Abstract
Insulin receptor substrate-1 (IRS-1) and IRS-2 are known to transduce and amplify signals emanating from the insulin receptor. Here we show that Grb2-associated binder 1 (Gab1), despite its structural similarity to IRS proteins, is a negative modulator of hepatic insulin action. Liver-specific Gab1 knockout (LGKO) mice showed enhanced hepatic insulin sensitivity with reduced glycemia and improved glucose tolerance. In LGKO liver, basal and insulin-stimulated tyrosine phosphorylation of IRS-1 and IRS-2 was elevated, accompanied by enhanced Akt/PKB activation. Conversely, Erk activation by insulin was suppressed in LGKO liver, leading to defective IRS-1 Ser612 phosphorylation. Thus, Gab1 acts to attenuate, through promotion of the Erk pathway, insulin-elicited signals flowing through IRS and Akt proteins, which represents a novel balancing mechanism for control of insulin signal strength in the liver.
Publication types
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Comparative Study
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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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Adaptor Proteins, Signal Transducing
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Animals
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Blood Chemical Analysis
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Blood Glucose
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DNA Primers
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Enzyme-Linked Immunosorbent Assay
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Genetic Engineering
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Glucose Tolerance Test
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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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Liver / metabolism*
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Mice
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Mice, Transgenic
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Signal Transduction / physiology*
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Tyrosine / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Blood Glucose
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DNA Primers
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Gab1 protein, mouse
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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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Irs2 protein, mouse
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Phosphoproteins
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Proto-Oncogene Proteins
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Tyrosine
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases