Protein Kinase B

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Brian A. Hemmings - One of the best experts on this subject based on the ideXlab platform.

  • <B>ProteinB> <B>KinaseB> B/Akt at a glance
    Journal of Cell Science, 2005
    Co-Authors: Elisabeth Fayard, Lionel A. Tintignac, Anne Baudry, Brian A. Hemmings
    Abstract:

    Among the signalling <B>ProteinB>s that respond to a large variety of signals, <B>ProteinB> <B>KinaseB> B (PKB, also known as Akt) appears to Be a central player in regulation of metaBolism, cell survival, motility, transcription and cell-cycle progression. Conserved from primitive metazoans to humans, PKB Belongs

  • Advances in <B>ProteinB> <B>KinaseB> B signalling: AKTion on multiple fronts
    Trends in biochemical sciences, 2004
    Co-Authors: Derek P. Brazil, Zhong-zhou Yang, Brian A. Hemmings
    Abstract:

    The role of the serine/threonine <B>ProteinB> <B>KinaseB> B (PKB, also known as Akt) is Becoming increasingly more evident to researchers investigating diverse cellular processes such as glucose uptake, cell-cycle progression, apoptosis and transcriptional regulation. New roles for PKB/Akt have Been descriBed in various organisms and Biological processes. From the regulation of ovarian ecdysteroid production in the humBle mosquito (Aedes aegypti), through the seasonal, tissue-specific regulation of PKB/Akt during the hiBernation of yellow-Bellied marmots (Marmota flaviventris), to the control of glucose metaBolism and insulin signalling in the mouse (Mus musculus), our knowledge of the function of this <B>ProteinB> <B>KinaseB> has expanded greatly in recent years. Significant advances in all aspects of PKB/Akt signalling have occurred in the past 2 years, including Biological insights, novel suBstrates and newly discovered regulatory mechanisms of PKB/Akt. Collectively, these data expand the current models of PKB/Akt signalling and highlight potential directions for PKB/Akt research in the future.

  • inhiBition of <B>ProteinB> <B>KinaseB> B akt implications for cancer therapy
    Pharmacology & Therapeutics, 2002
    Co-Authors: Michelle M. Hill, Brian A. Hemmings
    Abstract:

    <B>ProteinB> <B>KinaseB> B (PKB, also called Akt) is an important regulator of cell proliferation and survival. Amplification of genes encoding PKB isoforms has Been found in several types of human cancers. In addition, mutations in the phosphatase and tensin homolog deleted on chromosome ten (PTEN), one of the most frequently mutated tumor suppressor genes, results in elevated PKB activity. PKB has a wide range of cellular targets, and the oncogenicity of PKB arises from activation of Both proliferative and anti-apoptotic signaling. Furthermore, PKB contriButes to tumor progression By promoting cell invasiveness and angiogenesis. These oBservations estaBlish PKB as an attractive target for cancer therapy. A cellular inhiBitor of PKB, termed carBoxyl-terminal modulator <B>ProteinB>, reverts the phenotype of viral akt-transformed cells, suggesting that a specific PKB inhiBitor will Be useful in the treatment of tumors with elevated PKB activity. Since inhiBition of PKB activity induces apoptosis in a range of mammalian cells, a PKB inhiBitor may Be effective, in comBination with other anticancer drugs, for the treatment of tumors with other mutations.

  • Analysis of <B>ProteinB> <B>KinaseB> B/Akt.
    Methods in enzymology, 2002
    Co-Authors: Michelle M. Hill, Brian A. Hemmings
    Abstract:

    <B>ProteinB> <B>KinaseB> B (PKB or Akt) was initially identified as a serine/threonine <B>KinaseB> with homology to <B>ProteinB> <B>KinaseB>s A and C, and as an onco<B>ProteinB>. Three isoforms of PKB have suBsequently Been identified: PKBα, PKBβ, and PKBγ, which are 80% identical in amino acid sequence, and all contain an N-terminal pleckstrin homology (PH) domain and a C-terminal regulatory domain. Activation of PKB By growth factors is mediated By phosphatidylinositol 3,4,5-trisphosphate (P13,4,5Ps), generated By phosphoinositide 3-<B>KinaseB> (PI3K) at the inner surface of the plasma memBrane. PKB is recruited to the plasma memBrane through an interaction of its PH domain with PI3,4,5P 3 , resulting in a conformational change of PKB, allowing it to Be phosphorylated. Maximal activation of PKB requires the phosphorylation of two residues conserved in all PKB isoforms—namely, threonine at position 308 (Thr-308) in the activation loop and serine at position 473 (Ser-473) in the C-terminal regulatory domain. The <B>KinaseB> responsiBle for phosphorylating Thr-308 has Been cloned and named 3-phosphoinositide-dependent <B>KinaseB> 1 (PDK1), s while the authentic upstream <B>KinaseB> for Ser-473 is yet to Be identified.

  • Ten years of <B>ProteinB> <B>KinaseB> B signalling: a hard Akt to follow.
    Trends in biochemical sciences, 2001
    Co-Authors: Derek P. Brazil, Brian A. Hemmings
    Abstract:

    It is ten years since the puBlication of three papers descriBing the cloning of a new proto-oncogene serine/threonine <B>KinaseB> termed <B>ProteinB> <B>KinaseB> B (PKB)/Akt. Key roles for this <B>ProteinB> <B>KinaseB> in cellular processes such as glucose metaBolism, cell proliferation, apoptosis, transcription and cell migration are now well estaBlished. The explosion of puBlications involving PKB/Akt in the past three years emphasizes the high level of current interest in this signalling molecule. This review focuses on tracing the characterization of this <B>KinaseB>, through the elucidation of its mechanism of regulation, to its role in regulating physiological and pathophysiological processes, to our current understanding of the Biology of PKB/Akt, and prospects for the future.

Jeremy M Tavare - One of the best experts on this subject based on the ideXlab platform.

  • role of <B>ProteinB> <B>KinaseB> B in insulin regulated glucose uptake
    Biochemical Society Transactions, 2005
    Co-Authors: Gavin I Welsh, Ingeborg Hers, Daniel C. Berwick, Ghislaine Dell, Matthew Wherlock, R Birkin, Sophie E Leney, Jeremy M Tavare
    Abstract:

    The activation of <B>ProteinB> <B>KinaseB> B (or Akt) plays a central role in the stimulation of glucose uptake By insulin. Currently, however, numerous questions remain unanswered regarding the role of this <B>KinaseB> in Bringing aBout this effect. For example, we do not know precisely where in the GLUT4 trafficking pathway this <B>KinaseB> acts. Nor do we know which <B>ProteinB> suBstrates are responsiBle for mediating the effects of <B>ProteinB> <B>KinaseB> B, although two recently identified <B>ProteinB>s (AS160 and PIKfyve) may play a role. This paper addresses these important questions By reviewing recent progress in the field.

  • the identification of atp citrate lyase as a <B>ProteinB> <B>KinaseB> B akt suBstrate in primary adipocytes
    Journal of Biological Chemistry, 2002
    Co-Authors: Daniel C. Berwick, Ingeborg Hers, Kelly S Moule, Kate J Heesom, Jeremy M Tavare
    Abstract:

    <B>ProteinB> <B>KinaseB> B (Akt) plays a central role in cellular regulation, although many of the physiologically relevant suBstrates for the <B>KinaseB> remain to Be identified. In this study, we have isolated a <B>ProteinB> from primary epididymal adipocytes with an apparent molecular weight of 125,000. This <B>ProteinB> exhiBited immunoreactivity, in an insulin-dependent manner, with a phosphospecific antiBody raised against the <B>ProteinB> <B>KinaseB> B suBstrate consensus sequence RXRXX(pS/pT) as well as a phosphospecific antiBody that recognizes serine 21/9 of GSK-3alpha/Beta. MALDI-TOF mass spectrometry revealed the <B>ProteinB> to Be ATP-citrate lyase, suggesting that the two phosphospecific antiBodies recognize phosphoserine 454, a previously reported insulin- and isoproterenol-stimulated ATP-citrate lyase phosphorylation site. Indeed, Both insulin and isoproterenol stimulated the phosphorylation of this <B>ProteinB> on the site recognized By the phosphospecific antiBodies in a wortmannin-sensitive and -insensitive manner, respectively. In addition, transient expression of a constitutively active <B>ProteinB> <B>KinaseB> B in primary adipocytes mimicked the effect of insulin on ATP-citrate lyase phosphorylation. Furthermore, ATP-citrate lyase was phosphorylated in vitro By recomBinant <B>ProteinB> <B>KinaseB> B on the same site. Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo suBstrate for <B>ProteinB> <B>KinaseB> B.

  • Functional consequence of targeting <B>ProteinB> <B>KinaseB> B/Akt to GLUT4 vesicles.
    Journal of cell science, 2002
    Co-Authors: Pierre-henri Ducluzeau, Laura M Fletcher, Gavin I Welsh, Jeremy M Tavare
    Abstract:

    We have investigated the role of <B>ProteinB> <B>KinaseB> B (Akt) in the insulin-stimulated translocation of vesicles containing the insulin-responsive isoform of glucose transporter (GLUT4) to the plasma memBrane of adipocytes. Previous reports have suggested that <B>ProteinB> <B>KinaseB> B can Bind to intracellular GLUT4 vesicles in an insulin-dependent manner, But the functional consequence of this translocation is not known. In this study we have artificially targeted constitutively active and <B>KinaseB>-inactive mutants of <B>ProteinB> <B>KinaseB> B to intracellular GLUT4 vesicles By fusing them with the N-terminus of GLUT4 itself. We examined the effect of these mutants on the insulin-dependent translocation of the insulin-responsive amino peptidase IRAP (a Bona fide GLUT4-vesicle-resident <B>ProteinB>). A <B>KinaseB>-inactive <B>ProteinB> <B>KinaseB> B targeted to GLUT4 vesicles was an extremely effective dominant-negative inhiBitor of insulin-stimulated IRAP translocation to the plasma memBrane. By contrast, a <B>KinaseB>-inactive <B>ProteinB> <B>KinaseB> B expressed in the cytoplasm did not have an effect. The results suggest that <B>ProteinB> <B>KinaseB> B has an important functional role at, or in the vicinity of, GLUT4 vesicles in the insulin-dependent translocation of those vesicles to the plasma memBrane of adipocytes.

  • The Identification of ATP-citrate Lyase as a <B>ProteinB> <B>KinaseB> B (Akt) SuBstrate in Primary Adipocytes
    Journal of Biological Chemistry, 2002
    Co-Authors: Daniel C. Berwick, Ingeborg Hers, S. Kelly Moule, Kate J Heesom, Jeremy M Tavare
    Abstract:

    <B>ProteinB> <B>KinaseB> B (Akt) plays a central role in cellular regulation, although many of the physiologically relevant suBstrates for the <B>KinaseB> remain to Be identified. In this study, we have isolated a <B>ProteinB> from primary epididymal adipocytes with an apparent molecular weight of 125,000. This <B>ProteinB> exhiBited immunoreactivity, in an insulin-dependent manner, with a phosphospecific antiBody raised against the <B>ProteinB> <B>KinaseB> B suBstrate consensus sequence RXRXX(pS/pT) as well as a phosphospecific antiBody that recognizes serine 21/9 of GSK-3α/β. MALDI-TOF mass spectrometry revealed the <B>ProteinB> to Be ATP-citrate lyase, suggesting that the two phosphospecific antiBodies recognize phosphoserine 454, a previously reported insulin- and isoproterenol-stimulated ATP-citrate lyase phosphorylation site. Indeed, Both insulin and isoproterenol stimulated the phosphorylation of this <B>ProteinB> on the site recognized By the phosphospecific antiBodies in a wortmannin-sensitive and -insensitive manner, respectively. In addition, transient expression of a constitutively active <B>ProteinB> <B>KinaseB> B in primary adipocytes mimicked the effect of insulin on ATP-citrate lyase phosphorylation. Furthermore, ATP-citrate lyase was phosphorylated in vitro By recomBinant <B>ProteinB> <B>KinaseB> B on the same site. Taken together, these results demonstrate that serine 454 of ATP-citrate lyase is a novel and major in vivo suBstrate for <B>ProteinB> <B>KinaseB> B.

Eric R Blough - One of the best experts on this subject based on the ideXlab platform.

  • akt <B>ProteinB> <B>KinaseB> B in skeletal muscle physiology and pathology
    Journal of Cellular Physiology, 2011
    Co-Authors: Miaozong Wu, Marco Falasca, Eric R Blough
    Abstract:

    The Akt/<B>ProteinB> <B>KinaseB> B is critical regulator of cellular homeostasis with diminished Akt activity Being associated with dysregulation of cellular metaBolism and cell death while Akt over-activation has Been linked to inappropriate cell growth and proliferation. Although the regulation of Akt function has Been well characterized in vitro, much less is known regarding the function of Akt in vivo. Here we examine how skeletal muscle Akt expression and enzymatic activity are controlled, the role of Akt in the regulation of skeletal muscle contraction, stress response glucose utilization, and <B>ProteinB> metaBolism, and the potential participation of this important molecule in skeletal muscle atrophy, aging, and cancer. J. Cell. Physiol. 226: 29–36, 2010. © 2010 Wiley-Liss, Inc.

  • Akt/<B>ProteinB> <B>KinaseB> B in skeletal muscle physiology and pathology.
    Journal of cellular physiology, 2010
    Co-Authors: Marco Falasca, Eric R Blough
    Abstract:

    The Akt/<B>ProteinB> <B>KinaseB> B is critical regulator of cellular homeostasis with diminished Akt activity Being associated with dysregulation of cellular metaBolism and cell death while Akt over-activation has Been linked to inappropriate cell growth and proliferation. Although the regulation of Akt function has Been well characterized in vitro, much less is known regarding the function of Akt in vivo. Here we examine how skeletal muscle Akt expression and enzymatic activity are controlled, the role of Akt in the regulation of skeletal muscle contraction, stress response glucose utilization, and <B>ProteinB> metaBolism, and the potential participation of this important molecule in skeletal muscle atrophy, aging, and cancer. J. Cell. Physiol. 226: 29–36, 2010. © 2010 Wiley-Liss, Inc.

Harinder S. Hundal - One of the best experts on this subject based on the ideXlab platform.

  • <B>ProteinB> <B>KinaseB> B (PKB/Akt) – a key regulator of glucose transport?
    FEBS letters, 2001
    Co-Authors: Eric Hajduch, Gary J. Litherland, Harinder S. Hundal
    Abstract:

    The serine/threonine <B>KinaseB> <B>ProteinB> <B>KinaseB> B (PKB/Akt) has Been shown to play a crucial role in the control of diverse and important cellular functions such as cell survival and glycogen metaBolism. There is also convincing evidence that PKB plays a role in the insulin-mediated regulation of glucose transport. Furthermore, states of cellular insulin resistance have Been shown to involve impaired PKB activation, and this usually coincides with a loss of glucose transport activation. However, evidence to the contrary is also availaBle, and the role of PKB in the control of glucose transport remains controversial. Here we provide an overview of recent findings, discuss the potential importance of PKB in the regulation of glucose transport and metaBolism, and comment on future directions.

  • Ceramide impairs the insulin-dependent memBrane recruitment of <B>ProteinB> <B>KinaseB> B leading to a loss in downstream signalling in L6 skeletal muscle cells.
    Diabetologia, 2001
    Co-Authors: Eric Hajduch, A. Balendran, Ian H. Batty, Gary J. Litherland, Anne S. Blair, C. P. Downes, Harinder S. Hundal
    Abstract:

    Aims/hypothesis. Increased cellular production of ceramide has Been implicated in the pathogenesis of insulin resistance and in the impaired utilisation of glucose. In this study we have used L6 muscle cells to investigate the mechanism By which the short-chain ceramide analogue, C2-ceramide, promotes a loss in insulin sensitivity leading to a reduction in insulin stimulated glucose transport and glycogen synthesis. Method. L6 muscle cells were pre-incuBated with C2-ceramide and the effects of insulin on glucose transport, glycogen synthesis and the activities of key molecules involved in proximal insulin signalling determined. Results. IncuBation of L6 muscle cells with ceramide (100 μmol/l) for 2 h led to a complete loss of insulin-stimulated glucose transport and glycogen synthesis. This inhiBition was not due to impaired insulin receptor suBstrate 1 phosphorylation or a loss in phosphoinositide 3-<B>KinaseB> activation But was caused By a failure to activate <B>ProteinB> <B>KinaseB> B. This defect could not Be attriButed to inhiBition of 3-phosphoinositide-dependent <B>KinaseB>-1, or to impaired Binding of phosphatidylinositol 3,4,5 triphosphate (PtdIns(3,4,5)P3) to the PH domain of <B>ProteinB> <B>KinaseB> B, But results from the inaBility to recruit <B>ProteinB> <B>KinaseB> B to the plasma memBrane. Expression of a memBrane-targetted <B>ProteinB> <B>KinaseB> B led to its constitutive activation and an increase in glucose transport that was not inhiBited By ceramide. Conclusions/interpretation. These findings suggest that a defect in <B>ProteinB> <B>KinaseB> B recruitment underpins the ceramide-induced loss in insulin sensitivity of key cell responses such as glucose transport and glycogen synthesis in L6 cells. They also suggest that a stimulated rise in PtdIns(3,4,5)P3 is necessary But not sufficient for <B>ProteinB> <B>KinaseB> B activation in this system. [DiaBetologia (2001) 44: 173–183]

