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MafA Stability in Pancreatic ß Cells Is Regulated by Glucose and Is Dependent on Its Constitutive Phosphorylation at Multiple Sites by Glycogen Synthase Kinase 3

Song-iee Han, Shinsaku Aramata, Kunio Yasuda, and Kohsuke Kataoka^*

Laboratory of Molecular and Developmental Biology, Graduate School of Biological Science, Nara Institute of Science and Technology, Ikoma, Japan

Received 23 August 2006/ Returned for modification 22 September 2006/ Accepted 23 July 2007

Regulation of insulin gene expression by glucose in pancreatic ß cells is largely dependent on a cis-regulatory element, termed RIPE3b/C1, in the insulin gene promoter. MafA, a member of the Maf family of basic leucine zipper (bZip) proteins, is a ß-cell-specific transcriptional activator that binds to the C1 element. Based on increased C1-binding activity, MafA protein levels appear to be up-regulated in response to glucose, but the underlying molecular mechanism for this is not well understood. In this study, we show evidence supporting that the amino-terminal region of MafA is phosphorylated at multiple sites by glycogen synthase kinase 3 (GSK3) in ß cells. Mutational analysis of MafA and pharmacological inhibition of GSK3 in MIN6 ß cells strongly suggest that the rate of MafA protein degradation is regulated by glucose, that MafA is constitutively phosphorylated by GSK3, and that phosphorylation is a prerequisite for rapid degradation of MafA under low-glucose conditions. Our data suggest a new glucose-sensing signaling pathway in islet ß cells that regulates insulin gene expression through the regulation of MafA protein stability.

Published ahead of print on 6 August 2007.

Present address: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan.