Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action.
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.
Bard-Chapeau
Emilie A
EA
Signal Transduction Program, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Hevener
Andrea L
AL
Long
Shinong
S
Zhang
Eric E
EE
Olefsky
Jerrold M
JM
Feng
Gen-Sheng
GS
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001774:Blood Chemical Analysis; D001786:Blood Glucose; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005818:Genetic Engineering; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D017931:DNA Primers; C490897:Gab1 protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases