Author: ["Marie-Julie Dubois","Sébastien Bergeron","Hyo-Jeong Kim","Luce Dombrowski","Mylène Perreault","Bénédicte Fournès","Robert Faure","Martin Olivier","Nicole Beauchemin","Gerald I Shulman","Katherine A Siminovitch","Jason K Kim","André Marette"]
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Abstract
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.Cite this article
Dubois, MJ., Bergeron, S., Kim, HJ. et al. The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis. Nat Med 12, 549–556 (2006). https://doi.org/10.1038/nm1397 