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)

At present, the mechanism(s) underlying the reduced spontaneous and stimulated GH secretion in aging is still unclear. To obtain new information on this mechanism(s), the GH responses to both single and combined administration of GH-releasing hormone (GHRH; 1 microgram/kg iv) and arginine (ARG; 30 g infused over 30 min), a well known GH secretagogue probably acting via inhibition of hypothalamic somatostatin release, were studied in seven elderly normal subjects and seven young healthy subjects. Basal GH levels were similar in both groups, while insulin-like growth factor-I levels were lower in elderly subjects (76.7 +/- 9.2 vs. 258.3 +/- 29.2 micrograms/L; P = 0.01). In aged subjects GHRH induced a GH increase (area under the curve, 314.9 +/- 91.9 micrograms/L.h) which was lower (P = 0.01) than that in young subjects (709.1 +/- 114.4 micrograms/L.h). On the other hand, the ARG-induced GH increase in the elderly was not significantly different from that in young subjects (372.8 +/- 81.8 vs. 470.6 +/- 126.5 micrograms/L.h). ARG potentiated GH responsiveness to GHRH in both elderly (1787.1 +/- 226.0 micrograms/L.h; P = 0.0001 vs. GHRH alone) and young subjects (2113.0 +/- 444.3 micrograms/L.h; P = 0.001 vs. GHRH alone). The potentiating effect of ARG on the GHRH-induced GH response was greater in elderly than in young subjects (1013.0 +/- 553.5% vs. 237.9 +/- 79.1%; P = 0.0001); thus, the GH increase induced by combined administration of ARG and GHRH overlapped in two groups. In conclusion, these results show that, differently from the GHRH-induced GH increase, the somatotroph response to combined administration of ARG and GHRH does not vary with age. Our finding suggests that an increased somatostatinergic activity may underlie the reduced GH secretion in normal aging.
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PMID:Growth hormone (GH) responsiveness to combined administration of arginine and GH-releasing hormone does not vary with age in man. 222 4

In the current studies, we examined whether focal adhesion kinase (FAK) and paxillin play a role in insulin-like growth factor-I (IGF-I)-stimulated morphological changes in neuronal cells. In SH-SY5Y human neuroblastoma cells, 10 nM IGF-I enhanced the extension of lamellipodia within 30 min. Scanning electron microscopy and staining with rhodamine-phalloidin showed that these lamellipodia displayed ruffles, filopodia, and a distinct meshwork of actin filaments. Immunofluorescent staining identified focal concentrations of FAK, paxillin, and phosphotyrosine within the lamellipodia. Immunoprecipitation experiments revealed that FAK and paxillin are tyrosine-phosphorylated during IGF-I-stimulated lamellipodial extension. Maximal phosphorylation of FAK and paxillin was observed 15-30 min after the addition of 10 nM IGF-I, whereas maximal IGF-I receptor phosphorylation occurred within 5 min. FAK, paxillin, and IGF-I receptor tyrosine phosphorylation had similar concentration-response curves and were inhibited by the receptor blocking antibody alphaIR-3. These results indicate that FAK and paxillin are tyrosine-phosphorylated during IGF-I-stimulated lamellipodial advance and suggest that the tyrosine phosphorylation of these two proteins helps mediate IGF-I-stimulated cell and growth cone motility. These responses contrast directly with recent reports showing insulin-stimulated dephosphorylation of FAK and paxillin.
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PMID:Tyrosine phosphorylation of paxillin and focal adhesion kinase during insulin-like growth factor-I-stimulated lamellipodial advance. 903 May 91

