Nature Medicine
- 12, 549 - 556 (2006)
Published online: 16 April 2006; | doi:10.1038/nm1397
The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasisMarie-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 Marette11
Department of Anatomy-Physiology and Lipid Research Unit, Laval University Hospital Research Center, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada. 2
Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale Mouse Metabolic Phenotyping Center, Yale University School of Medicine, The Anlyan Center, 300 Cedar Street, New Haven, Connecticut 06520, USA. 3
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, USA. 4
McGill Cancer Centre, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec H3G 1Y6, Canada. 5
Department of Pediatrics, Laval University Hospital Research Center, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada. 6
Departments of Experimental Medicine, Microbiology and Immunology, McGill University, 3775 University Street, Montreal, Quebec H3A 2B4, Canada. 7
Howard Hughes Medical Institute, University of Toronto, Mount Sinai Hospital Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. 8
Departments of Medicine and Immunology, University of Toronto, Mount Sinai Hospital Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. 9
These authors contributed equally to this work.
Correspondence should be addressed to André Marette andre.marette@crchul.ulaval.ca 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 Ptpn6
me-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.
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