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) regulates muscle and fat metabolism, which impacts on body composition and insulin sensitivity, but the underlying GH signaling pathways have not been studied in vivo in humans. We investigated GH signaling in biopsies from muscle and abdominal fat obtained 30 (n = 3) or 60 (n = 3) min after an intravenous bolus of GH (0.5 mg) vs. saline in conjunction with serum sampling in six healthy males after an overnight fast. Expression of the following signal proteins were assayed by Western blotting: STAT5/p-STAT5, MAPK, and Akt/PKB. IRS-1-associated PI 3-kinase activity was measured by in vitro phosphorylation of PI. STAT5 DNA binding activity was assessed with EMSA, and the expression of IGF-I and SOCS mRNA was measured by real-time RT-PCR. GH induced a 52% increase in circulating FFA levels with peak values after 155 min (P = 0.03). Tyrosine-phosphorylated STAT5 was detected in muscle and fat of all subjects after GH. Activation of MAPK was observed in several lysates but without GH dependency. Neither PKB/Akt nor PI 3-kinase activity was affected by GH. GH-induced STAT5 DNA binding and expression of IGF-I mRNA were detected in fat, whereas expression of SOCS-1 and -3 tended to increase after GH in muscle and fat, respectively. We conclude that 1) STAT5 is acutely activated in human muscle and fat after a GH bolus, but additional downstream GH signaling was significant only in fat; 2) the direct GH effects in muscle need further characterization; and 3) this human in vivo model may be used to study the mechanisms subserving the actions of GH on substrate metabolism and insulin sensitivity in muscle and fat.
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PMID:GH receptor signaling in skeletal muscle and adipose tissue in human subjects following exposure to an intravenous GH bolus. 1675 51

Growth hormone binds to its membrane receptor (GHR), whereby it regulates many cellular functions, including proliferation, differentiation and chemotaxis. However, although the activation of growth hormone-mediated signalling is well understood, the precise mechanism responsible for its regulation has not been elucidated. Here, we demonstrate that phospholipase Cgamma1 (PLCgamma1) modulates the action of growth hormone-mediated signalling by interacting with tyrosine kinase Jak2 (janus kinase 2) in a growth hormone-dependent manner. In the absence of PLCgamma1 (PLCgamma1(-/-)), growth hormone-induced JAK2 and STAT5 phosphorylation significantly increased in mouse embryonic fibroblasts (MEFs). Furthermore, the re-expression of PLCgamma1 reduced growth hormone-induced Jak2 activation. Growth hormone-induced Jak2 phosphorylation was enhanced by siRNA-specific knockdown of PLCgamma1. Interestingly, PLCgamma1 physically linked Jak2 and protein tyrosine phosphatase-1B (PTP-1B) by binding to both using different domains, and this process was implicated in the modulation of cytokine signalling through Jak2. In addition, in PLCgamma1(-/-) MEFs, growth hormone-dependent c-Fos activation was upregulated and growth hormone-induced proliferation was potentiated. These results suggest that PLCgamma1 has a key function in the regulation of growth hormone-mediated signalling by negatively regulating Jak2 activation.
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PMID:Phospholipase Cgamma1 negatively regulates growth hormone signalling by forming a ternary complex with Jak2 and protein tyrosine phosphatase-1B. 1712 63

Growth hormone (GH) is a major regulatory factor for overall body growth as evidenced by the height extremes in people with abnormal circulating GH levels or GH receptor (GHR) disruptions. GH also affects metabolism, cardiac and immune function, mental agility and aging. Currently, GH is being used therapeutically for a variety of clinical conditions including promotion of growth in short statured children, treatment of adults with GH deficiency and HIV-associated wasting. To help reveal previous unrecognized functions of GH, better understand the known functions of GH, and avoid adverse consequences that are often associated with exogenous GH administration, careful delineation of the molecular mechanisms whereby GH induces its diverse effects is needed. GH is a peptide hormone that is secreted into the circulation by the anterior pituitary and acts upon various target tissues expressing GHR. GH binding of GHR activates the tyrosine kinase Janus kinase 2 (JAK2), thus initiating a multitude of signaling cascades that result in a variety of biological responses including cellular proliferation, differentiation and migration, prevention of apoptosis, cytoskeletal reorganization and regulation of metabolic pathways. A number of signaling proteins and pathways activated by GH have been identified, including JAKs, signal transducers and activators of transcription (Stats), the mitogen activated protein kinase (MAPK) pathway, and the phosphatidylinositol 3'-kinase (PI3K) pathway. Although these signal transduction pathways have been well characterized, the manner by which GH activates these pathways, the downstream signals induced by these pathways, and the cross-talk with other pathways are not completely understood. Recent findings have added vital information to our understanding of these downstream signals induced by GH and mechanisms that terminate GH signaling, and identified new GH signaling proteins and pathways. This review will highlight some of these findings, many of which are unexpected and some of which challenge previously held beliefs about the mechanisms of GH signaling.
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PMID:Recent advances in growth hormone signaling. 1730 65

Growth hormone (GH) binding to a membrane receptor dimer triggers multiple intracellular signaling pathways. Signal transducers and activators of transcription are the most relevant of these pathways for GH action. GH also activates several inhibitory mechanisms, particularly suppressors of cytokine signaling (SOCS/CIS) proteins. GH-overexpressing mice exhibit hepatic desensitization of the JAK2/STAT5 GH-signaling pathway, associated with an increased abundance of CIS. Vitamin D3 has been shown to inhibit GH-induced expression of CIS and SOCS-3 and therefore prolong GH signaling in osteoblast-like cells. The purpose of the present study is to determine if vitamin D3 could attenuate CIS expression in GH-overexpressing mice, and consequently allow GH JAK2/STAT5 signaling in GH-responsive tissues in these animals. The abundance of CIS, SOCS-2, SOCS-3, STAT5b and GHR, as well as STAT5b tyrosine phosphorylation after a GH stimulus, were measured in liver and muscle of GHRH-transgenic mice treated with 1alpha,25-dihydroxyvitamin D3 for 7 days. This treatment did not diminish CIS expression in GH-overexpressing mice tissues, nor did the content of SOCS-2 and SOCS-3 significantly vary. GH-induced STAT5b phosphorylation levels were similar to basal values in transgenic mice liver treated with or without vitamin D; the refractoriness to GH was also present in muscle. Therefore, treatment with vitamin D was not sufficient to revert STAT5 GH signaling desensitization in non-calcemic tissues in GH-overexpressing mice.
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PMID:Vitamin D3 cannot revert desensitization of growth hormone (GH)-induced STAT5-signaling in GH-overexpressing mice non-calcemic tissues. 1788 Dec 71

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults. Growth hormone-insulin-like growth factor I (GH-IGF-I) system has an important role in the recovery of the central nervous system. The aim of the study was to evaluate the relationship between pituitary function (in particular, the GH-IGF-I axis) and outcome from TBI. We studied 72 patients (56 males; mean age 37.2 +/- 1.8 years) receiving rehabilitation after TBI. According to the Glasgow Coma Scale (GCS), 10 patients had moderate and 52 severe TBI. Ten patients had growth hormone GH deficiency (GHD), 10 LH-FSH, three TSH, and three ACTH deficiency. Overall pituitary dysfunction occurred in 22 (30.5%) patients, with anterior hypopituitarism in 19 (26.4%), isolated diabetes insipidus in one, and isolated hyperprolactinemia in two. GH response to GHRH + ARG (arginine) positively correlated with Functional Independence Measure (FIM D; r = 0.267, p < 0.02) and Level of Cognitive Functioning Scale (LCFS D; r = 0.287, p < 0.01) at discharge, and negatively with Disability Rating Score at discharge (DRS D; r = -0.324, p < 0.005). Unfavorable outcome measures (FIM D, LCFS D, and DRS D) occurred in patients with hypopituitarism as compared with normal pituitary function (p < 0.05). Multiple regression analysis identified both GCS (p < 0.005) and GH peak (p < 0.05) as strong independent predictors of outcome. In conclusion, recovery after TBI may be negatively influenced by concomitant pituitary dysfunction. The GH peak value is an independent predictor of outcome, indicating that recovery during an intensive rehabilitation program after TBI may be positively influenced by normal GH secretion.
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PMID:Anterior pituitary function may predict functional and cognitive outcome in patients with traumatic brain injury undergoing rehabilitation. 1800 Nov 99

Deficiency in insulin secretion is a fundamental part in the pathogenesis of all forms of diabetes, determined by impaired secretory function and inadequate beta-cell mass. Growth hormone (GH) is a multifunctional hormone, involved in cellular metabolism, mitogenesis and differentiation. In pancreatic islets, GH is involved in maintaining beta-cell mass, stimulating islet hormone production and insulin secretion, and, therefore, plays a role in maintaining normal insulin sensitivity and glucose homeostasis. The intracellular events that convey the GH signal into various cellular responses remain incompletely understood. In this review, we discuss GH signaling in the beta-cells, with emphasis on Ca(2+) handling and insulin secretion regulated by human GH (hGH). hGH-stimulated rise in [Ca(2+)](i) is dependent on extracellular Ca(2+) and is mediated by Ca(2+)-induced Ca(2+) release (CICR) in the beta-cell. This process is triggered by hGH-stimulated activation of the non-receptor tyrosine kinases JAK2 and c-Src, which causes tyrosine phosphorylation of RyRs, resulting in sensitization of CICR. The rise in [Ca(2+)](i) elicited by hGH is associated with an enhanced insulin secretion, effects that are mediated mainly through the prolactin receptor. These mechanisms indicate that a rise in [Ca(2+)](i) elicited by activation of PRLR is JAK2-dependent and is associated with enhanced insulin secretion. In contrast, GH receptor-mediated increase in [Ca(2+)](i) is JAK2-independent and is dissociated from insulin secretion.
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PMID:Growth hormone signaling in pancreatic beta-cells--calcium handling regulated by growth hormone. 1860 47

Cytoplasmic polyadenylation element binding protein 1 (CPEB-1) resides at postsynaptic sites in hippocampal neurons in which it controls polyadenylation-induced translation. CPEB-1 knock-out (KO) mice display defects in some forms of synaptic plasticity and hippocampal-dependent memories. To identify CPEB-1-regulated mRNAs, we used proteomics to compare polypeptides in wild-type (WT) and CPEB-1 KO hippocampus. Growth hormone (GH) was reduced in the KO hippocampus, as were the GH signaling molecules phospho-JAK2 and phospho-STAT3. GH mRNA and pre-mRNA were reduced in the KO hippocampus, suggesting that CPEB-1 controls GH transcription. The transcription factor c-Jun, which binds the GH promoter, was also reduced in the KO hippocampus, as was its ability to coimmunoprecipitate chromatin containing the GH promoter. CPEB-1 binds c-Jun 3' untranslated region CPEs in vitro and coimmunoprecipitates c-Jun RNA in vivo. GH induces long-term potentiation (LTP) when applied to hippocampal slices from WT and CPEB-1 KO mice, but the magnitude of LTP induced by GH in KO mice is reduced. Pretreatment with GH did not reverse the LTP deficit observed in KO mice after theta-burst stimulation (TBS). Cordycepin, an inhibitor of polyadenylation, disrupted LTP induced by either GH application or TBS. Finally, GH application to hippocampal slices induced JAK2 phosphorylation in WT but not KO animals. These results indicate that CPEB-1 control of c-Jun mRNA translation regulates GH gene expression and resulting downstream signaling events (e.g., synaptic plasticity) in the mouse hippocampus.
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PMID:A molecular circuit composed of CPEB-1 and c-Jun controls growth hormone-mediated synaptic plasticity in the mouse hippocampus. 1871 8

