TITLE

Turn motif phosphorylation negatively regulates activation loop phosphorylation in Akt

AUTHOR(S)
Hiraoka, D; Okumura, E; Kishimoto, T
PUB. DATE
November 2011
SOURCE
Oncogene;11/3/2011, Vol. 30 Issue 44, p4487
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Akt, also known as protein kinase B, has a central role in various signaling pathways that regulate cellular processes such as metabolism, proliferation and survival. On stimulation, phosphorylation of the activation loop (A-loop) and hydrophobic motif (HM) of Akt by the kinase phosphoinositide-dependent kinase 1 (PDK1) and the mammalian target of rapamycin complex 2 (mTORC2), respectively, results in Akt activation. A well-conserved threonine in the turn motif (TM) is also constitutively phosphorylated by mTORC2 and contributes to the stability of Akt. The role of TM phosphorylation in HM and A-loop phosphorylation has not been sufficiently evaluated. Using starfish oocytes as a model system, this study provides the first evidence that TM phosphorylation has a negative role in A-loop phosphorylation. In this system, the maturation-inducing hormone, 1-methyladenine, stimulates Akt to reinitiate meiosis through activation of cyclin B-Cdc2. The phosphorylation status of Akt was monitored via introduction of exogenous human Akt (hAkt) in starfish oocytes. TM and HM phosphorylation was inhibited by microinjection of an anti-starfish TOR antibody, but not by rapamycin treatment, suggesting that both phosphorylation events depend on TORC2, as reported in mammalian cells. A single or double alanine substitution at each of three phosphorylation residues revealed that TM phosphorylation renders Akt susceptible to dephosphorylation on the A-loop. When A-loop phosphatase was inhibited by okadaic acid (OA), TM phosphorylation still reduced A-loop phosphorylation, suggesting that the effect is caused at least partially through reduction of sensitivity to PDK1. Negative regulation by TM phosphorylation was also observed in constitutively active Akt and was functionally reflected in meiosis resumption. By contrast, HM phosphorylation enhanced A-loop phosphorylation and achieved full activation of Akt via a mechanism at least partially independent of TM phosphorylation. These observations provide new insight into the mechanism controlling Akt phosphorylation in the cell.
ACCESSION #
66954163

 

Related Articles

  • Assessing adaptation of the cancer kinome in response to targeted therapies. Zawistowski, Jon S.; Graves, Lee M.; Johnson, Gary L. // Biochemical Society Transactions;Aug2014, Vol. 42 Issue 4, p765 

    Cancer cells are dependent on protein kinase signalling networks to drive proliferation and to promote survival, and, accordingly, kinases continue to represent a major target class for development of anticancer therapeutics. Kinase inhibitors nevertheless have yielded only limited success with...

  • A brief introduction to FOXOlogy. Burgering, B. M. Th. // Oncogene;4/7/2008, Vol. 27 Issue 16, p2258 

    Members of the Forkhead box O (FOXO) class of transcription factors are key players in the regulation of cell-fate decisions, such as cell death, cell proliferation and cell metabolism. Furthermore, in model organisms, it has by now been demonstrated that FOXO function affects the life span of...

  • Conformational Changes in Protein Loops and Helices Induced by Post-Translational Phosphorylation. Groban, Eli S.; Narayanan, Arjun; Jacobson, Matthew P. // PLoS Computational Biology;Apr2006, Vol. 2 Issue 4, pe32 

    Post-translational phosphorylation is a ubiquitous mechanism for modulating protein activity and protein-protein interactions. In this work, we examine how phosphorylation can modulate the conformation of a protein by changing the energy landscape. We present a molecular mechanics method in...

  • Skp2: caught in the Akt. Ecker, Karin; Hengst, Ludger // Nature Cell Biology;Apr2009, Vol. 11 Issue 4, p377 

    To control cell proliferation, signal transduction needs to regulate the cell-cycle machinery. Recent findings show that Akt — a major kinase that coordinates diverse signalling pathways — phosphorylates Skp2, a subunit of the SCF-Skp2 ubiquitin ligase that targets key cell-cycle...

  • Activation of Arabidopsis MAPK kinase kinase (AtMEKK1) and induction of AtMEKK1–AtMEK1 pathway by wounding. Hadiarto, Toto; Nanmori, Takashi; Matsuoka, Daisuke; Iwasaki, Tetsushi; Sato, Ken-ichi; Fukami, Yasuo; Azuma, Tetsushi; Yasuda, Takeshi // Planta;Apr2006, Vol. 223 Issue 4, p708 

    We have constructed a series of deletion mutants of Arabidopsis MAPK kinase kinase (AtMEKK1) and obtained a constitutively active mutant, AtMEKK1Δ166, which lacks in self-inhibitory sequence of N-terminal 166 amino acids but still has substrate specificity. AtMEKK1Δ166 predominantly...

  • Computational Modelling of the Metabolic States Regulated by the Kinase Akt. Mosca, Ettore; Alfieri, Roberta; Maj, Carlo; Bevilacqua, Annamaria; Canti, Gianfranco; Milanesi, Luciano // Frontiers in Physiology;Oct2012, Vol. 3, p1 

    Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular...

  • MAPK Signaling Pathway Regulates p27 Phosphorylation at Threonin 187 as Part of the Mechanism Triggered by Early-Weaning to Induce Cell Proliferation in Rat Gastric Mucosa. Osaki, Luciana H.; Gama, Patricia // PLoS ONE;Jun2013, Vol. 8 Issue 6, p1 

    During rat postnatal development, gastric cell proliferation and differentiation depend on many elements, which include dietary pattern, hormones, growth factors and their signaling pathways. Among them, EGFR activity is increased through MAPK and Src cascades in response to early weaning that...

  • Computational modeling of the metabolic states regulated by the kinase Akt. Mosca, Ettore; Alfieri, Roberta; Maj, Carlo; Bevilacqua, Annamaria; Canti, Gianfranco; Milanesi, Luciano // Frontiers in Physiology;Nov2012, Vol. 3, p1 

    Signal transduction and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two...

  • Mammalian MAP kinase signalling cascades. Lufen Chang; Karin, Michael // Nature;3/1/2001, Vol. 410 Issue 6824, p37 

    Discusses mitogen-activated protein kinases (MAPK) as important signal transducing enzymes, unique to eukaryotes, that are involved in many facets of cellular regulation. Mammalian MAPK; Specificity in MAPK activation and general function of MAPK cascades; In vivo analysis; Physiological...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics