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)

p21ras is activated by the T cell antigen receptor (TCR) and then co-ordinates important signaling pathways for T lymphocyte activation. Effector pathways for this guanine nucleotide binding protein in T cells are mediated by the serine/threonine kinase Raf-1 and the Ras-related GTPase Rac-1. In fibroblasts, an important effector for the Ras oncogene is Phosphatidylinositol 3-kinase (PtdIns 3-kinase). Activation of this lipid kinase is able to induce critical Rac-1 signaling pathways and can couple p21ras to cell survival mechanisms via the serine/threonine kinase Akt/PKB. The role of PtdIns 3-kinase in Ras signaling in T cells has not been explored. In the present study, we examined the ability of PtdIns 3-kinase to initiate the Rac-1 signaling pathways important for T cell activation. We also examined the possibility that Akt/PKB is regulated by Ras signaling pathways in T lymphocytes. The results show that Ras can initiate a Rac-1 mediated pathway that regulates the transcriptional function of AP-1 complexes. PtdIns 3-kinase signals cannot mimic p21ras and induce the Rac mediated responses of AP-1 transcriptional activation. Moreover, neither TCR or Ras activation of AP-1 is dependent on PtdIns 3-kinase. PKB is activated in response to triggering of the T cell antigen receptor; PtdIns 3-kinase activity is both required and sufficient for this TCR response. In contrast, p21ras signals are unable to induce Akt/PKB activity in T cell nor is Ras function required for Akt/PKB activation in response to the TCR. The present data thus highlight that PtdIns 3-kinase and Akt/PKB are not universal Ras effector molecules. Ras can initiate Rac-1 regulated signaling pathways in the context of T cell antigen receptor function independently of PtdIns 3-kinase activity.
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PMID:p21ras initiates Rac-1 but not phosphatidyl inositol 3 kinase/PKB, mediated signaling pathways in T lymphocytes. 979 2

Glioblastomas are highly malignant tumors of the central nervous system that are resistant to radiation and chemotherapy [1]. We explored the role of the phosphatidylinositol (PI) 3-kinase signal transduction pathway in glioblastomas, as this pathway has been shown to inhibit apoptosis induced by cytokine withdrawal and the detachment of cells from the extracellular matrix [2]. Components of this pathway have been implicated in tumor development [3-6]. We show that glioblastoma cells, in contrast to primary human astrocytes, contain high endogenous protein kinase B (PKB/Akt) activity and high levels of PI 3,4,5-triphosphate (PI(3,4,5)P3) and PI(3,4)P2, the lipid products of PI 3-kinase. These glioblastoma cells express mutant forms of the putative 3' phospholipid phosphatase PTEN, also known as MMAC. Expression of wild-type PTEN derived from primary astrocytes, but not of mutant forms of PTEN, reduced the levels of 3' phosphoinositides and inhibited PKB/Akt activity. PTEN antagonized the activation of PKB/Akt by growth factors, by activated PI 3-kinase and by PI-dependent protein kinase-1 (PDK1), but did not antagonize the phospholipid-independent activation of PKB/Akt lacking the pleckstrin homology (PH) domain. These results suggest a role for PTEN in regulating the activity of the PI 3-kinase pathway in malignant human cells.
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PMID:Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. 979 39

Prior investigations document that proliferative signaling cascades, under some circumstances, initiate apoptosis, although mechanisms that dictate the final outcome are largely unknown. In COS-7 cells, ceramide signals Raf-1 activation through Ras (Zhang, Y., Yao, B., Delikat, S., Bayoumy, S., Lin, X. H., Basu, S., McGinley, M., Chan-Hui, P. Y., Lichenstein, H., and Kolesnick, R. (1997) Cell 89, 63-72), but not apoptosis. However, expression of small amounts of the pro-apoptotic Bcl-2 family member, BAD, conferred ceramide-induced apoptosis onto COS-7 cells. Ceramide signaled apoptosis in BAD-expressing cells by a pathway involving sequentially kinase suppressor of Ras (KSR)/ceramide-activated protein kinase, Ras, c-Raf-1, and MEK1. Downstream, this pathway linked to BAD dephosphorylation at serine 136 by prolonged inactivation of Akt/PKB. Further, mutation of BAD at serine 136 abrogated ceramide signaling of apoptosis. The present study indicates that when ceramide signals through the Ras/Raf cascade, the availability of a single target, BAD, may dictate an apoptotic outcome.
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PMID:BAD enables ceramide to signal apoptosis via Ras and Raf-1. 980 8

