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)

Human placental alkaline phosphatase (PALP) is synthesized in the placenta during pregnancy and is also expressed in many cancer patients; however, its physiological role is unknown. Here we show that in human fetus fibroblasts as well as normal and H-ras-transformed mouse embryo fibroblasts PALP stimulates DNA synthesis and cell proliferation in synergism with insulin, zinc and calcium. The mitogenic effects of PALP are associated with the activation of c-Raf-1, p42/p44 mitogen-activated protein kinases, p70 S6 kinase, Akt/PKB kinase and phosphatidylinositol 3'-kinase. The results suggest that in vivo PALP may promote fetus development as well as the growth of cancer cells which express oncogenic Ras.
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PMID:Growth factor-like effects of placental alkaline phosphatase in human fetus and mouse embryo fibroblasts. 1071 64

In the present study we have investigated the effect of increased serine/threonine phosphorylation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) by okadaic acid pretreatment on brown adipocyte insulin signalling leading to glucose transport, an important metabolic effect of insulin in brown adipose tissue. Okadaic acid pretreatment before insulin stimulation decreased IRS-1 and IRS-2 tyrosine phosphorylation in parallel to a decrease in their sodium dodecyl sulfate-polyacrylamide gel electrophoresis mobility. IRS-1/IRS-2-associated p85alpha and phosphatidylinositol (PI) 3-kinase enzymatic activity were partly reduced in brown adipocytes pretreated with okadaic acid upon stimulation with insulin. Furthermore, insulin-induced glucose uptake was totally abolished by the inhibitor in parallel with a total inhibition of insulin-induced protein kinase C (PKC) zeta activity. However, activation of Akt/PKB or p70 S6 kinase (p70(s6k)) by insulin remained unaltered. Our results suggest that downstream of PI 3-kinase, insulin signalling diverges into at least two independent pathways through Akt/PKB and PKC zeta, the PKC zeta pathway contributing to glucose transport induced by insulin in fetal brown adipocytes.
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PMID:Okadaic acid inhibits insulin-induced glucose transport in fetal brown adipocytes in an Akt-independent and protein kinase C zeta-dependent manner. 1078 24

We compared the role of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MEK)/extracellular signal-regulated protein kinase (ERK)/p90(RSK) cascade in gp130-mediated cardiac hypertrophy with the contribution of the Janus kinase (JAK)/signal transduction and activation of transcription (STAT) and phosphatidylinositide 3-kinase (PI3-K) pathways. Primary cultured neonatal rat cardiomyocytes were stimulated with leukemia inhibitory factor (LIF). LIF sequentially activated Raf-1, MEK1/2, ERK1/2, and p90(RSK). We used PD-98059 (a specific MEK inhibitor), AG-490 (a JAK2 inhibitor), and wortmannin (a PI3-K inhibitor) to confirm that this cascade was independent of the JAK/STAT and PI3-K/p70 S6 kinase (S6K) pathways. PD-98059, AG-490, and wortmannin suppressed the LIF-induced increase in [(3)H]phenylalanine uptake by 54.7, 21.5, and 25.6%, respectively, and inhibited the increase in cell area by 61.2, 42.8, and 39.2%, respectively. Reorganization of myofilaments was predominantly suppressed by AG-490. LIF-induced expression of c-fos, brain natriuretic peptide, and skeletal alpha-actin mRNA was markedly suppressed by PD-98059 and moderately suppressed by wortmannin and AG-490. Atrial natriuretic peptide was significantly suppressed by AG-490. These findings indicate that this pathway is critically involved in protein synthesis, induction of c-fos, brain natriuretic peptide, and skeletal alpha-actin expression and is partially involved in myofilament reorganization and atrial natriuretic peptide induction in gp130-mediated cardiac hypertrophy.
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PMID:Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy. 1100 50