The focal adhesion kinase p125(Fak) is a widely expressed cytosolic tyrosine kinase, which is involved in integrin signaling and in signal transduction of a number of growth factors. In contrast to tyrosine kinase receptors such as the platelet-derived growth factor and the hepatocyte growth factor receptors, which induce p125(Fak) phosphorylation, insulin has been shown to promote its dephosphorylation. In this study, we compared p125(Fak) phosphorylation in insulin-stimulated cells maintained in suspension or in an adhesion state. We found that, in nonattached cells, insulin promotes p125(Fak) phosphorylation, whereas dephosphorylation occurred in attached cells. This was observed in Rat-1 fibroblasts overexpressing the insulin receptor, as well as in Hep G2 hepatocytes and in 3T3-L1 adipocytes expressing more natural levels of insulin receptors. Insulin-induced p125(Fak) phosphorylation correlated with an increase in paxillin phosphorylation, indicating that p125(Fak) kinase activity may be stimulated by insulin. Mixing of purified insulin or insulin-like growth factor-I (IGF-I) receptors with p125(Fak) resulted in an increase in p125(Fak) phosphorylation. Using a kinase-deficient p125(Fak) mutant, we found that this protein is a direct substrate of the insulin and IGF-I receptor tyrosine kinases. This view is supported by two additional findings. (i) A peptide corresponding to p125(Fak) sequence comprising amino acids 568-582, which contains tyrosines 576 and 577 of the kinase domain regulatory loop, is phosphorylated by the insulin receptor; and (ii) p125(Fak) phosphorylation by the insulin receptor is prevented by addition of this peptide. Finally, we observed that p125(Fak) phosphorylation by the receptor results in its activation. Our results show that the nature of the cross-talk between the insulin/IGF-I receptors and p125(Fak) is dependent on the cell architecture, and hence the interaction of the insulin/IGF-I signaling system with the integrin system will vary accordingly.
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PMID:p125Fak focal adhesion kinase is a substrate for the insulin and insulin-like growth factor-I tyrosine kinase receptors. 950 31

There is now wide consensus that, within an appropriate clinical context, GH deficiency (GHD) in adults must be shown biochemically by provocative testing of GH secretion and that appropriate cut-off limits have to be defined for each provocative test. Insulin-induced hypoglycemia (ITT) is indicated as the test of choice, and severe GHD, to be treated with recombinant human GH replacement, is defined by a GH peak response to ITT of less than 3 micrograms/L. GHRH + arginine (GHRH + ARG) is one of the most promising tests in alternative to ITT. In fact, it has been reported as a potent, reproducible, and age-independent test and that it is able to distinguish between GHD and normal adults. The aim of the present study was to compare the GH response to ITT and GHRH + ARG in a large group of hypopituitary adults (n = 40; 29 male and 11 female; age: 36.4 +/- 2.1 yr). The third centile limit of the peak GH response to ITT has been reported as 5 micrograms/L, whereas in our lab, that to GHRH + ARG is 16.5 micrograms/L. In hypopituitary adults, the mean peak GH response to ITT (1.5 +/- 0.2 micrograms/L, range: 0.1-8.5 micrograms/L) was lower (P < 0.001) than that to GHRH + ARG (3.0 +/- 0.4 micrograms/L, range 0.1-12.0 micrograms/L), though there was positive correlation (r = 0.61, P < 0.001) between the GH responses to the 2 tests. The peak GH response to GHRH + ARG, but not that to ITT, was positively (though weakly) associated with insulin-like growth factor-I levels (r = 0.35, P < 0.03). Childhood and adult onset GHD patients, as well as patients with single and multiple pituitary insufficiencies, had similar peak GH responses to ITT or GHRH + ARG. Analyzing individual GH responses, 4/40 (10%) of the hypopituitary patients had GH peaks higher than 5 micrograms/L after ITT; moreover, 3 other patients (7%) had GH peaks, after ITT, higher than 3 micrograms/L. On the other hand, after GHRH + ARG, all patients had GH peaks lower than 16.5 micrograms/L, whereas 21/40 (52.5%) had GH peaks higher than 3 micrograms/L. Because 3 micrograms/L is the arbitrary cut-off for ITT, the third centile limit of which is 5 micrograms/L, we arbitrarily considered 9 micrograms/L as the cut-off point for GHRH + ARG. It is noteworthy that 37/40 (92.5%) patients had a GH peak, after GHRH + ARG, below this limit. In conclusion, our present results confirm that the ITT test is a reliable provocative test for the diagnosis of adult GHD, whereas they show that the GHRH + ARG test is, at least, as sensitive as the ITT test (provided that appropriate cut-off limits are considered). Note that even the arbitrary cut-off point below which severe GHD is demonstrated has to be appropriate to the potency of the test.
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PMID:Comparison between insulin-induced hypoglycemia and growth hormone (GH)-releasing hormone + arginine as provocative tests for the diagnosis of GH deficiency in adults. 958 65

