Role of Rho-kinase in regulation of insulin action and glucose homeostasis

被引:139
作者
Furukawa, N
Ongusaha, P
Jahng, WJ
Araki, K
Choi, CS
Kim, HJ
Lee, YH
Kaibuchi, K
Kahn, BB
Masuzaki, H
Kim, JK
Lee, SW
Kim, YB [1 ]
机构
[1] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA
[3] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA
[4] Harvard Univ, Sch Med, Charlestown, MA 02129 USA
[5] Yale Univ, Sch Med, Dept Internal Med, Sect Endocrinol & Metab, New Haven, CT 06520 USA
[6] Chungbuk Natl Univ, Inst Tumor Res, Chungbuk 361763, South Korea
[7] Chungbuk Natl Univ, Coll Med, Chungbuk 361763, South Korea
[8] Nagoya Univ, Dept Cell Pharmacol, Grad Sch Med, Aichi 4668550, Japan
[9] Kyoto Univ, Grad Sch Med, Dept Med & Clin Sci, Kyoto 6068507, Japan
关键词
D O I
10.1016/j.cmet.2005.06.011
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Accumulating evidence indicates an important role for serine phosphorylation of IRS-1 in the regulation of insulin action. Recent studies suggest that Rho-kinase (ROK) is a mediator of insulin signaling, via interaction with IRS-1. Here we show that insulin stimulation of glucose transport is impaired when ROK is chemically or biologically inhibited in cultured adipocytes and myotubes and in isolated soleus muscle ex vivo. Inactivation of ROK also reduces insulin-stimulated IRS-1 tyrosine phosphorylation and PI3K activity. Moreover, inhibition of ROK activity in mice causes insulin resistance by reducing insulin-stimulated glucose uptake in skeletal muscle in vivo. Mass spectrometry analysis identifies IRS-1 Ser632/635 as substrates of ROK in vitro, and mutation of these sites inhibits insulin signaling. These results strongly suggest that ROK regulates insulin-stimulated glucose transport in vitro and in vivo. Thus, ROK is an important regulator of insulin signaling and glucose metabolism.
引用
收藏
页码:119 / 129
页数:11
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