Akt kinase C-terminal modifications control activation loop dephosphorylation and enhance insulin response

作者：Chan Tung O^*; Zhang Jin; Tiegs Brian C; Blumhof Brian; Yan Linda; Keny Nikhil; Penny Morgan; Li Xue; Pascal John M; Armen Roger S; Rodeck Ulrich; Penn Raymond B

来源：Biochemical Journal, 2015, 471(1): 37-51.

DOI：10.1042/BJ20150325

• ceramide
• dephosphorylation resistance
• insulin sensitivity
• protein kinase A
• protein kinase B/Akt

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.

• 出版日期2015-10-1