We have previously shown that interferon-alpha (IFN alpha)-dependent tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) is impaired by serine phosphorylation of IRS-1 due to the reduced ability of serine phosphorylated IRS-1 to serve as a substrate for Janus kinase 1 (JAK1). Here we report that FKBP12-rapamycin-associated protein (FRAP) is a physiologic IRS-1 kinase that blocks IFN alpha signaling by serine phosphorylating IRS-1. We found that both FRAP and insulin-activated p70 S6 kinase (p70(s6k)) serine phosphorylated IRS-1 between residues 511 and 772 (IRS-1(511-772)). Importantly, only FRAP-dependent IRS-1(511-772) serine phosphorylation inhibited by 50% subsequent JAK1-dependent tyrosine phosphorylation of IRS-1. Furthermore, treatment of U266 cells with the FRAP inhibitor rapamycin increased IFN alpha-dependent tyrosine phosphorylation by twofold while reducing constitutive IRS-1 serine phosphorylation within S/T-P motifs by 80%. Taken together, these data indicate that FRAP, but not p70(s6k), is a likely physiologic IRS-1 serine kinase that negatively regulates JAK1-dependent IRS-1 tyrosine phosphorylation and suggests that FRAP may modulate IRS-dependent cytokine signaling.
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PMID:Frap-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation. 1116 88

Erythropoietin (EPO) is a lineage-restricted growth factor that is required for erythroid proliferation and differentiation. EPO stimulates the phosphorylation and activation of p70 S6 kinase (p70 S6K), which is required for cell cycle progression. Here, the minimal cytoplasmic domains of the EPO receptor (EPO-R) required for p70 S6K activation were determined.Ba/F3 cells were stably transfected with wild-type (WT) EPO-R or EPO-R carboxyl-terminal deletion mutants, designated by the number of amino acids deleted from the cytoplasmic tail (-99, -131, -221). Transfected cells were growth factor deprived and then stimulated with EPO. p70 S6K, JAK2, IRS-2, and ERK1/2 phosphorylation/activation were examined. The ability of transfected 3-phosphoinositide-dependent protein kinase 1 (PDK1) to reconstitute p70 S6K phosphorylation in EPO-R mutants also was determined. Phosphorylation and activation of p70 S6K, JAK2, IRS-2, and ERK1/2 in Ba/F3 cells transfected with EPO-R-99 or EPO-R-99Y343F were similar to WT EPO-R. In contrast, EPO-dependent p70 S6K phosphorylation/activation, as well as IRS-2 and ERK1/2 phosphorylation, were minimal or absent in cells transfected with EPO-R-131 or EPO-R-221. JAK2 phosphorylation was reduced significantly in cells transfected with EPO-R-131 and abolished with EPO-R-221. To examine the role of PDK1, a kinase known to phosphorylate p70 S6K, Ba/F3 EPO-R-131 cells were transiently transfected with PDK1. WT constitutively active PDK1 restored p70 S6K phosphorylation in Ba/F3 EPO-R-131 cells but not in Ba/F3 EPO-R-221 cells. The results demonstrate that a minimal cytoplasmic subdomain of the EPO-R extending between -99 and -131 is required for p70 S6K phosphorylation and activation. The results also demonstrate that PDK1 is a critical component in this signaling pathway, which requires the presence of domains between -131 and -221 for its activation of p70 S6K.
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PMID:A minimal cytoplasmic subdomain of the erythropoietin receptor mediates p70 S6 kinase phosphorylation. 1130 Nov 83

Phosphatidylinositol 3-kinase (PI3-K) is a growth factor-activated transforming lipid (and protein) kinase, involved in cell motility and invasion, that has multiple effectors. Relatively little is known about its expression and enzymatic activity in human breast cancer. Since growth factor receptors are amplified in breast cancer, and the tumor suppressor PTEN may be mutated in human breast cancer, it was hypothesized that PI3-K and its downstream effectors would be activated in this disease. In 11 resected tumors analyzed for expression of this kinase, a mean 3-fold increase in protein expression was observed over the corresponding adjacent control tissue. Using an in vitro lipid kinase assay of the immunoprecipitated PI3-K protein, a greater than 2-fold increase in activation was observed. These changes were observed in the absence of an activation of either protein kinase B (PKB, akt1) or p70 S6 kinase (p70 S6K). However, p21-activated kinase (Pak), p38 mitogen-activated protein kinase (p38 MAPK) and mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK 2) were all overexpressed and demonstrated increased enzyme activity. It may be concluded that aberrant mitogenic signaling in human breast cancer in vivo involves Pak, p38 MAPK and MAPKAPK2 downstream of PI3-K, but neither of PKB or p70 S6K. It is proposed that this pathway may serve as a useful targeting nexus for investigation of small molecule inhibitors in human breast cancer.
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PMID:Dysregulation of phosphatidylinositol 3-kinase and downstream effectors in human breast cancer. 1185 99

