title: The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis.
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 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.
authors.affiliation: Department of Anatomy-Physiology and Lipid Research Unit, Laval University Hospital Research Center, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada.
authors.forename: Marie-Julie
authors.initials: MJ
authors.lastname: Dubois
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bergeron
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Luce
authors.initials: L
authors.lastname: Dombrowski
authors.forename: Mylène
authors.initials: M
authors.lastname: Perreault
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Fournès
authors.forename: Robert
authors.initials: R
authors.lastname: Faure
authors.forename: Martin
authors.initials: M
authors.lastname: Olivier
authors.forename: Nicole
authors.initials: N
authors.lastname: Beauchemin
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Siminovitch
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: André
authors.initials: A
authors.lastname: Marette
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000378:metabolism; D020868:Gene Silencing; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007328:Insulin / Q000737:chemistry / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse