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)

GH stimulates the tyrosine phosphorylation of various cellular polypeptides, including the GH receptor itself, in an early part of the intracellular response. Some of these phosphorylations are catalyzed by a GH receptor-associated kinase identified as JAK2, a member of the Janus family of tyrosine kinases. In cultured cells, GH stimulates the tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-2, and Shc. This study investigated whether GH could cause the tyrosine phosphorylation of IRSs and Shc proteins in fasted rat tissues in vivo. GH was administered to fasted Wistar rats via a portal vein, and extracts of different tissues were immunoprecipitated with specific antibodies. GH increased the tyrosine phosphorylation of IRS-1, IRS-2, JAK2, and Shc proteins in the liver, heart, kidney, muscle, and adipose tissue of rats. The roles of these substrates as signaling molecules for GH were further demonstrated by the finding that GH stimulated the association of IRS-1/2 with phosphatidylinositol 3-kinase, Grb2, and phosphotyrosine phosphatase and of Shc with Grb2. The correlation between JAK2 tyrosyl phosphorylation and IRS-1 tyrosyl phosphorylation in response to GH together with the results of the in vitro tyrosine kinase assay are consistent with the hypothesis that JAK2 may mediate GH-induced phosphorylation of IRS-1.
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PMID:Growth hormone stimulates the tyrosine kinase activity of JAK2 and induces tyrosine phosphorylation of insulin receptor substrates and Shc in rat tissues. 988 7

STAT5b (signal transducer and activator of transcription 5b) is a key mediator of the effects of plasma GH pulses on male-specific liver gene expression. STAT5b is activated in liver cells in vivo by physiological pulses of GH and then is rapidly deactivated. Investigation of the cellular events involved in this activation/deactivation cycle using the rat liver cell line CWSV-1 established that a brief exposure to GH and the associated activation of JAK2 (Janus kinase 2) tyrosine kinase activity are both necessary and sufficient to initiate all of the downstream steps associated with STAT5b activation by tyrosine phosphorylation and the subsequent deactivation of both JAK2 kinase and STAT5b. JAK2 signaling to STAT5b at the conclusion of a GH pulse could be sustained by the protein synthesis inhibitor cycloheximide or by the proteasome inhibitor MG132, indicating that termination of this JAK2-catalyzed STAT activation loop requires synthesis of a labile or GH-inducible protein factor and is facilitated by the proteasome pathway. This factor may be a phosphotyrosine phosphatase, since the phosphatase inhibitor pervanadate both sustained GH pulse-induced JAK2 signaling to STAT5b and blocked the rapid deactivation of phosphorylated STAT5b (t(1/2) = 8.8 +/- 0.9 min) seen in its absence. Finally, the serine kinase inhibitor H7 blocked down-regulation of JAK2 signaling to STAT5b in a manner that enabled cells to respond to a subsequent GH pulse without the need for the approximately 3-h interpulse interval normally required for full recovery of GH pulse responsiveness. Termination of GH pulse-induced STAT5b signaling is thus a complex process that involves multiple biochemical events. These are proposed to include the down-regulation of JAK2 signaling to STAT5b via a cycloheximide- and H7-sensitive step, proteasome-dependent degradation of a key component or regulatory factor, and dephosphorylation leading to deactivation of the receptor-kinase signaling complex and its STAT5b substrate via the action of a phosphotyrosine phosphatase.
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PMID:Termination of growth hormone pulse-induced STAT5b signaling. 989 11