Vav3 is a member of the Vav family of guanine nucleotide exchange factors (GEFs) for the Rho family GTPases. Deleting the N-terminal calponin homology (CH) domain to generate Vav3-(5-10) or deleting both the CH and the acidic domain to generate Vav3-(6-10) results in activating the transforming potential of Vav3. Expression of either the full-length Vav3 or its truncation mutants led to activation of phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK), and Stat3. We investigated the requirement of these signaling molecules for Vav3-induced focus formation and found that PI3K and its downstream signaling molecules, Akt and p70 S6 kinase, are required, albeit to varying degrees. Inhibition of PI3K had a more dramatic effect than inhibition of MAPK on Vav3-(6-10)-induced focus formation. Activated PI3K enhanced the focus-forming activity of Vav3-(6-10). Wild type FAK but not Y397F mutant FAK enhanced Vav3-(6-10)-induced focus formation. Dominant negative (dn) mutant of Stat3 resulted in a 60% inhibition of the focus-forming activity of Vav3-(6-10). Moreover, Rac1, RhoA, and to a lesser extent, Cdc42, are important for Vav3-(6-10)-induced focus formation. Constitutively activated (ca) Rac synergizes with Vav3-(6-10) in focus formation. This synergy requires signaling via Rho-associated kinase (ROK) and p21-activated kinase (PAK), downstream effectors of Rac. Consistently, a ca PAK mutant enhanced, whereas a dn PAK mutant inhibited the focus-forming ability of Vav3-(6-10). Despite having potent focus-forming ability, Vav3-(6-10) has very weak colony-forming ability. This colony-forming ability of Vav3-(6-10) can be enhanced dramatically by co-expressing an activated PI3K and to some extent by co-expressing an activated PAK mutant or c-Myc. Interestingly, inhibition of PI3K and MAPK had no effect on the ability of either wild type or Vav3-(6-10) to induce cytoskeletal changes including formation of lamellipodia and filopodia in NIH 3T3 cells. Over expression of Vav3 or Vav3-(6-10) resulted in an enhancement of cell motility. This enhancement was dependent on PI3K, Rac1, and Cdc42 but not on Rho. Overall, our results show that signaling pathways of PI3K, MAPK, and Rho family GTPases are differentially required for Vav3-induced focus formation, colony formation, morphological changes, and cell motility.
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PMID:Distinct role of phosphatidylinositol 3-kinase and Rho family GTPases in Vav3-induced cell transformation, cell motility, and morphological changes. 1188 91

The mechanisms by which insulin-like growth factor I (IGF-I) and insulin regulate eukaryotic initiation factor (eIF)4F formation were examined in the ovine fetus. Insulin infusion increased phosphorylation of eIF4E-binding protein (4E-BP1) in muscle and liver. IGF-I infusion did not alter 4E-BP1 phosphorylation in liver. In muscle, IGF-I increased 4E-BP1 phosphorylation by 27%; the percentage in the gamma-form in the IGF-I group was significantly lower than that in the insulin group. In liver, only IGF-I increased eIF4G. Both IGF-I and insulin increased eIF4E. eIF4G binding in muscle, but only insulin decreased the amount of 4E-BP1 associated with eIF4E. In liver, only IGF-I increased eIF4E. eIF4G binding. Insulin increased the phosphorylation of p70 S6 kinase (p70(S6k)) in both muscle and liver and protein kinase B (PKB/Akt) in muscle, two indicative signal proteins in the phosphatidylinositol (PI) 3-kinase pathway. IGF-I increased PKB/Akt phosphorylation in muscle but had no effect on p70(S6k) phosphorylation in muscle or liver. We conclude that insulin and IGF-I modulate eIF4F formation; however, the two hormones have different regulatory mechanisms. Insulin increases phosphorylation of 4E-BP1 and eIF4E. eIF4G binding in muscle, whereas IGF-I regulates eIF4F formation by increasing total eIF4G. Insulin, but not IGF-I, decreased 4E-BP1 content associated with eIF4E. Insulin regulates translation initiation via the PI 3-kinase-p70(S6k) pathway, whereas IGF-I does so mainly via mechanisms independent of the PI 3-kinase-p70(S6k) pathway.
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PMID:IGF-I and insulin regulate eIF4F formation by different mechanisms in muscle and liver in the ovine fetus. 1216 54