Growth hormone (GH) plays important roles in oocyte development and facilitates the successful production of competent oocytes in many species both in vivo and in vitro. However, the mechanism of GH action on oocyte maturation is not well known. In this paper, the temporospatial messenger ribonucleic acid expression patterns of GH and several other GH-related factors were quantitatively analyzed in porcine cumulus-oocytes complex throughout in vitro maturation (IVM). GH expression was decreased in oocytes during IVM while absent in cumulus cells. GH receptor, insulin-like growth factor-1 (IGF-1), and IGF-1 receptor expressions were also downregulated in oocytes. In cumulus cells, the expression of IGF-1 decreased significantly while IGF-1 receptor expression remained constant. The transcripts of Janus kinase 2 increased in both oocytes and cumulus cells during IVM. The current precise gene expression information provides further evidence to explain the complex network of GH signaling involved in IVM of porcine oocyte.
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PMID:Growth hormone pathway gene expression varies in porcine cumulus-oocyte complexes during in vitro maturation. 1880 39

Growth hormone (GH) and IGF-I have been implicated in the pathogenesis of type I diabetic (DM) nephropathy. We investigated renal GH receptor (GHR) and IGF-type 1 receptor (IGF1R) signaling in an animal model of type I DM. Kidney tissue was examined for GHR and IGF1R key signaling molecules. GHR levels were unchanged and IGF-I mRNA levels were decreased in the diabetic group (D). Basal and GH stimulated phosphorylated (p-) JAK2 and STAT5 levels were similar in controls (C) and D. The levels of p-IGF1R were similar in the two groups at baseline, while pAkt, pGSK3, p-mTOR, p-rpS6, p-erk1/2 (Mapk), and pSTAT-3 were increased in D. Following IGF-I administration p-Akt, p-rpS6, p-Mapk, and p-GSK levels increased more pronouncedly in D versus C. In conclusion, the lack of JAK2-STAT5 activation and the decrease in kidney IGF-I mRNA levels in D argue against a role for the GH activated JAK2-STAT5 pathway in the pathogenesis of diabetic nephropathy. On the other hand while IGF1R phosphorylation was unchanged, Akt/mTOR and MAPK signaling were hyperactivate in DM, suggesting their involvement. The increase in baseline activated Akt, mTOR, rpS6, and MAPK cannot be explained by activation of the IGF1R, but may be triggered by other growth factors and nutrients.
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PMID:Increased renal Akt/mTOR and MAPK signaling in type I diabetes in the absence of IGF type 1 receptor activation. 1938 75

Growth hormone is widely used clinically to promote growth and anabolism and for other purposes. Its actions are mediated via the growth hormone receptor, both directly by tyrosine kinase activation and indirectly by induction of insulin-like growth factor 1 (IGF-1). Insensitivity to growth hormone (Laron syndrome) can result from mutations in the growth hormone receptor and can be treated with IGF-1. This treatment is, however, not fully effective owing to the loss of the direct actions of growth hormone and altered availability of exogenous IGF-1. Excessive activation of the growth hormone receptor by circulating growth hormone results in gigantism and acromegaly, whereas cell transformation and cancer can occur in response to autocrine activation of the receptor. Advances in understanding the mechanism of receptor activation have led to a model in which the growth hormone receptor exists as a constitutive dimer. Binding of the hormone realigns the subunits by rotation and closer apposition, resulting in juxtaposition of the catalytic domains of the associated tyrosine-protein kinase JAK2 below the cell membrane. This change results in activation of JAK2 by transphosphorylation, then phosphorylation of receptor tyrosines in the cytoplasmic domain, which enables binding of adaptor proteins, as well as direct phosphorylation of target proteins. This model is discussed in the light of salient information from closely related class 1 cytokine receptors, such as the erythropoietin, prolactin and thrombopoietin receptors.
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PMID:The growth hormone receptor: mechanism of activation and clinical implications. 2066 32


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