Insulin receptor substrate-1 (IRS-1) is a major substrate of insulin and insulin-like growth factor-I receptors, which upon phosphorylation on tyrosine docks several signaling molecules. Recently, IRS-1 was found to interact with alphav beta3 integrins upon insulin stimulation. Integrins are transmembrane proteins that play an important role in adhesion between cells and between cells and extracellular matrix. One of the major proteins implicated in integrin signaling is pp125(FAK), a cytosolic tyrosine kinase, which upon integrin engagement becomes tyrosine-phosphorylated and subsequently binds to c-Src. Here, we established a mammalian two-hybrid system to show that pp125(FAK) binds to IRS-1. This association depends largely on the C terminus of pp125(FAK) but not on pp125(FAK) tyrosine kinase activity. Furthermore, we observed co-immunoprecipitation of pp125(FAK) with IRS-1 in 293 cells, suggesting a possible biological function of this association. When IRS-1 was expressed in 293 cells together with pp125(FAK) or Src, we found extensive IRS-1 tyrosine phosphorylation. In pp125(FAK)-expressing cells, this was concomitant with increased association of IRS-1 with Src homology 2-containing proteins such as growth factor receptor-bound protein 2, phosphatidylinositol (PI) 3-kinase p85alpha subunit, and Src homology 2-containing protein-tyrosine phosphatase-2. In addition, pp125(FAK)-induced association of IRS-1 with PI 3-kinase resulted in increased PI 3-kinase activity. In contrast, no change in mitogen-activated protein kinase activity was observed, indicating that pp125(FAK)-induced association between IRS-1 and growth factor receptor-bound protein 2 does not affect the mitogen-activated protein kinase pathway. Moreover, we found that engagement of integrins induced IRS-1 tyrosine phosphorylation. Considering our results together, we suggest that integrins and insulin/insulin-like growth factor-I receptor signaling pathways converge at an early point in the signaling cascade, which is the IRS-1 protein.
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PMID:Insulin receptor substrate-1 as a signaling molecule for focal adhesion kinase pp125(FAK) and pp60(src). 982 3

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

The molecular mechanisms behind phenotypic modulation of smooth muscle cells (SMCs) remain unclear. In our recent paper, we reported the establishment of novel culture system of gizzard SMCs (Hayashi, K., H. Saga, Y. Chimori, K. Kimura, Y. Yamanaka, and K. Sobue. 1998. J. Biol. Chem. 273: 28860-28867), in which insulin-like growth factor-I (IGF-I) was the most potent for maintaining the differentiated SMC phenotype, and IGF-I triggered the phosphoinositide 3-kinase (PI3-K) and protein kinase B (PKB(Akt)) pathway. Here, we investigated the signaling pathways involved in de-differentiation of gizzard SMCs induced by PDGF-BB, bFGF, and EGF. In contrast to the IGF-I-triggered pathway, PDGF-BB, bFGF, and EGF coordinately activated ERK and p38MAPK pathways. Further, the forced expression of active forms of MEK1 and MKK6, which are the upstream kinases of ERK and p38MAPK, respectively, induced de-differentiation even when SMCs were stimulated with IGF-I. Among three growth factors, PDGF-BB only triggered the PI3-K/PKB(Akt) pathway in addition to the ERK and p38MAPK pathways. When the ERK and p38MAPK pathways were simultaneously blocked by their specific inhibitors or an active form of either PI3-K or PKB(Akt) was transfected, PDGF-BB in turn initiated to maintain the differentiated SMC phenotype. We applied these findings to vascular SMCs, and demonstrated the possibility that the same signaling pathways might be involved in regulating the vascular SMC phenotype. These results suggest that changes in the balance between the PI3-K/PKB(Akt) pathway and the ERK and p38MAPK pathways would determine phenotypes of visceral and vascular SMCs. We further reported that SMCs cotransfected with active forms of MEK1 and MKK6 secreted a nondialyzable, heat-labile protein factor(s) which induced de-differentiation of surrounding normal SMCs.
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PMID:Changes in the balance of phosphoinositide 3-kinase/protein kinase B (Akt) and the mitogen-activated protein kinases (ERK/p38MAPK) determine a phenotype of visceral and vascular smooth muscle cells. 1033 Apr 2

Integrin-induced focal adhesion kinase (FAK) phosphorylation as well as insulin-like growth factor-I (IGF-I) and insulin activate MAP kinase. Since IGF-I or insulin have been suggested to affect FAK phosphorylation, we analyzed the role of FAK in IGF-I- or insulin-induced MAP kinase activation. Although MAP kinase was stimulated by IGF-I or insulin, FAK tyrosine phosphorylation remained unchanged in fibroblasts expressing normal or transiently elevated levels of IGF-I and insulin receptors. Further analysis in FAK deficient fibroblasts suggested that FAK impedes MAP kinase activation by IGF-I or insulin.
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PMID:Role of focal adhesion kinase in MAP kinase activation by insulin-like growth factor-I or insulin. 1043 17

