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Papers In Press, published online ahead of print November 30, 2004
Department of Human Genetics and Molecular Medicine, Tel Aviv University, Tel Aviv 69978
Corresponding Author: heldar{at}post.tau.ac.il
The ability of glycogen synthase kinase-3 (GSK-3) to phosphorylate insulin receptor substare-1 (IRS-1) is a potential inhibitory mechanism for insulin resistance in type 2 diabetes. However, the serine site(s), phosphorylated by GSK-3 within IRS-1 had not been yet identified. Using N-terminal deleted IRS-1 mutant and two IRS-1 fragments, PTB-11-320 and PTB-21-350, we localized GSK-3-phosphorylation site(s) within amino acid sequence 320-350. Mutations of serine 332 or serine 336, which lie in the GSK-3 consensus motif (SXXXS) within PTB-2 or IRS-1, to alanine abolished their phosphorylation by GSK-3. This suggested that serine332 is a GSK-3 phosphorylation site and that serine336 serves as the “priming” site typically required for GSK-3 action. Indeed, dephosphorylation of IRS-1 prevented GSK-3 phosphorylation. Furthermore, the phosphorylated peptide derived from IRS-1 sequence was readily phosphorylated by GSK-3, in contrast to the non-phosphorylated peptide, which was not phosphorylated by the enzyme.When IRS-1 mutants, S332AIRS-1, S336AIRS-1, or S332A/336AIRS-1 were expressed in CHO cells overexpressing insulin receptors, their insulin-induced-tyrosine phosphorylation levels increased, compared with that of wild-type (WT) IRS-1. This effect was stronger in the double mutant S332A/336AIRS-1, and led to enhanced insulin-mediated activation of protein kinase B. Finally, immunoblot analysis with polyclonal antibody directed against IRS-1 phosphorylated at Serine332 confirmed IRS-1 phosphorylation in cultured cells. Moreover, treatment with GSK-3 inhibitor, lithium, reduced serine332 phosphorylation, while overexpression of GSK-3 enhanced this phosphorylation. In summary, our studies identify Ser332 as the GSK-3 phosphorylation target in IRS-1, indicating its physiological relevance and demonstrating its novel inhibitory role in insulin signaling.
J. Biol. Chem, 10.1074/jbc.M410610200
Submitted on September 15, 2004
Revised on November 29, 2004
Accepted on November 30, 2004
Serine332 phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 attenuates insulin signaling
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