecule for growth hormone. 751 45

Both the growth hormone (GH) and interferon gamma (IFN gamma) receptors are members of the cytokine receptor family that activate tyrosine phosphorylation despite the lack of a tyrosine kinase domain. Recently, the Janus kinase (JAK) family of tyrosine kinases have been shown to play an integral role in intracellular signaling by the cytokine receptors. We demonstrate that, in the human IM-9 lymphocyte, both JAK1 and JAK2 are tyrosine-phosphorylated in response to IFN gamma, whereas only JAK2 is tyrosine-phosphorylated in response to GH. Furthermore, dimerization of the GH receptor appears to be necessary for GH stimulated tyrosine phosphorylation of JAK2. We provide two lines of evidence that the JAK2 kinases can be regulated independently by GH and IFN gamma in IM-9 cells: 1) desensitization of JAK2 to GH stimulation does not affect the IFN gamma stimulated tyrosine phosphorylation of JAK2; and 2) JAK2 tyrosine phosphorylation by GH and IFN gamma is additive to that seen with either hormone alone. Furthermore, we demonstrate that although IFN gamma activates the tyrosine phosphorylation of the p91 signal transducer and activator of transcription (STAT1) in IM-9 cells, GH does not. GH does activate the tyrosine phosphorylation of a 93-kDa protein that appears to be distinct from STAT1.
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PMID:Differential tyrosine phosphorylation of JAK1, JAK2, and STAT1 by growth hormone and interferon-gamma in IM-9 cells. 752 56

Growth hormone (GH) has been shown to stimulate the mitogen-activated protein (MAP) kinases designated ERKs (extracellular signal regulated kinases) 1 and 2. One pathway by which ERKs 1 and 2 are activated by tyrosine kinases involves the Src homology (SH)-2 containing proteins SHC and Grb2. To gain insight into pathways coupling GH receptor (GHR) to MAP kinase activation and signaling molecules that might interact with GHR and its associated tyrosine kinase JAK2, we examined whether SHC and Grb2 proteins serve as signaling molecules for GH. Human GH was shown to promote the rapid tyrosyl phosphorylation of 66-, 52-, and 46-kDa SHC proteins in 3T3-F442A fibroblasts. GH also promoted binding of GHR and JAK2 to the SH2 domain of 46/52-kDa SHC protein fused to glutathione S-transferase (GST). Constitutively phosphorylated JAK2, from COS-7 cells transiently transfected with murine JAK2 cDNA, bound to SHC SH2-GST fusion protein, demonstrating that the SHC SH2 domain can bind tyrosyl-phosphorylated JAK2 in the absence of GHR. Regions of GHR required for GH-dependent tyrosyl phosphorylation of SHC were examined using Chinese hamster ovary cells expressing mutated rat GHR. In cells expressing GHR1-638 and GHR1-638(Y333,338F), GH stimulated phosphorylation of all 3 SHC proteins whereas GH stimulated phosphorylation of only the 66- and 52-kDa SHC proteins in cells expressing GHR1-454. GH had no effect on SHC phosphorylation in cells expressing GHR1-294 or GHR delta P, the latter lacking amino acids 297-311 containing the proline-rich motif required for JAK2 activation by GH. In contrast to SHC, Grb2 appeared not to interact directly with GHR or JAK2. However, Grb2 was shown to associate rapidly with SHC proteins in a GH-dependent manner. These findings suggest that GH stimulates: 1) the association of SHC proteins with JAK2.GHR complexes via the SHC-SH2 domain, 2) tyrosyl phosphorylation of SHC proteins, and 3) subsequent Grb2 association with SHC proteins. These events are likely to be early events in GH activation of MAP kinases and possibly of other responses to GH.
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PMID:Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2. 753 73

Growth hormone (GH) treatment of cells promotes activation of JAK2, a GH receptor (GHR)-associated tyrosine kinase. We now explore JAK2 regions required for GHR-induced signaling. Wild-type (WT) JAK2 and JAK2 molecules with deletions of the amino terminus (JAK2ATD), carboxyl terminus (JAK2CTD), or kinase-like domain (JAK2PKD) were each transiently coexpressed in COS-7 cells with the rabbit GHR. The following responses were assayed: GH-induced transactivation of a luciferase reporter governed by a c-fos enhancer element; GH-induced shift in the molecular mass of a cotransfected epitope-tagged extracellular signal-regulated kinase molecule; and GH-induced antiphosphotyrosine immunoprecipitability of the transfected JAK2 form. In each assay, WTJAK2 and JAK2PKD allowed GH-induced signaling, whereas JAK2ATD and JAK2CTD did not. Anti-GHR serum coimmunoprecipitated WTJAK2, JAK2PKD, and JAK2CTD, but not JAK2ATD. Finally, a chimera in which the JAK2 kinase domain replaced the GHR cytoplasmic domain signaled GH-induced transactivation. We conclude: 1) kinase-like domain deletion eliminates neither physical nor functional interaction between JAK2 and the GHR; 2) kinase domain deletion eliminates functional but not physical coupling of JAK2 to the GHR; 3) interaction with the GHR appears dependent on the NH2-terminal one-fifth of JAK2; and 4) a GH-responsive signaling unit can include as little as the GHR external and transmembrane domains and the JAK2 kinase domain.
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PMID:Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor. 754 Jan 78

Many signaling pathways initiated by ligands that activate receptor tyrosine kinases have been shown to involve the binding of SH2 domain-containing proteins to specific phosphorylated tyrosines in the receptor. Although the receptor for growth hormone (GH) does not contain intrinsic tyrosine kinase activity, GH has recently been shown to promote the association of its receptor with JAK2 tyrosine kinase, to activate JAK2, and to promote the tyrosyl phosphorylation of both GH receptor (GHR) and JAK2. In this work, we examined whether tyrosines 333 and/or 338 in GHR are phosphorylated by JAK2 in response to GH. Tyrosines 333 and 338 in rat full-length (GHR1-638) and truncated (GHR1-454) receptor were replaced with phenylalanines and the mutated GHRs expressed in Chinese hamster ovary cells. These substitutions caused a loss of GH-dependent tyrosyl phosphorylation of truncated receptor and a reduction of GH-dependent phosphorylation of the full-length receptor. Consistent with Tyr333 and/or Tyr338 serving as substrates of JAK2, these substitutions resulted in a loss of tyrosyl phosphorylation of truncated receptor in an in vitro kinase assay using substantially purified GH.GHR.JAK2 complexes. The Tyr to Phe substitutions did not substantially alter GH-dependent JAK2 association with GHR or tyrosyl phosphorylation of JAK2. These results suggest that Tyr333 and/or Tyr338 in GHR are phosphorylated in response to GH and may therefore serve as binding sites for SH2 domain-containing proteins in GH signal transduction pathways.
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PMID:Growth hormone-dependent phosphorylation of tyrosine 333 and/or 338 of the growth hormone receptor. 754 68

Supraphysiological levels of glucocorticoids, whether endogenous (Cushing's syndrome) or exogenous (glucocorticoid therapy), inhibit growth in children and immature animals. This effect has long been suspected to be due to glucocorticoid antagonism of GH action at the level of peripheral tissues. In the present study we demonstrate direct antagonism of GH action at the cellular level by the artificial glucocorticoid dexamethasone. Dexamethasone was found to inhibit the ability of GH to elicit several early events in GH signaling in 3T3-F442A fibroblasts. Dexamethasone (100 nM) for 24 h decreases by 50-75% GH-induced tyrosyl phosphorylation of mitogen-activated protein kinases ERK1 and ERK2, the transcription factor Stat3/APRF, the GH receptor-associated tyrosine kinase JAK2, and the GH receptor. These effects appear to be specific to GH. Dexamethasone does not inhibit induction of tyrosyl phosphorylation of ERK proteins by epidermal growth factor or phorbol myristate acetate, nor does it block induction of tyrosyl phosphorylation of Stat3/APRF by leukemia inhibitory factor or interleukin-6, or induction of JAK2 by leukemia inhibitory factor or interferon-gamma. Dexamethasone does not decrease the expression of ERK1 or -2, Stat3, or JAK2 proteins. Rather, the effects of dexamethasone on GH action appear to be due to a decrease in the number of GH receptors in the plasma membrane. Twenty-four-hour treatment with dexamethasone leads to a 50% decrease i GH binding, which Scatchard analysis suggests is due to a decrease in GH receptor number. These findings suggest that glucocorticoids antagonize cellular GH action by decreasing GH binding, suggesting a mechanism by which systemic glucocorticoids could antagonize GH action in peripheral tissues.
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PMID:Dexamethasone-induced antagonism of growth hormone (GH) action by down-regulation of GH binding in 3T3-F442A fibroblasts. 758 9