Insulin-like growth factor-I (IGF-I) is a potent stimulator of vascular smooth muscle cell (SMC) migration, a process that contributes to the accumulation of SMC within atherosclerotic lesions. Our previous studies have shown that IGF-I increases the affinity of the alphaVbeta3 integrin toward ligands and that occupancy of this integrin is indispensable for IGF-I to stimulate cell migration. In this study, the role of phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinase (MAPK) pathways in IGF-I induced cell motility and integrin activation was studied using porcine aortic smooth muscle cells (pSMC). Two structurally different inhibitors of PI 3-kinase decreased IGF-I-stimulated pSMC migration in a dose-dependent manner. The IC50 of wortmannin for inhibiting migration was 10 nM, and that of LY294002 was 0.3 microM. These inhibitors also suppressed IGF-I-induced phosphorylation of protein kinase B PKB/Akt at Ser437 using concentrations that also inhibited cell motility. PD98059, an inhibitor of the MAPK pathway, was somewhat less potent than PI 3-kinase inhibitors in blocking cell migration that had been stimulated by IGF-I. When IGF-I increased migration of pSMC 2.1-fold above control, 100 nM wortmannin inhibited this response by 79%, 1 microM LY294002 inhibited it by 58%, and 50 microM PD98059 caused a 34% reduction. In comparison, 100 nM wortmannin inhibited IGF-I stimulated DNA synthesis by 57%, 1 microM LY294002 inhibited it by 59%, whereas 50 microM PD98059 suppressed it completely. Thus, activation of PI 3-kinase plays the major role in IGF-I-stimulated migration and proliferation of pSMC. While the activation of the MAPK pathway seems to be necessary for stimulation of mitogenesis by IGF-I, the contribution of this pathway in IGF-I-induced cell migration is limited in pSMC. Interestingly, neither PI 3-kinase inhibitors nor PD98059 blocked the increase in alphaVbeta3 integrin affinity that followed IGF-I treatment. Therefore, although both the PI 3-kinase and MAPK pathways were used by IGF-I to increase migration of pSMC, alphaVbeta3 integrin activation did not depend on either PI 3-kinase or MAPK activation, suggesting the possible importance of some other signal transduction pathway to account for its full actions on pSMC.
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PMID:Roles of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in stimulation of vascular smooth muscle cell migration and deoxyriboncleic acid synthesis by insulin-like growth factor-I. 1046 96

We have examined the mechanism by which collagen-binding integrins co-operate with insulin-like growth factor-I (IGF-I) receptors (IGF-IR) to regulate chondrocyte phenotype and differentiation. Adhesion of chondrocytes to anti-beta1 integrin antibodies or collagen type II leads to phosphorylation of cytoskeletal and signalling proteins localized at focal adhesions, including alpha-actinin, vinculin, paxillin and focal adhesion kinase (FAK). These stimulate docking proteins such as Shc (Src-homology collagen). Moreover, exposure of collagen type II-cultured chondrocytes to IGF-I leads to co-immunoprecipitation of Shc protein with the IGF-IR and with beta1, alpha1 and alpha5 integrins, but not with alpha3 integrin. Shc then associates with growth factor receptor-bound protein 2 (Grb2), an adaptor protein and extracellular signal-regulated kinase. The expression of the docking protein Shc occurs only when chondrocytes are bound to collagen type II or integrin antibodies and increases when IGF-I is added, suggesting a collaboration between integrins and growth factors in a common/shared biochemical signalling pathway. Furthermore, these results indicate that focal adhesion assembly may facilitate signalling via Shc, a potential common target for signal integration between integrin and growth-factor signalling regulatory pathways. Thus, the collagen-binding integrins and IGF-IR co-operate to regulate focal adhesion components and these signalling pathways have common targets (Shc-Grb2 complex) in subcellular compartments, thereby linking to the Ras-mitogen-activated protein kinase signalling pathway. These events may play a role during chondrocyte differentiation.
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PMID:Signal transduction by beta1 integrin receptors in human chondrocytes in vitro: collaboration with the insulin-like growth factor-I receptor. 1047 72


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