The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis.
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.
Dubois
Marie-Julie
MJ
Department of Anatomy-Physiology and Lipid Research Unit, Laval University Hospital Research Center, 2705 Laurier Boulevard, Québec, Québec G1V 4G2, Canada.
Bergeron
Sébastien
S
Kim
Hyo-Jeong
HJ
Dombrowski
Luce
L
Perreault
Mylène
M
Fournès
Bénédicte
B
Faure
Robert
R
Olivier
Martin
M
Beauchemin
Nicole
N
Shulman
Gerald I
GI
Siminovitch
Katherine A
KA
Kim
Jason K
JK
Marette
André
A
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*
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