Thyroid-stimulating hormone (TSH) action in adipose tissue remains largely unknown. Our previous work indicates that human preadipocytes express functional TSH receptor (TSHR) protein, demonstrated by TSH activation of p70 S6 kinase (p70 S6K). We have now studied murine 3T3-L1 preadipocytes to further characterize TSH signaling and cellular action. Western blot analysis of 3T3-L1 preadipocyte lysate revealed the 100-kDa mature processed form of TSHR. TSH activated p70 S6K and protein kinase B (PKB/Akt), as measured by immunoblot analysis. Preincubation with wortmannin or LY-294002 completely blocked TSH activation of p70 S6K and PKB/Akt, implicating phosphoinositide 3-kinase (PI3K) in their regulation. TSH increased phosphotyrosine protein(s) in the 125-kDa region and augmented the associated PI3K activity fourfold. TSH had no effect on cAMP levels in 3T3-L1 preadipocytes, suggesting that adenylyl cyclase is not involved in TSH activation of the PI3K-PKB/Akt-p70 S6K pathway. 3T3-L1 preadipocyte cell death was reduced by 29-76% in serum-deprived (6 h) preadipocytes treated with 1-20 microM TSH. In the presence of 20 microM TSH, an 88% reduction in terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-positive cells was observed in serum-starved (3 h) 3T3-L1 preadipocytes as well as a 93% reduction in the level of cleaved activated caspase 3. In summary, TSH acts as a survival factor in 3T3-L1 preadipocytes. TSH does not stimulate cAMP accumulation in these cells but instead activates a PI3K-PKB/Akt-p70 S6K pathway.
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PMID:TSH signaling and cell survival in 3T3-L1 preadipocytes. 1222 69

Human immunodeficiency virus (HIV) gp120 induces multiple cellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3-kinase) pathway. The role of the PI3-kinase pathway in HIV-1 replication is not understood. Here we examined whether HIV-1 gp120 upregulates the PI3-kinase pathway and whether PI3-kinase activity plays a role in virus replication in primary human CD4(+) T cells and macrophages. Soluble and virion-associated HIV-1 gp120 induced calcium mobilization and phosphorylation of the PI3-kinase downstream effectors PKB/Akt and p70 S6 kinase. gp120-induced PI3-kinase activity and calcium mobilization were inhibited by pertussis toxin and blocking antibodies directed against CCR5 and CXCR4, suggesting that the signaling is mediated through the chemokine receptor. The PI3-kinase inhibitor LY294002 inhibited infection of CD4(+) T cells and macrophages with X4 and R5 HIV-1-pseudotyped viruses at concentrations that did not induce cell toxicity or downregulate HIV-1 coreceptor expression. When gp120-induced signaling was bypassed with the vesicular stomatitis virus G envelope protein, infection was still sensitive to PI3-kinase inhibition, suggesting that basal PI3-kinase activity is required for infection. LY294002 inhibited HIV-1 infection when added after viral entry and did not affect formation of the HIV-1 reverse transcriptase products R/U5 and long terminal repeat/Gag in the presence of the inhibitor. However, when the inhibitor was added after viral integration had occurred, no inhibition of HIV infection was observed. Our studies show that inhibition of the PI3-kinase signaling pathway suppresses virus infection post-viral entry and post-reverse transcription but prior to HIV gene expression. This type of host-virus interaction has implications for anti-HIV therapeutics that target cellular signaling machinery.
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PMID:Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages. 1255 92


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