Abstract
The Src homology 2 domain-containing protein-tyrosine phosphatase Shp2 has been implicated in a variety of growth factor signaling pathways, but its role in insulin signaling has remained unresolved. In vitro studies suggest that Shp2 is both a negative and positive regulator of insulin signaling, although its physiological function in a number of peripheral insulin-responsive tissues remains unknown. To address the metabolic role of Shp2 in the liver, we generated mice with either chronic or acute hepatic Shp2 deletion using tissue-specific Cre-LoxP and adenoviral Cre approaches, respectively. We then analyzed insulin sensitivity, glucose tolerance, and insulin signaling in liver-specific Shp2-deficient and control mice. Mice with chronic Shp2 deletion exhibited improved insulin sensitivity and increased glucose tolerance compared with controls. Acute Shp2 deletion yielded comparable results, indicating that the observed metabolic effects are directly caused by the lack of Shp2 in the liver. These findings correlated with, and were most likely caused by, direct dephosphorylation of insulin receptor substrate (IRS)1/2 in the liver, accompanied by increased PI3K/Akt signaling. In contrast, insulin-induced ERK activation was dramatically attenuated, yet there was no effect on the putative ERK site on IRS1 (Ser612) or on S6 kinase 1 activity. These studies show that Shp2 is a negative regulator of hepatic insulin action, and its deletion enhances the activation of PI3K/Akt pathway downstream of the insulin receptor.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 39750-39758 |
| Number of pages | 9 |
| Journal | Journal of Biological Chemistry |
| Volume | 285 |
| Issue number | 51 |
| DOIs | |
| State | Published - Dec 17 2010 |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase. / Matsuo, Kosuke; Delibegovic, Mirela; Matsuo, Izumi; Nagata, Naoto; Liu, Siming; Bettaieb, Ahmed; Xi, Yannan; Araki, Kazushi; Yang, Wentian; Kahn, Barbara B.; Neel, Benjamin G.; Haj, Fawaz.
In: Journal of Biological Chemistry, Vol. 285, No. 51, 17.12.2010, p. 39750-39758.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase
AU - Matsuo, Kosuke
AU - Delibegovic, Mirela
AU - Matsuo, Izumi
AU - Nagata, Naoto
AU - Liu, Siming
AU - Bettaieb, Ahmed
AU - Xi, Yannan
AU - Araki, Kazushi
AU - Yang, Wentian
AU - Kahn, Barbara B.
AU - Neel, Benjamin G.
AU - Haj, Fawaz
PY - 2010/12/17
Y1 - 2010/12/17
N2 - The Src homology 2 domain-containing protein-tyrosine phosphatase Shp2 has been implicated in a variety of growth factor signaling pathways, but its role in insulin signaling has remained unresolved. In vitro studies suggest that Shp2 is both a negative and positive regulator of insulin signaling, although its physiological function in a number of peripheral insulin-responsive tissues remains unknown. To address the metabolic role of Shp2 in the liver, we generated mice with either chronic or acute hepatic Shp2 deletion using tissue-specific Cre-LoxP and adenoviral Cre approaches, respectively. We then analyzed insulin sensitivity, glucose tolerance, and insulin signaling in liver-specific Shp2-deficient and control mice. Mice with chronic Shp2 deletion exhibited improved insulin sensitivity and increased glucose tolerance compared with controls. Acute Shp2 deletion yielded comparable results, indicating that the observed metabolic effects are directly caused by the lack of Shp2 in the liver. These findings correlated with, and were most likely caused by, direct dephosphorylation of insulin receptor substrate (IRS)1/2 in the liver, accompanied by increased PI3K/Akt signaling. In contrast, insulin-induced ERK activation was dramatically attenuated, yet there was no effect on the putative ERK site on IRS1 (Ser612) or on S6 kinase 1 activity. These studies show that Shp2 is a negative regulator of hepatic insulin action, and its deletion enhances the activation of PI3K/Akt pathway downstream of the insulin receptor.
AB - The Src homology 2 domain-containing protein-tyrosine phosphatase Shp2 has been implicated in a variety of growth factor signaling pathways, but its role in insulin signaling has remained unresolved. In vitro studies suggest that Shp2 is both a negative and positive regulator of insulin signaling, although its physiological function in a number of peripheral insulin-responsive tissues remains unknown. To address the metabolic role of Shp2 in the liver, we generated mice with either chronic or acute hepatic Shp2 deletion using tissue-specific Cre-LoxP and adenoviral Cre approaches, respectively. We then analyzed insulin sensitivity, glucose tolerance, and insulin signaling in liver-specific Shp2-deficient and control mice. Mice with chronic Shp2 deletion exhibited improved insulin sensitivity and increased glucose tolerance compared with controls. Acute Shp2 deletion yielded comparable results, indicating that the observed metabolic effects are directly caused by the lack of Shp2 in the liver. These findings correlated with, and were most likely caused by, direct dephosphorylation of insulin receptor substrate (IRS)1/2 in the liver, accompanied by increased PI3K/Akt signaling. In contrast, insulin-induced ERK activation was dramatically attenuated, yet there was no effect on the putative ERK site on IRS1 (Ser612) or on S6 kinase 1 activity. These studies show that Shp2 is a negative regulator of hepatic insulin action, and its deletion enhances the activation of PI3K/Akt pathway downstream of the insulin receptor.
UR - http://www.scopus.com/inward/record.url?scp=78650044708&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78650044708&partnerID=8YFLogxK
U2 - 10.1074/jbc.M110.153734
DO - 10.1074/jbc.M110.153734
M3 - Article
C2 - 20841350
AN - SCOPUS:78650044708
VL - 285
SP - 39750
EP - 39758
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 51
ER -