We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Akt kinase C-terminal modifications control activation loop dephosphorylation and enhance insulin response.
- Authors
Chan, Tung O.; Jin Zhang; Tiegs, Brian C.; Blumhof, Brian; Linda Yan; Keny, Nikhil; Penny, Morgan; Xue Li; Pascal, John M.; Armen, Roger S.; Rodeck, Ulrich; Penn, Raymond B.
- 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 (Thr308 in Akt1 or protein kinase B isoform alpha) in an ATP-dependent manner. In the present paper, we describe a distinct mechanism to control Thr308 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 (Ser473) increased phosphatase resistance of the phosphorylated activation loop (pThr308) and amplified Akt phosphorylation. Furthermore, the phosphatase-resistant Akt was refractory to ceramidedependent dephosphorylation and amplified insulin-dependent Thr308 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.
- Subjects
PROTEIN kinase B; ADENOSINE triphosphate; DEPHOSPHORYLATION; INSULIN receptors; REGULATION of cell growth; CELLULAR signal transduction
- Publication
Biochemical Journal, 2015, Vol 471, Issue 1, p37
- ISSN
0264-6021
- Publication type
Article
- DOI
10.1042/BJ20150325