The survival of cells in multicellular organisms requires continuous stimulation from the extracellular environment. The phosphatidylinositol-3' kinase/Akt signaling cascade has been identified as a critical pathway for the transduction of extracellular survival signals. The finding that the pro-apoptotic protein BAD is a substrate of Akt/PKB has provided the first link between extracellular survival signals and the apoptotic machinery.
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PMID:Linking extracellular survival signals and the apoptotic machinery. 981 24

Angiogenesis, the formation of new blood vessels from pre-existing ones, occurs during development, wound healing and cancer and involves stages that orchestrate a network of cooperative interactions. Peptide growth factors and extracellular matrix (ECM) components are two major groups of angiogenesis mediators. Among the different ECM proteins, collagens have been well-associated with in vivo angiogenesis. Using human umbilical vein endothelial cells (HUVEC) grown in 3-D collagen gels we show that: (1) HUVEC do not survive well in 3-D collagen gels due to rapid induction of apoptosis. (2) VEGF, a potent in vivo angiogenic factor, fails to induce tube formation. (3) PMA was effective in inducing tube formation and survival in HUVEC dispersed in 3-D collagen gels, activating MAP kinase, phosphoinositide 3-OH kinase (PI-3-kinase) and Akt/PKB (protein kinase B) pathways. (4) VEGF was effective in preventing PMA-induced tube-like structure regression after PMA-withdrawal by (5) activating the mitogen activated protein kinase (MAPK), rather than the Akt/PKB, signaling pathway.
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PMID:Distinct signal transduction pathways are utilized during the tube formation and survival phases of in vitro angiogenesis. 981 53

To examine which lipid product of phosphatidylinositol 3-kinase (PI3-K) is essential for the survival-promoting pathway in cultured cerebellar granule neurons, three synthetic derivatives of lipid products of PI3-K were added to culture medium containing a low concentration (5 mM) of potassium (LK+) which induces apoptotic cell death. We found that dipalmitoylphosphatidylinositol 3,4-bisphosphate and dipalmitoylphosphatidylinositol 3,4,5-trisphosphate, but not dipalmitoylphosphatidylinositol 3-monophosphate, effectively blocked the LK+-induced apoptosis. These two synthetic phospholipids increased Akt activity but not that of PI3-K. These findings demonstrated that specific lipid products of PI3-K which are added to culture medium activate Akt/PKB without modulating PI3-K itself, and as a result prevent neuronal cell death in cerebellar granule neurons.
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PMID:Synthetic lipid products of PI3-kinase which are added to culture medium prevent low K+-induced apoptosis of cerebellar granule neurons via Akt kinase activation. 982 94

The nuclear factor CREB stimulates the expression of cellular genes following its protein kinase A-mediated phosphorylation at Ser-133. Ser-133 phosphorylation, in turn, activates target gene expression by promoting recruitment of the co-activator CBP. Recent studies showing that CREB and its paralog CREM are required for survival of certain cell types prompted us to examine whether CREB is a nuclear target for activation via the growth factor-dependent Ser/Thr kinase Akt/PKB. When overexpressed in serum-stimulated cells, Akt/PKB potently induced Ser-133 phosphorylation of CREB and promoted recruitment of CBP. Correspondingly, Akt/PKB stimulated target gene expression via CREB in a phospho(Ser-133)-dependent manner. Akt/PKB induced CREB activity only in response to serum stimulation, and this effect was suppressed by the phosphatidylinositol 3-kinase inhibitor LY 294002. Our results support the notion that Akt/PKB promotes cell survival, at least in part, by stimulating the expression of cellular genes via the CREB/CBP nuclear transduction pathway.
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PMID:CREB is a regulatory target for the protein kinase Akt/PKB. 982 64

