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)

Neutral endopeptidase 24.11 (NEP, CD10) is a cell-surface enzyme expressed by prostatic epithelial cells that cleaves and inactivates neuropeptides implicated in the growth of androgen-independent prostate cancer (PC). NEP substrates such as bombesin and endothelin-1 induce cell migration. We investigated the mechanisms of NEP regulation of cell migration in PC cells, including regulation of phosphorylation on tyrosine of focal adhesion kinase (FAK). Western analyses and cell migration assays revealed an inverse correlation between NEP expression and the levels of FAK phosphorylation and cell migration in PC cell lines. Constitutively expressed NEP, recombinant NEP, and induced NEP expression using a tetracycline-repressive expression system inhibited bombesin- and endothelin-1-stimulated FAK phosphorylation and cell migration. This results from NEP-induced inhibition of neuropeptide-stimulated association of FAK with cSrc protein. Expression of a mutated catalytically inactive NEP protein also resulted in partial inhibition of FAK phosphorylation and cell migration. Coimmunoprecipitation experiments show that NEP associates with tyrosine-phosphorylated Lyn kinase, which then binds the p85 subunit of phosphatidylinositol 3-kinase (PI3-K) resulting in an NEP-Lyn-PI3-K protein complex. This complex competitively blocks FAK-PI3-K interaction, suggesting that NEP protein inhibits cell migration via a protein-protein interaction independent of its catalytic function. These experiments demonstrate that NEP can inhibit FAK phosphorylation on tyrosine and PC cell migration through multiple pathways and suggest that cell migration which contributes to invasion and metastases in PC cells can be regulated by NEP.
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PMID:Neutral endopeptidase inhibits prostate cancer cell migration by blocking focal adhesion kinase signaling. 1110 93

The glycoprotein hormones, ACTH, TSH, FSH, and LH regulate diverse functions in endocrine cells. Although cAMP and PKA have long been shown to mediate specific intracellular signaling events including the transcription of specific genes via the CREB-CBP complex, recent observations have indicated that PKA does not account for all of the intracellular targets of cAMP. For example, TSH stimulation of thyroid cell proliferation is not completely blocked by PKA inhibitors. TSH and FSH can stimulate PKB phosphorylation by a PKAindependent but PI3-K/PDK1-dependent pathway. An FSH inducible kinase, Sgk, has recently been shown to be a close relative of PKB. Sgk is also a target of PI3-K-PDK1 pathway, indicating that some effects previously ascribed to PKB may be mediated by this inducible kinase. The identification of novel cAMP-binding proteins that exhibit guanine nucleotide exchange (GEF) activity (cAMP-GEFS; Epacs) has open new doors for cAMP action that include activation of small GTPases such as Rap1a, Rap2, and possibly Ras. These GTPases are known activators of downstream kinase cascades, including p38MAPK and Erk1/2 as well as PI3-K. Thus, FSH and TSH activation of PKB and Sgk may occur via this alternative cAMP pathway that involves cAMP-GEFs and the activation of the PI3-K/PDK1 pathway.
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PMID:New signaling pathways for hormones and cyclic adenosine 3',5'-monophosphate action in endocrine cells. 1115 28

Glucocorticoid hormones influence manifold neuronal processes including learning, memory, and emotion via the glucocorticoid receptor (GR). Catecholamines further modulate these functions, although the underlying molecular mechanisms are poorly understood. Here, we show that epinephrine and norepinephrine potentiate ligand-dependent GR transactivation in a hippocampal cell line (HT22) via beta(2)-adrenergic receptors. This enhancement was strongest at low concentrations of glucocorticoids and was accompanied by increased GR binding to a glucocorticoid-responsive element (GRE). beta(2)-Adrenergic receptor-mediated GR enhancement was relayed via G protein beta gamma-subunits, insensitive to pertussis toxin and independent of protein kinase A (PKA). In contrast, the catecholamine-evoked GR enhancement was strongly reduced by wortmannin, suggesting a critical role for phosphoinositide 3-kinase (PI3-K). In agreement, epinephrine directly activated PI3-K in vivo. Similarly, stimulation of tyrosine kinase receptors coupled to PI3-K activation, e.g. receptors for insulin-like growth factor I (IGF-I) or fibroblast growth factor (FGF), increased GR transactivation. Further analysis indicated that G protein-coupled receptor (GPCR) and tyrosine kinase receptor signals converge on PI3-K through separate mechanisms. Blockade of GR enhancement by wortmannin was partially overcome by expression of the downstream-acting protein kinase B (PKB/Akt). Collectively, our findings demonstrate that GPCRs can regulate GR transactivation by stimulating PI3-K. This novel cross-talk may provide new insights into the molecular processes of learning and memory and the treatment of stress-related disorders.
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PMID:Beta(2)-adrenergic receptors potentiate glucocorticoid receptor transactivation via G protein beta gamma-subunits and the phosphoinositide 3-kinase pathway. 1126 7

