Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adipocytes / cytology
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Adipocytes / metabolism
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Animals
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Cell Line
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Cricetinae
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Glucose / metabolism*
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Homeostasis*
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Humans
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Insulin / metabolism*
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Mice
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Muscle Fibers, Skeletal / cytology
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Muscle Fibers, Skeletal / metabolism
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Muscle, Skeletal / metabolism
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction / physiology
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rho-Associated Kinases
Substances
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IRS1 protein, human
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Insulin
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs1 protein, mouse
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Phosphoproteins
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RNA, Small Interfering
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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Glucose