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) signaling requires activation of the GH receptor (GHR)-associated tyrosine kinase, JAK2. JAK2 activation by GH is believed to facilitate initiation of various pathways including the Ras, mitogen-activated protein kinase, STAT, insulin receptor substrate (IRS), and phosphatidylinositol 3-kinase systems. In the present study, we explore the biochemical and functional involvement of the Src homology 2 (SH2)-containing protein-tyrosine phosphatase, SHP-2, in GH signaling. GH stimulation of murine NIH 3T3-F442A fibroblasts, cells that homologously express GHRs, resulted in tyrosine phosphorylation of SHP-2. As assessed specifically by anti-SHP-2 coimmunoprecipitation and by affinity precipitation with a glutathione S-transferase fusion protein incorporating the SH2 domains of SHP-2, GH induced formation of a complex of tyrosine phosphoproteins including SHP-2, GHR, JAK2, and a glycoprotein with properties consistent with being a SIRP-alpha-like molecule. A reciprocal binding assay using IM-9 cells as a source of SHP-1 and SHP-2 revealed specific association of SHP-2 (but not SHP-1) with a glutathione S-transferase fusion incorporating GHR cytoplasmic domain residues 485-620, but only if the fusion was first rendered tyrosine-phosphorylated. GH-dependent tyrosine phosphorylation of SHP-2 was also observed in murine 32D cells (which lack IRS-1 and -2) stably transfected with the GHR. Further, GH-dependent anti-SHP-2 coimmunoprecipitation of the Grb2 adapter protein was detected in both 3T3-F442A and 32D-rGHR cells, indicating that biochemical involvement of SHP-2 in GH signaling may not require IRS-1 or -2. Finally, GH-induced transactivation of a c-Fos enhancer-driven luciferase reporter in GHR- and JAK2-transfected COS-7 cells was significantly reduced when a catalytically inactive SHP-2 mutant (but not wild-type SHP-2) was coexpressed; in contrast, expression of a catalytically inactive SHP-1 mutant allowed modestly enhanced GH-induced transactivation of the reporter in comparison with that found with expression of wild-type SHP-1. Collectively, these biochemical and functional data imply a positive role for SHP-2 in GH signaling.
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PMID:Involvement of the Src homology 2-containing tyrosine phosphatase SHP-2 in growth hormone signaling. 944 80

Growth hormone (GH) and prolactin (PRL) binding to their receptors, which belong to the cytokine receptor superfamily, activate Janus kinase (JAK) 2 tyrosine kinase, thereby leading to their biological actions. We recently showed that GH mainly stimulated tyrosine phosphorylation of epidermal growth factor receptor and its association with Grb2, and concomitantly stimulated mitogen-activated protein kinase activity in liver, a major target tissue. Using specific antibodies, we now show that GH was also able to induce tyrosine phosphorylation of insulin receptor substrate (IRS)-1/IRS-2 in liver. In addition, the major tyrosine-phosphorylated protein in anti-p85 phosphatidylinositol 3-kinase (PI3-kinase) immunoprecipitate from liver of wild-type mice was IRS-1, and IRS-2 in IRS-1 deficient mice, but not epidermal growth factor receptor. These data suggest that tyrosine phosphorylation of IRS-1 may be a major mechanism for GH-induced PI3-kinase activation in physiological target organ of GH, liver. We also show that PRL was able to induce tyrosine phosphorylation of both IRS-1 and IRS-2 in COS cells transiently transfected with PRLR and in CHO-PRLR cells. Moreover, we show that tyrosine phosphorylation of IRS-3 was induced by both GH and PRL in COS cells transiently transfected with IRS-3 and their cognate receptors. By using the JAK2-deficient cell lines or by expressing a dominant negative JAK2 mutant, we show that JAK2 is required for the GH- and PRL-dependent tyrosine phosphorylation of IRS-1, -2, and -3. Finally, a specific PI3-kinase inhibitor, wortmannin, completely blocked the anti-lipolytic effect of GH in 3T3 L1 adipocytes. Taken together, the role of IRS-1, -2, and -3 in GH and PRL signalings appears to be phosphorylated by JAK2, thereby providing docking sites for p85 PI3-kinase and activating PI3-kinase and its downstream biological effects.
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PMID:Growth hormone and prolactin stimulate tyrosine phosphorylation of insulin receptor substrate-1, -2, and -3, their association with p85 phosphatidylinositol 3-kinase (PI3-kinase), and concomitantly PI3-kinase activation via JAK2 kinase. 962 69

Growth hormone (GH)-dependent activation of the rat serine protease inhibitor 2.1 (spi 2.1) gene in vivo requires both a modification of the chromatin structure and the activation of transcription factors mediated by the tyrosine protein Janus kinase JAK2. To address the question of the relationship between those two GH effects, we used interleukin 1 beta (Il-1 beta) that was previously shown to inhibit spi 2.1 gene expression. In cultured hepatocytes from normal rats, Il-1 beta did not antagonize GH-dependent stimulation of promoter activity (i.e., in episomal constructs) mediated by transcription factors activated by JAK2. In hepatocytes from inflamed rats, GH triggered JAK2-dependent activation of transcription factors as in control cells but failed to stimulate genomic spi 2.1 gene expression. It thus appears that the Il-1 beta-insensitive activation of transcription factors by GH is independent of its action on the nucleosomal structure of the spi 2.1 gene which, in contrast, is sensitive to this cytokine.
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PMID:Growth hormone-mediated transcriptional activation of the rat serine protease inhibitor 2.1 gene involves both interleukin-1 beta-sensitive and -insensitive pathways. 987 34

Growth hormone (GH) clearly has the potential to dramatically enhance skeletal muscle accretion in red meat animals such as swine. It is generally accepted that this anabolic effect is mediated by insulin-like growth factor-I (IGF-I), a potent stimulator of proliferation and differentiation of satellite cells that are important for myofiber hypertrophy and for regeneration in postnatal muscle tissue. All available evidence suggests that the capacity for IGF-I-mediated actions of GH on avian myogenic cells is intact, and recent evidence is accumulating that GH may even have direct effects on avian skeletal muscle satellite cell proliferation and differentiation. However, with little exception, exogenous GH does not improve skeletal muscle mass, carcass protein, or any measure of muscle anabolism in domestic poultry. A primary lesion would appear to be the inability of GH to induce significant increases in circulating IGF-I concentrations in sexually immature, growing poultry. This is the case despite clear evidence of GH binding to hepatic receptors, GH-induced tyrosine phosphorylation of Janus kinase 2 (JAK2), and GH-induced expression of hepatic IGF-I mRNA and protein. Factors that should be explored with respect to this apparent discrepancy are discussed, including the regulation of IGF-I release, uptake, and interaction with cell-associated IGF binding proteins or receptors. In addition to its growth-promoting effects via IGF-I, GH has direct metabolic effects that are expressed as changes in circulating regulatory hormone and metabolite concentrations. The possibility that such changes may influence IGF-I release and action is also proposed.
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PMID:Absence of growth hormone-induced avian muscle growth in vivo. 1022 74

Growth hormone (GH) resistance/insensitivity (GHIS) is the finding of elevated GH levels associated with a reduction in the biologic actions of GH. It may be congenital or acquired. In congenital GHIS, over 30 mutations in the GH receptor (GHR) have been described. Dimerization of the GHR activates phosphorylation cascades involving MAP kinases and the Janus kinase, JAK2. This in turn activates the STAT (Signal transducers and activators of transcription) proteins, which translocate to the nucleus. A soluble form of the GHR circulates as a GH binding protein (GHBP), and is derived from the proteolytic cleavage of the extracellular domain of the GHR. The majority of GHR mutations resulting in GHIS are though to affect GH binding, hence the finding of low levels of GHBP in many patients. However, a small group of patients with GHIS have been identified in whom there are normal or high levels of GHBP. Mutations in these patients include, among others, a splice-site mutation that results in the skipping of exon 9. The resultant protein is a truncated GHR that lacks 97% of the intracellular domain of the normal receptor. Patients heterozygous for this mutation have GHIS. In vitro studies have shown the truncated receptor acts as a dominant-negative inhibitor of receptor signalling. The truncated receptor lacks the domains essential for internalization, and is therefore highly expressed on the cell surface. It heterodimerizes with the full-length receptor and blocks signaling. Analysis of GHIS has increased our understanding of the molecular basis for GHIS and helped elucidate the factors that regulate GHR trafficking and signalling.
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PMID:The GH receptor and GH insensitivity. 1054 5

1. The growth hormone (GH) receptor was the first of the class 1 cytokine receptors to be cloned. It shares a number of structural characteristics with other family members and common signalling mechanisms based on common usage of the Janus kinase 2 (JAK2). 2. Growth hormone receptor activation is initiated by GH-induced homodimerization of receptor molecules. This has enabled the creation of specific hormone antagonists that block receptor dimerization. 3. The details of the transcription factors used by the activated receptor are being revealed as a result of promoter analyses and electrophoretic mobility gelshift analysis. 4. Growth hormone receptors are widespread and their discovery in certain tissues has led to the assignment of new physiological roles for GH. Some of these involve local or paracrine roles for GH, as befits its cytokine status. 5. Four examples of such novel roles are discussed. These are: (i) the brain GH axis; (ii) GH and the vitamin B12 axis; (iii) GH in early pre-implantation development; and (iv) GH in development of the tooth. 6. We propose that the view that GH acts through the intermediacy of insulin-like growth factor-1 is simplistic; rather, GH acts to induce an array of growth factors and their receptors and the composition of this array varies with tissue type and, probably, stage of development.
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PMID:Growth hormone as a cytokine. 1054 98

Growth hormone (GH) regulates body growth and metabolism. GH exerts its biological action by stimulating JAK2, a GH receptor (GHR)-associated tyrosine kinase. Activated JAK2 phosphorylates itself and GHR, thus initiating multiple signaling pathways. In this work, we demonstrate that platelet-derived growth factor (PDGF) and lysophosphatidic acid (LPA) down-regulate GH signaling via a protein kinase C (PKC)-dependent pathway. PDGF substantially reduces tyrosyl phosphorylation of JAK2 induced by GH but not interferon-gamma or leukemia inhibitory factor. PDGF, but not epidermal growth factor, decreases tyrosyl phosphorylation of GHR (by approximately 90%) and the amount of both total cellular GHR (by approximately 80%) and GH binding (by approximately 70%). The inhibitory effect of PDGF on GH-induced tyrosyl phosphorylation of JAK2 and GHR is abolished by depletion of 4beta-phorbol 12-myristate 13-acetate (PMA)-sensitive PKCs with chronic PMA treatment and is severely inhibited by GF109203X, an inhibitor of PKCs. In contrast, extracellular signal-regulated kinases 1 and 2 and phosphatidylinositol 3-kinase appear not to be involved in this inhibitory effect of PDGF. LPA, a known activator of PKC, also inhibits GH-induced tyrosyl phosphorylation of JAK2 and GHR and reduces the number of GHR. We propose that ligands that activate PKC, including PDGF, LPA, and PMA, down-regulate GH signaling by decreasing the number of cell surface GHR through promoting GHR internalization and degradation and/or cleavage of membrane GHR and release of the extracellular domain of GHR.
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PMID:Platelet-derived growth factor and lysophosphatidic acid inhibit growth hormone binding and signaling via a protein kinase C-dependent pathway. 1064 56

Growth hormone acts through binding to membrane receptors that belong to the cytokine receptor superfamily. Ligand binding induces receptor dimerization and activation of the receptor-associated kinase: JAK2; this results in phosphorylation of the kinase itself, of the receptor, and of many cellular proteins. Among these are the Stat proteins as well as adaptors leading to the activation of the Ras/MAP kinase pathway and of the PI-3 kinase pathway. Activation by growth hormone is very transient and several mechanisms are involved in this downregulation: internalization and degradation of the receptor and recruitment of phosphatases or of specific inhibitors of the JAK/Stat pathway, the SOCS proteins.
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PMID:Regulators of growth hormone signaling. 1071 37

Growth hormone initiates signaling by inducing homodimerization of two GH receptors. Here, we have sought to determine whether constitutively active receptor can be created in the absence of the extracellular domain by substituting it with high affinity leucine zippers to create dimers of the growth hormone receptor (GHR) signaling domain. The entire extracellular domain of the GHR was replaced by the hemagglutinin-tagged zipper sequence of either the c-Fos or c-Jun transcription factor (termed Fos-GHR and Jun-GHR, respectively). Transient transfection of Fos-GHR or Jun-GHR resulted in activation of the serine protease inhibitor 2.1 promoter in Chinese hamster ovary-K1 cells to a level equal to that achieved by fully activated wild type GHR. Furthermore, stable expression of Jun-GHR alone or Fos-GHR and Jun-GHR together in the interleukin 3-dependent BaF-B03 cell line resulted in cell proliferation after interleukin 3 withdrawal at a rate equal to maximally stimulated wild type GHR-expressing cells. Activation of STAT 5b was also observed in Fos-Jun-GHR-expressing cells at a level equal to that in chronically GH-treated GHR-expressing cells. Thus, forced dimerization of the transmembrane and cytoplasmic domains of the GHR in the absence of the extracellular domain can lead to the constitutive activation of known GH signaling end points, supporting the view that proximity of Janus kinase 2 (JAK2) kinases is the essential element in signaling. Such constitutively active GH receptors may have particular utility for transgenic livestock applications.
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PMID:Growth hormone (GH)-independent dimerization of GH receptor by a leucine zipper results in constitutive activation. 1082 73

Growth hormone (GH) has long been known to be the body's primary regulator of body growth and a regulator of metabolism, yet the mechanisms by which GH regulates the transcription of specific genes required for these processes are just now being delineated. GH binding to its receptor recruits and activates the receptor-associated JAK2 that in turn phosphorylates tyrosines within itself and the GH receptor. These tyrosines form binding sites for a number of signaling proteins, including members of the family of signal transducers and activators of transcription (STAT). Among the known signaling molecules for GH, STAT proteins play a particularly prominent role in the regulation of gene transcription. This paper will review what is currently understood about which STAT proteins are regulated by GH, how they are regulated by GH, the GH-dependent genes they regulate, and discuss current theories about how GH-activated STAT signaling is regulated. Particular attention will be given to the novel role that STAT5 plays in sexually dimorphic gene expression in the liver as determined by the secretory pattern of GH and the role of STAT5 in body growth. Oncogene (2000).
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PMID:The role of STAT proteins in growth hormone signaling. 1085 Oct 57


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