The suppression of male-specific, GH pulse-induced, liver transcription in adult female rats has been linked to the down-regulation of STAT5b activation by the female plasma pattern of near-continuous GH exposure. The mechanism underlying this down-regulation was studied in the rat liver cell line CWSV-1, where continuous GH suppressed the level of activated (tyrosine- phosphorylated) STAT5b to approximately 10-20% of the maximal GH pulse-induced STAT5b signal within 3 h. In contrast to the robust JAK2 kinase-dependent STAT5b activation loop that is established by a GH pulse, JAK2 kinase signaling to individual STAT5b molecules was found to be short lived in cells treated with GH continuously. Moreover, maintenance of the low-level STAT5b signal required ongoing protein synthesis and persisted for at least 7 days provided that GH was present in the culture continuously. Increased STAT5b DNA-binding activity was observed in cells treated with the proteasome inhibitor MG132, suggesting that at least one component of the GH receptor (GHR)-JAK2-STAT5b signaling pathway becomes labile in response to continuous GH treatment. The phosphotyrosine phosphatase inhibitor pervanadate fully reversed the down-regulation of STAT5b DNA-binding activity in continuous GH-treated cells by a mechanism that involves both increased STAT5b activation and decreased STAT5b dephosphorylation. Moreover, the requirement for ongoing GH stimulation and active protein synthesis to maintain STAT5b activity in continuous GH-treated cells were both eliminated by pervanadate treatment, suggesting that phosphotyrosine dephosphorylation may be an obligatory first step in the internalization/degradation pathway for the GHR-JAK2 complex. Finally, the sustaining effect of the serine kinase inhibitor H7 on GH pulse-induced JAK2 signaling to STAT5b was not observed in continuous GH-treated cells. These findings suggest a model where continuous GH exposure of liver cells down-regulates the STAT5b pathway by a mechanism that involves enhanced dephosphorylation of both STAT5b and GHR-JAK2, with the latter step leading to increased internalization/degradation of the re-ceptor-kinase complex.
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PMID:Down-regulation of liver JAK2-STAT5b signaling by the female plasma pattern of continuous growth hormone stimulation. 997 52

Insulin-like growth factor I (IGF-I) promotes the motility of different cell types. We investigated the role of IGF-I receptor (IGF-IR) signaling in locomotion of MCF-7 breast cancer epithelial cells overexpressing the wild-type IGF-IR (MCF-7/IGF-IR). Stimulation of MCF-7/IGF-IR cells with 50 ng/ml IGF-I induced disruption of the polarized cell monolayer followed by morphological transition toward a mesenchymal phenotype. Immunofluorescence staining of the cells with rhodamine-phalloidin revealed rapid disassembly of actin fibers and development of a cortical actin meshwork. Activation of phosphatidylinositol (PI)3-kinase downstream of the IGF-IR was necessary for this process, as blocking PI 3-kinase activity with the specific inhibitor LY 294002 at 10 microM prevented disruption of the filamentous actin. In parallel, IGF-IR activation induced rapid and transient tyrosine dephosphorylation of focal adhesion proteins p125 focal adhesion kinase (FAK), p130 Crk-associated substrate (Cas), and paxillin. This process required phosphotyrosine phosphatase (PTP) activity, since pretreatment of the cells with 5 microM phenylarsine oxide (PAO), an inhibitor of PTPs, rescued FAK and its associated proteins Cas and paxillin from IGF-I-induced dephosphorylation. In addition, PAO-pretreated cells were refractory to IGF-I-induced morphological transition. Thus, our findings reveal a new function of the IGF-IR, the ability to depolarize epithelial cells. In MCF-7 cells, mechanisms of IGF-IR-mediated cell depolarization involve PI 3-kinase signaling and putative PTP activities.
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PMID:The activated insulin-like growth factor I receptor induces depolarization in breast epithelial cells characterized by actin filament disassembly and tyrosine dephosphorylation of FAK, Cas, and paxillin. 1043 90