Cyclooxygenase (COX) 2 expression is regulated via the Ras signaling pathway, and induction of mutated Ras rapidly increases COX-2 levels in intestinal epithelial cells. Protein kinase B (Akt/PKB) is an important effector of Ras signaling and a critical component of Ras-mediated transformation. Here we investigate the role of Akt/PKB in K-Ras-mediated induction of COX-2. Rat intestinal epithelial cells (IEC-6) were transfected with an inducible K-RasVal12 cDNA (IEC-iK-Ras cells). Addition of 5 mM isopropyl-1-thio-beta-D-galactopyranoside induced the expression of K-RasVal12, followed by increased activity of extracellular signal-regulated kinase and Akt/PKB. COX-2 levels were dramatically increased after induction of K-RasVal12. Inhibition of MAPK/ERK kinase activity by PD 98059 completely blocked the K-Ras-mediated induction of COX-2, whereas inhibition of PI3K/Akt/PKB activity with LY 294002 or by expressing a dominant negative Akt (Akt-K179M) partially blocked the induction of COX-2 by K-Ras. Transient transfection of cells with phosphatidylinositol 3-kinase and Akt expression vectors revealed that PI3/Akt/PKB activity predominantly regulates the stability of COX-2 mRNA. Thus, Akt/PKB activity is involved in K-Ras-induced expression of COX-2 and stabilization of COX-2 mRNA largely depends on the activation of Akt/PKB.
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PMID:K-Ras-mediated increase in cyclooxygenase 2 mRNA stability involves activation of the protein kinase B1. 1128 46

Tyrosine 1062 of Ret, which represents an intracytoplasmic docking site for multiple signaling molecules, is essential for Ret-mediated activation of phosphatidylinositol 3-Kinase (PI3-K). PI3-K, in turn, has been implicated in inducing cell survival and neoplastic transformation mediated by Ret. We have examined the mechanisms by which Ret stimulates PI3-K. Here we show that the Insulin Receptor Substrate-1 (IRS-1) is tyrosine phosphorylated and associated with the p85 regulatory subunit of PI3-K in response to Ret activation. IRS-1 coimmunoprecipitates with Ret and co-expression of IRS-1 results in the potentiation of Ret-mediated activation of Akt(PKB), a bona fide effector of PI3-K. The association with the PTB domain of IRS-1 depends on the phosphorylation of tyrosine 1062 of Ret. The deletion of asparagine 1059 (delN1059) and the substitution of leucine 1061 (L1061P), two Ret mutations identified in families affected by congenital megacolon (Hirschsprung's disease), impair the binding of IRS-1 to Ret as well as Ret-mediated Akt(PKB) stimulation. Finally, we show that Shc, which was previously identified as another ligand of Y1062 of Ret, competes with IRS-1 for the binding to Ret pY1062. All together, these findings suggest that IRS-1 is a component of the signaling pathway which leads to Ret-mediated PI3-K activation, a pathway which can be targeted by Hirschsprung-associated Ret mutations. The alternative binding of Shc and IRS-1 to Ret pY1062 can be a system to modulate the activation of different intracellular signaling pathways and to elicit different biological responses following Ret activation.
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PMID:The insulin receptor substrate (IRS)-1 recruits phosphatidylinositol 3-kinase to Ret: evidence for a competition between Shc and IRS-1 for the binding to Ret. 1131 48

We demonstrate that PI3 kinase and protein kinase B (PKB or Akt) control cell polarity and chemotaxis, in part, through the regulation of PAKa, which is required for myosin II assembly. We demonstrate that PI3K and PKB mediate PAKa's subcellular localization, PAKa's activation in response to chemoattractant stimulation, and chemoattractant-mediated myosin II assembly. Mutation of the PKB phosphorylation site in PAKa to Ala blocks PAKa's activation and inhibits PAKa redistribution in response to chemoattractant stimulation, whereas an Asp substitution leads to an activated protein. Addition of the PI3K inhibitor LY294002 results in a rapid loss of cell polarity and the axial distribution of actin, myosin, and PAKa. These results provide a mechanism by which PI3K regulates chemotaxis.
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PMID:Control of cell polarity and chemotaxis by Akt/PKB and PI3 kinase through the regulation of PAKa. 1138 41

Stimulation of Gq-coupled acetylcholine muscarinic receptors leads to proliferation of astroglial cells, but the signal transduction pathway(s) that mediate this mitogenic response have not been fully elucidated. In this study, we report on the ability of carbachol to stimulate the phosphorylation of Akt/PKB, an important target of phosphatidylinositol 3 kinase (PI3 kinase) in 1321N1 human astrocytoma cells. Carbachol induced a dose-dependent phosphorylation of Ser473 on Akt, peaking after 15 min. This effect was mediated by activation of the M3 subtype of muscarinic receptors and was inhibited by two PI3 kinase inhibitors. Inhibitors of protein kinase C, mitogen-activated protein kinase and p70S6 kinase, had no effect on carbachol-induced Akt phosphorylation. Carbachol-induced DNA synthesis was strongly inhibited by two PI3 kinase inhibitors, wortmannin and LY294002, suggesting that PI3 kinase activation plays an important role in carbachol-induced proliferation 1321N1 astrocytoma cells.
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PMID:Activation of phosphatidylinositol 3 kinase by muscarinic receptors in astrocytoma cells. 1140 31

The intracellular protozoan parasites Theileria parva and Theileria annulata transform leucocytes by interfering with host cell signal transduction pathways. They differ from tumour cells, however, in that the transformation process can be entirely reversed by elimination of the parasite from the host cell cytoplasm using a specific parasiticidal drug. We investigated the state of activation of Akt/PKB, a downstream target of PI3-K-generated phosphoinositides, in Theileria-transformed leucocytes. Akt/PKB is constitutively activated in a PI3-K- and parasite-dependent manner, as judged by the specific phosphorylation of key residues, in vitro kinase assays and its cellular distribution. In previous work, we demonstrated that the parasite induces constitutive activation of the transcription factor NF-kappaB, providing protection against spontaneous apoptosis that accompanies transformation. In a number of other systems, a link has been established between the PI3-K-Akt/PKB pathway and NF-kappaB activation, resulting in protection against apoptosis. In Theileria-transformed leucocytes, activation of the NF-kappaB and the PI3-K-Akt/PKB pathways are not directly linked. The PI3-K-Akt/PKB pathway does not contribute to the persistent induction of IkappaBalpha phosphorylation, NF-kappaB DNA-binding or transcriptional activity. We show that the two pathways are downregulated with different kinetics when the parasite is eliminated from the host cell cytoplasm and that NF-kappaB-dependent protection against apoptosis is not dependent on a functional PI3-K-Akt/PKB pathway. We also demonstrate that Akt/PKB contributes, at least in part, to the proliferation of Theileria-transformed T cells.
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PMID:The Akt/PKB pathway is constitutively activated in Theileria-transformed leucocytes, but does not directly control constitutive NF-kappaB activation. 1148 15

The BCR-ABL oncoprotein transmits transformation signals mainly through pathways involving Ras, Myc and PI3 kinase. Here we report that inhibition of protein kinase C (PKC) delta had negative influence on anchorage-independent growth of Rat1 cells transformed by BCR-ABL. The effect was observed with delta isoform-specific inhibitor rottlerin, but not with Go6976 that inhibits only conventional isoforms. The kinase activity of delta isoform was found to be roughly two-fold higher in BCR-ABL-expressing Rat1 cells than that in mock. Although overexpression of wild type PKC delta did not enhance soft agar colony number by BCR-ABL-transformed Rat1 cells, that of dominant-negative delta isoform reduced it by approximately 40%.
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PMID:Inhibition of protein kinase C delta has negative effect on anchorage-independent growth of BCR-ABL-transformed Rat1 cells. 1148 76

Recent advances in defining neurotrophin signaling mediators have provided insights into the signal transduction mechanisms that underlie axon growth. Evidence is accumulating that major Trk effectors regulate the morphological development of embryonic peripheral neurons. Less is known about signaling related to the robust axon extension that follows peripheral axotomy of adult neurons. Regenerative axon growth can be mimicked in vitro by a "conditioning" lesion performed 2 weeks before culture (Smith and Skene, 1997). Previous work has implicated both neurotrophins and cytokines in this response. Because signal transduction mediators of both of these families of growth factors are well characterized, we have compared the role of neurotrophin and cytokine signaling in developmental versus regenerative sensory axon growth. Chemical inhibitors were administrated to embryonic and axotomized sensory neurons in vitro to block the activation of Erk kinase (MEK)-extracellular signal-regulated kinase (ERK), phosphatidylinositol-3 kinase (PI3-K), and janus kinase (JAK) signaling. As expected, both MEK and PI3-K inhibition blocked axon growth from both naive and NGF-stimulated embryonic day 13 sensory neurons, whereas inhibition of JAK phosphorylation had no effect. In contrast, neither MEK nor PI3-K inhibitors blocked elongation of adult sensory neurons after a conditioning lesion. However, the addition of a JAK2 inhibitor prevented the regenerative axon response. Consistent with these pharmacological results, the percentage of neurons showing intense nuclear signal transducers and activators of transcription 3 phosphorylation after a conditioning lesion was markedly increased compared with controls. These observations demonstrate that the signaling mediators that underlie regenerative axon growth are distinct from those used during development and suggest that cytokine signaling may be critical to peripheral nervous system regeneration.
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PMID:Different signaling pathways mediate regenerative versus developmental sensory axon growth. 1151 95


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