3 years ago

Modulation of GSK3β autoinhibition by Thr-7 and Thr-8

Thurl E. Harris, David L. Brautigan, Zheng Fu, Sohyun Park, Yixin Tong, Christopher A. Moskaluk, Di Wu
Glycogen synthase kinase 3β (GSK-3β) is a pivotal signaling node that regulates a myriad of cellular functions and is deregulated in many pathological conditions, making it an attractive therapeutic target. Inhibitory Ser-9 phosphorylation of GSK3β by AKT is an important mechanism for negative regulation of GSK3β activity upon insulin stimulation. Here, we report that Thr-7 and Thr-8 residues located in the AKT/PKB substrate consensus sequence on GSK3β are essential for insulin-stimulated Ser-9 phosphorylation in vivo and for GSK3β inactivation. Intestinal cell kinase (ICK) phosphorylates GSK3β Thr-7 in vitro and in vivo. Thr-8 phosphorylation partially inhibits GSK3β, but Thr-7 phosphorylation promotes GSK3β activity and blocks phospho-Ser-9-dependent GSK3β autoinhibition. Our findings uncover novel mechanistic and signaling inputs involved in the autoinhibition of GSK3β. This article is protected by copyright. All rights reserved.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/1873-3468.12990

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