Cell-matrix interactions exert a profound influence on cell function and behavior. Our earlier observations suggested that disruption of the actin cytoskeleton results in the inhibition of phorbol ester-induced matrix metalloproteinase (MMP)-9 expression. In this study, to understand the role of protein tyrosine phosphatases in matrix metalloproteinase-9 expression, we treated glioblastoma cells with vanadate and phenylarsine oxide (PAO), which are inhibitors of protein tyrosine phosphatases. Vanadate and PAO inhibited expression of phorbol ester-induced MMP-9 as well as constitutive expression of matrix metalloproteinase-2 in a dose- and time-dependent fashion. An assay of the activity of phosphotyrosine phosphatase (PTPase) indicated that vanadate-treated cells had reduced PTPase activity compared with that of untreated controls. Vanadate and PAO also inhibited actin polymerization, cell spreading, migration, and invasion of glioma cells. Furthermore, elevated levels of protein tyrosine phosphorylation were observed in vanadate- and PAO-treated cells in both a concentration- and time-dependent fashion and were seen to have an inverse correlation with focal adhesion kinase protein expression. These results suggest that vanadate and PAO inhibited migration and invasion of glioma cells by their effect on the cytoskeleton and inhibition of MMP expression.
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PMID:Altered actin cytoskeleton and inhibition of matrix metalloproteinase expression by vanadate and phenylarsine oxide, inhibitors of phosphotyrosine phosphatases: modulation of migration and invasion of human malignant glioma cells. 1056 4

The BCR/ABL oncogene causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells and myeloid cells. It is shown here that transformation of the hematopoietic cell lines Ba/F3, 32Dcl3, and MO7e with BCR/ABL results in an increase in reactive oxygen species (ROS) compared with quiescent, untransformed cells. The increase in ROS was directly due to BCR/ABL because it was blocked by the ABL-specific tyrosine kinase inhibitor STI571. Oxidative stress through ROS is believed to have many biochemical effects, including the potential ability to inhibit protein-tyrosine phosphatases (PTPases). To understand the significance of increased production of ROS, a model system was established in which hydrogen peroxide (H(2)O(2)) was added to untransformed cells to mimic the increase in ROS induced constitutively by BCR/ABL. H(2)O(2) substantially reduced total cellular PTPase activity to a degree approximately equivalent to that of pervanadate, a well known PTPase inhibitor. Further, stimulation of untransformed cells with H(2)O(2) or pervanadate increased tyrosine phosphorylation of each of the most prominent known substrates of BCR/ABL, including c-ABL, c-CBL, SHC, and SHP-2. Treatment of the BCR/ABL-expressing cell line MO7/p210 with the reducing agents pyrrolidine dithiocarbamate or N-acetylcysteine reduced the accumulation of ROS and also decreased tyrosine phosphorylation of cellular proteins. Further, treatment of MO7e cells with H(2)O(2) or pervanadate increased the tyrosine kinase activity of c-ABL. Drugs that alter ROS metabolism or reactivate PTPases may antagonize BCR/ABL transformation.
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PMID:The BCR/ABL tyrosine kinase induces production of reactive oxygen species in hematopoietic cells. 1083 15

The effect of insulin on glucose transport, glucose transporter 4 (Glut4) translocation, and intracellular signaling were measured in fat cells from lean and obese Zucker rats of different ages. Insulin-stimulated glucose transport was markedly reduced in adipocytes from old and obese animals. The protein content of Glut4 and insulin receptor substrates (IRS) 1 and 2 were also reduced while other proteins, including the p85 subunit of PI3-kinase, Shc and the MAP kinases (ERK1 and 2) were essentially unchanged. There was a marked impairment in the insulin stimulated tyrosine phosphorylation of IRS-1 and 2 as well as activation of PI3-kinase and PKB in cells from old and obese animals. Furthermore, insulin-stimulated translocation of both Glut4 and PKB to the plasma membrane was virtually abolished. The phosphotyrosine phosphatase inhibitor, vanadate, increased the insulin-stimulated upstream signaling including PI3-kinase and PKB activities as well as rate of glucose transport. Thus, the insulin resistance in cells from old and obese Zucker rats can be accounted for by an impaired translocation process, due to signaling defects leading to a reduced activation of PI3-kinase and PKB, as well as an attenuated Glut4 protein content.
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PMID:Insulin resistance in fat cells from obese Zucker rats--evidence for an impaired activation and translocation of protein kinase B and glucose transporter 4. 1083 89