This review focuses on the recent advances made in our understanding of the mechanism by which insulin induces the activation of PI 3-kinase(s) whose role is to generate 3-phosphoinositide lipids which are the second messenger of the insulin signalling pathway. The mechanism by which these signalling molecules induce the activation of downstream signalling pathways leading to the activation of protein kinase B (PKB, also known as Akt) and other kinases is also discussed. PKB is likely to be a major mediator of many of the physiological responses of a cell to insulin and likely physiological cellular targets of this enzyme are highlighted.
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PMID:The role of PI 3-kinase in insulin action. 983 87

The serine-threonine kinase Akt/PKB is activated downstream of phosphatidylinositol 3-kinase in response to several growth factor stimuli and has been implicated in the promotion of cell survival. Although both phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 3,4-bisphosphate (PI 3,4-P2) have been implicated in the regulation of Akt activity in vitro, the relative roles of these two phospholipids in vivo are not well understood. Co-ligation of the B cell receptor (BCR) and the inhibitory FcgammaRIIB1 on B cells results in the recruitment of the 5'-inositol phosphatase SHIP to the signaling complex. Since SHIP is known to cleave PIP3 to generate PI 3,4-P2 both in vivo and in vitro, and Akt activity has been reported to be regulated by either PIP3 or PI 3,4-P2, we hypothesized that recruitment of SHIP through FcgammaRIIB1 co-cross-linking to the BCR in B cells might regulate Akt activity. The nature of this regulation, positive or negative, might also reveal the relative contribution of PIP3 and PI 3,4-P2 to Akt activation in vivo. Here we report that Akt is activated by stimulation through the BCR in a phosphatidylinositol 3-kinase-dependent manner and that this activation is inhibited by co-cross-linking of the BCR to FcgammaRIIB1. Using mutants of FcgammaRIIB1 and SHIP-deficient B cells, we demonstrate that inhibition of Akt activity is mediated by the immune cell tyrosine-based inhibitory motif within FcgammaRIIB1 as well as SHIP. The SHIP-dependent inhibition of Akt activation also suggests that PIP3 plays a greater role in Akt activation than PI 3,4-P2 in vivo.
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PMID:The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells. 985 43

The protection against apoptosis provided by growth factors in several cell lines is due to stimulation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway, which results in activation of protein kinase B (PKB; also known as c-Akt and Rac) and phosphorylation and sequestration to protein 14-3-3 of the proapoptotic Bcl-2-family member BAD. A modest increase in intracellular Ca2+ concentration also promotes survival of some cultured neurons through a pathway that requires calmodulin but is independent of PI(3)K and the MAP kinases. Here we report that Ca2+/calmodulin-dependent protein kinase kinase (CaM-KK) activates PKB directly, resulting in phosphorylation of BAD on serine residue 136 and the interaction of BAD with protein 14-3-3. Serum withdrawal induced a three- to fourfold increase in cell death of NG108 neuroblastoma cells, and this apoptosis was largely blocked by increasing the intracellular Ca2+ concentration with NMDA (N-methyl-D-aspartate) or KCl or by transfection with constitutively active CaM-KK. The effect of NMDA on cell survival was blocked by transfection with dominant-negative forms of CaM-KK or PKB. These results identify a Ca2+-triggered signalling cascade in which CaM-KK activates PKB, which in turn phosphorylates BAD and protects cells from apoptosis.
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PMID:Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway. 985 94


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