Article

The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis.

Department of Anatomy-Physiology and Lipid Research Unit, Laval University Hospital Research Center, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada.
Nature Medicine (impact factor: 22.46). 06/2006; 12(5):549-56. DOI:10.1038/nm1397 pp.549-56
Source: PubMed

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.

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Keywords

adenoviral expression
 
catalytically inert mutant
 
functionally deficient SHP-1 protein
 
glucose homeostasis
 
hematopoietic cells
 
hepatic insulin clearance
 
insulin receptor signaling
 
insulin sensitive
 
insulin signaling
 
insulin target tissues
 
novel role
 
protein tyrosine phosphatase SHP-1
 
SHP-1 activity
 
SHP-1-deficient hepatic cells
 
SHP-1-deficient mice
 
small hairpin RNA-mediated SHP-1
 
Tyrosine phosphorylation
 
viable motheaten
 
well-known inhibitor
 
wild-type littermates