A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation

Sheelagh Frame; Philip Cohen; Ricardo M. Biondi

doi:10.1016/S1097-2765(01)00253-2

A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation

Sheelagh Frame
, Philip Cohen
, Ricardo M. Biondi

Research output: Contribution to journal › Article › peer-review

650 Citations (Scopus)

Abstract

The inhibition of GSK3 is required for the stimulation of glycogen and protein synthesis by insulin and the specification of cell fate during development. Here, we demonstrate that the insulin-induced inhibition of GSK3 and its unique substrate specificity are explained by the existence of a phosphate binding site in which Arg-96 is critical. Thus, mutation of Arg-96 abolishes the phosphorylation of "primed" glycogen synthase as well as inhibition by PKB-mediated phosphorylation of Ser-9. Hence, the phosphorylated N terminus acts as a pseudosubstrate, occupying the same phosphate binding site used by primed substrates. Significantly, this mutation does not affect phosphorylation of "non-primed" substrates in the Wnt-signaling pathway (Axin and β-catenin), suggesting new approaches to design more selective GSK3 inhibitors for the treatment of diabetes.

Original language	English
Pages (from-to)	1321-1327
Number of pages	7
Journal	Molecular Cell
Volume	7
Issue number	6
DOIs	https://doi.org/10.1016/S1097-2765(01)00253-2
Publication status	Published - 1 Jan 2001

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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T1 - A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation

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AU - Cohen, Philip

AU - Biondi, Ricardo M.

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Y1 - 2001/1/1

N2 - The inhibition of GSK3 is required for the stimulation of glycogen and protein synthesis by insulin and the specification of cell fate during development. Here, we demonstrate that the insulin-induced inhibition of GSK3 and its unique substrate specificity are explained by the existence of a phosphate binding site in which Arg-96 is critical. Thus, mutation of Arg-96 abolishes the phosphorylation of "primed" glycogen synthase as well as inhibition by PKB-mediated phosphorylation of Ser-9. Hence, the phosphorylated N terminus acts as a pseudosubstrate, occupying the same phosphate binding site used by primed substrates. Significantly, this mutation does not affect phosphorylation of "non-primed" substrates in the Wnt-signaling pathway (Axin and β-catenin), suggesting new approaches to design more selective GSK3 inhibitors for the treatment of diabetes.

AB - The inhibition of GSK3 is required for the stimulation of glycogen and protein synthesis by insulin and the specification of cell fate during development. Here, we demonstrate that the insulin-induced inhibition of GSK3 and its unique substrate specificity are explained by the existence of a phosphate binding site in which Arg-96 is critical. Thus, mutation of Arg-96 abolishes the phosphorylation of "primed" glycogen synthase as well as inhibition by PKB-mediated phosphorylation of Ser-9. Hence, the phosphorylated N terminus acts as a pseudosubstrate, occupying the same phosphate binding site used by primed substrates. Significantly, this mutation does not affect phosphorylation of "non-primed" substrates in the Wnt-signaling pathway (Axin and β-catenin), suggesting new approaches to design more selective GSK3 inhibitors for the treatment of diabetes.

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JO - Molecular Cell

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A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation

Abstract

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