Treatment of confluent chicken embryo fibroblasts (CEFs) with trypsin results in a dose- and time-dependent increase in c-Src protein tyrosine kinase (PTK) activity. A similar, but less marked, increase in c-Src PTK activity occurs upon incubation of CEFs in calcium-free phosphate-buffered saline, which also causes a decrease in cell-substrate adhesion. The increase in c-Src PTK activity following disruption of cell-substrate adhesion correlates with a decrease in the phosphorylation of c-Src at the regulatory site, Tyr527. The phosphotyrosine phosphatase inhibitor phenylarsine oxide blocks the increase in c-Src PTK activity seen following treatment with trypsin and the morphological changes associated with the disruption of cell-substrate adhesion. In contrast, disruption of cell-substrate adhesion causes a decrease in FAK PTK activity that rapidly returns to control levels when the cells are plated on fibronection-coated dishes. Treatment of cells with cytochalasin D, which disrupts actin filaments but not cell-substrate adhesion, causes only a slight increase in c-Src PTK activity. Thus, these studies demonstrate a ligand-independent mechanism for the activation of c-Src that is consistent with its role in both cell adhesion and cell motility. Furthermore, these data suggest that similar to adhesion, loss of adhesion is not a passive process but can activate specific signaling pathways that may have significant effects on cellular function.
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PMID:Disruption of cell-substrate adhesion activates the protein tyrosine kinase pp60(c-src). 1103 13

Isolated rat pancreatic islets were incubated at 3.3 (low) and 16.7 (high) mM glucose with different concentrations of the phosphotyrosine phosphatase (PTP) inhibitor, peroxovanadate (pV). At low glucose, pV stimulated insulin secretion 2- to 4-fold, but it inhibited insulin secretion at 16.7 mM. The latter effect was not due to an inhibition of glucose metabolism, nor was it inhibited by pertussis toxin pretreatment. In addition, pV stimulated insulin secretion approximately 3-fold in depolarized cells at both low and high glucose. pV markedly increased the tyrosine phosphorylation of several proteins, including IRS-1 and -2, and also increased the phosphorylation of the downstream kinases PKB/Akt and MAPK. PKB/Akt, but not MAPK, was also phosphorylated in the absence of pV. Intracellular pV-stimulated tyrosine phosphorylation, including that of IRS-2, was generally increased by high glucose suggesting a further inhibition of PTP and/or enhanced tyrosine kinase activity. Thus, these data suggest that intracellular tyrosine and serine (PKB/Akt) phosphorylation are related to insulin secretion but they do not support a unique and direct link between IRS-2 tyrosine phosphorylation and glucose-stimulated insulin secretion.
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PMID:Effects of phosphotyrosine phosphatase inhibition on insulin secretion and intracellular signaling events in rat pancreatic islets. 1116 49

Low M(r) phosphotyrosine protein phosphatase interferes in vivo with the activation of several growth factor receptors and is transiently redistributed, following cell stimulation with platelet-derived growth factor, from the cytosol to the cytoskeleton. We demonstrate here that this phosphatase also participates in the regulation of cell spreading and migration, pointing to its involvement in cytoskeleton organization. Low M(r) phosphotyrosine protein phosphatase-overexpressing fibroblasts are, indeed, less spread than controls and display a significantly decreased number of focal adhesions and increased cell motility. Furthermore, p125 focal adhesion kinase is associated to, and dephosphorylated by, low M(r) phosphotyrosine protein phosphatase both in vitro and in vivo. This event is consistent with an altered association of pp60(src) with focal adhesion kinase. The activation of extracellular signal-regulated kinase, another well known event downstream of the focal adhesion kinase, is also affected. On the other hand, cells overexpressing the dominant-negative form of low M(r) phosphotyrosine protein phosphatase exhibit hyperphosphorylated focal adhesion kinase, reduced motility, and an increased number of focal adhesions, which are distributed all over the ventral cell surface. Taken together, the results reported here are in keeping with low M(r) phosphotyrosine protein phosphatase participation in FAK-mediated focal adhesion remodeling.
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PMID:Low Mr phosphotyrosine protein phosphatase associates and dephosphorylates p125 focal adhesion kinase, interfering with cell motility and spreading. 1205 85


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