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Nature Medicine 12, 549 - 556 (2006)
Published online: 16 April 2006 | doi:10.1038/nm1397

The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis

Marie-Julie Dubois1,9, Sébastien Bergeron1,9, Hyo-Jeong Kim2,3, Luce Dombrowski1, Mylène Perreault1, Bénédicte Fournès4, Robert Faure5, Martin Olivier6, Nicole Beauchemin4, Gerald I Shulman2,7, Katherine A Siminovitch8, Jason K Kim2 & André Marette1

The protein tyrosine phosphatase SHP-1 is a well-known inhibitor of activation-promoting signaling cascades in hematopoietic cells but its potential role in insulin target tissues is unknown. Here we show that Ptpn6me-v/me-v (also known as viable motheaten) mice bearing a functionally deficient SHP-1 protein are markedly glucose tolerant and insulin sensitive as compared to wild-type littermates, as a result of enhanced insulin receptor signaling to IRS-PI3K-Akt in liver and muscle. Downregulation of SHP-1 activity in liver of normal mice by adenoviral expression of a catalytically inert mutant of SHP-1, or after small hairpin RNA–mediated SHP-1 silencing, further confirmed this phenotype. Tyrosine phosphorylation of CEACAM1, a modulator of hepatic insulin clearance, and clearance of serum [125I]-insulin were markedly increased in SHP-1–deficient mice or SHP-1–deficient hepatic cells in vitro. These findings show a novel role for SHP-1 in the regulation of glucose homeostasis through modulation of insulin signaling in liver and muscle as well as hepatic insulin clearance.