James R. Woodgett - One of the best experts on this subject based on the ideXlab platform.

  • Recent advances in the <B>ProteinB> <B>KinaseB> B signaling pathway
    Current opinion in cell biology, 2005
    Co-Authors: James R. Woodgett
    Abstract:

    The phosphoinositide 3' <B>KinaseB> signaling pathway is activated in response to a plethora of growth factors and cytokines, and initiates a cascade of signaling events primarily via the induction of specific <B>ProteinB>-serine/threonine <B>KinaseB>s. Interest in the pathway has Been driven By its frequent aBerrant activation in disease and its impact on cell fate decisions owing to roles in survival signaling and metaBolic control. There have Been recent advances in our understanding of the primary components of this pathway, namely phosphoinositide-dependent <B>KinaseB>-1, <B>ProteinB> <B>KinaseB> B and glycogen synthase <B>KinaseB>-3, including insights into their mechanisms of regulation, suBstrate <B>ProteinB>s and cellular functions.

  • Unravelling the activation mechanisms of <B>ProteinB> <B>KinaseB> B/Akt
    FEBS letters, 2003
    Co-Authors: Michael P. Scheid, James R. Woodgett
    Abstract:

    Over the past decade, <B>ProteinB> <B>KinaseB> B (PKB, also termed Akt) has emerged as an important signaling mediator Between extracellular cues and modulation of gene expression, metaBolism, and cell survival. The enzyme is tightly controlled and consequences of its deregulation include loss of growth control and oncogenesis. Recent work has Better characterized the mechanism of PKB activation, including upstream regulators and secondary Binding partners. This minireview refreshes some old concepts with new twists and highlights current outstanding questions.

  • Minireview Unravelling the activation mechanisms of <B>ProteinB> <B>KinaseB> B/Akt
    2003
    Co-Authors: Michael P. Scheid, James R. Woodgett
    Abstract:

    Over the past decade, <B>ProteinB> <B>KinaseB> B (PKB, also termed Akt) has emerged as an important signaling mediator Between extracellular cues and modulation of gene expression, metaBolism, and cell survival. The enzyme is tightly controlled and consequences of its deregulation include loss of growth con- trol and oncogenesis. Recent work has Better characterized the mechanism of PKB activation, including upstream regulators and secondary Binding partners. This minireview refreshes some old concepts with new twists and highlights current out- standing questions. ! 2003 Federation of European Biochemical Societies. PuB- lished By Elsevier Science B.V. All rights reserved.

  • Regulation of Drosophila tracheal system development By <B>ProteinB> <B>KinaseB> B.
    Developmental cell, 2001
    Co-Authors: Jing Jin, James R. Woodgett, Norman Anthopoulos, Benjamin Wetsch, Richard Binari, Daniel D. Isaac, Deborah J. Andrew, Armen S. Manoukian
    Abstract:

    ABstract <B>ProteinB> <B>KinaseB> B (PKB, also termed Akt) is a phosphatidylinositol 3′ <B>KinaseB> (PI3′K)-dependent enzyme implicated in survival signaling and human tumorigenesis. To identify potential targets of this <B>ProteinB> <B>KinaseB>, we employed a genetic screen in Drosophila . Among several genes that genetically interacted with PKB was trachealess ( trh ), which encodes a BHLH-PAS domain transcription factor required for development of the trachea and other tuBular organs. Trh activates expression of the fiBroBlast growth factor receptor Breathless, which, in turn, is required for directed migration of all tracheal Branches. Using a comBination of Biochemical and transgenic approaches, we show that direct phosphorylation of Trh By PKB at serine 665 is essential for nuclear localization and functional activation of this regulator of Branching morphogenesis.

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