title: Akt kinase C-terminal modifications control activation loop dephosphorylation and enhance insulin response.
abstract: The Akt protein kinase, also known as protein kinase B, plays key roles in insulin receptor signalling and regulates cell growth, survival and metabolism. Recently, we described a mechanism to enhance Akt phosphorylation that restricts access of cellular phosphatases to the Akt activation loop (Thr(308) in Akt1 or protein kinase B isoform alpha) in an ATP-dependent manner. In the present paper, we describe a distinct mechanism to control Thr(308) dephosphorylation and thus Akt deactivation that depends on intramolecular interactions of Akt C-terminal sequences with its kinase domain. Modifications of amino acids surrounding the Akt1 C-terminal mTORC2 (mammalian target of rapamycin complex 2) phosphorylation site (Ser(473)) increased phosphatase resistance of the phosphorylated activation loop (pThr(308)) and amplified Akt phosphorylation. Furthermore, the phosphatase-resistant Akt was refractory to ceramide-dependent dephosphorylation and amplified insulin-dependent Thr(308) phosphorylation in a regulated fashion. Collectively, these results suggest that the Akt C-terminal hydrophobic groove is a target for the development of agents that enhance Akt phosphorylation by insulin.
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A. Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A. tung.chan@jefferson.edu.
authors.forename: Tung O
authors.initials: TO
authors.lastname: Chan
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Tiegs
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Brian
authors.initials: B
authors.lastname: Blumhof
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Linda
authors.initials: L
authors.lastname: Yan
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Keny
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Morgan
authors.initials: M
authors.lastname: Penny
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A. Department of Molecular Biology and Biochemistry, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: John M
authors.initials: JM
authors.lastname: Pascal
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Armen
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A. Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A. Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rodeck
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A. Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A. Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, PA 19107, U.S.A.
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Penn
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D046912:Multiprotein Complexes; C494920:Akt1 protein, rat; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: ceramide; dephosphorylation resistance; insulin sensitivity; protein kinase A; protein kinase B/Akt