Several investigations have clearly indicated that plasma concentrations of insulin-like growth factor I (IGF-I) decrease with age and contribute to the decrease in tissue function that is characteristic of aging animals and man. Plasma IGF-I is regulated by GH released from the pituitary gland, and although data demonstrate a decline in GH secretion with age, GH receptor (GHR) density in liver tissue has been reported to increase. In this study, the effects of aging on GHR signal transduction were assessed in hepatic tissue to determine whether alterations in the response to GH contribute to the decline in IGF-I. Liver slices from female C57BL/6 mice (10, 17, and 31 months old) were prepared in medium and stimulated with GH. Basal GHR binding increased more than 2-fold in 31-month-old animals compared to that in either 10- or 17-month-old animals (P < 0.01), whereas the Ka values were similar in the three age groups. However, GH (2 nM)-induced IGF-I gene expression decreased dramatically with age (P < 0.01). In 10-month-old animals, GH-induced phosphorylation of the GHR complex was maximal 10 min after the addition of hormone, whereas GH-induced MAP kinase activity was maximal at 15 min. GH-induced JAK2 kinase and GHR complex phosphorylation as well as MAP kinase activity were significantly lower in 31-month-old animals than in either the 10- or 17-month-old groups (P < 0.05). The results of this study demonstrate that GH induces phosphorylation of JAK2 and the GHR complex, activates MAP kinase, and increases the expression of IGF-I messenger RNA in liver. In 17-month-old animals, decreases in IGF-I gene expression were evident that were not directly associated with diminished GHR complex phosphorylation or MAP kinase activity. By 31 months, there was a decrease in IGF-I gene expression that was associated with a marked decline in JAK2 and GHR complex phosphorylation. These data suggest that the signal transduction pathway for GH is impaired with age and that these changes may contribute to the decline in IGF-I gene expression.
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PMID:Decreases in growth hormone receptor signal transduction contribute to the decline in insulin-like growth factor I gene expression with age. 766 76

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

The identification of JAK2 as a growth hormone (GH) receptor-associated, GH-activated tyrosine kinase has established tyrosyl phosphorylation as a signaling mechanism for GH. In the present study, GH is shown to stimulate tyrosyl phosphorylation of insulin receptor substrate 1 (IRS-1), the principle substrate of the insulin receptor. Tyrosyl phosphorylation of IRS-1 is a critical step in insulin signaling and provides binding sites for proteins with the appropriate Src homology 2 domains, including the 85-kDa regulatory subunit of phosphatidylinositol (PI) 3'-kinase. In 3T3-F442A fibroblasts, GH-dependent tyrosyl phosphorylation of IRS-1 was detected by 1 min and at GH concentrations as low as 5 ng/ml (0.23 nM). Tyrosyl phosphorylation of IRS-1 was transient, with maximal stimulation detected at 30 min and diminished signal detected at 60 min. The ability of GH receptor (GHR) to transduce the signal for IRS-1 tyrosyl phosphorylation is mediated by the intracellular region of GHR between amino acids 295 and 380 by a mechanism not involving the two tyrosines in this region. This region of GHR is required for GH-dependent JAK2 association and activation (VanderKuur, J. A., Wang, X., Zhang, L., Campbell, G. S., Allevato, G., Billestrup, N., Norstedt, G., and Carter-Su, C. (1994) J. Biol. Chem. 269, 21709-21717). When other cytokines that activate JAK2 were tested for the ability to stimulate the tyrosyl phosphorylation of IRS-1, stimulation was detected with interferon-gamma and leukemia inhibitory factor. The correlation between JAK2 tyrosyl phosphorylation and IRS-1 tyrosyl phosphorylation in response to GH, interferon-gamma, and leukemia inhibitory factor and in cells expressing different GHR mutants, provides evidence that IRS-1 may interact with JAK2 or an auxiliary molecule that binds to JAK2. GH is also shown to stimulate binding of IRS-1 to the 85-kDa regulatory subunit of PI 3'-kinase. The ability of GH to stimulate tyrosyl phosphorylation of IRS-1 and its association with PI 3'-kinase provides a biochemical basis for responses shared by insulin and GH including the well characterized insulin-like metabolic effects of GH observed in a variety of cell types.
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PMID:Growth hormone, interferon-gamma, and leukemia inhibitory factor promoted tyrosyl phosphorylation of insulin receptor substrate-1. 778 32


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