title: Evidence for an insulin receptor substrate 1 independent insulin signaling pathway that mediates insulin-responsive glucose transporter (GLUT4) translocation.
abstract: Interaction of the activated insulin receptor (IR) with its substrate, insulin receptor substrate 1 (IRS-1), via the phosphotyrosine binding domain of IRS-1 and the NPXY motif centered at phosphotyrosine 960 of the IR, is important for IRS-1 phosphorylation. We investigated the role of this interaction in the insulin signaling pathway that stimulates glucose transport. Utilizing microinjection of competitive inhibitory reagents in 3T3-L1 adipocytes, we have found that disruption of the IR/IRS-1 interaction has no effect upon translocation of the insulin-responsive glucose transporter (GLUT4). The activity of these reagents was demonstrated by their ability to block insulin stimulation of two distinct insulin bioeffects, membrane ruffling and mitogenesis, in 3T3-L1 adipocytes and insulin-responsive rat 1 fibroblasts. These data suggest that phosphorylated IRS-1 is not an essential component of the metabolic insulin signaling pathway that leads to GLUT4 translocation, yet it appears to be required for other insulin bioeffects.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla 92093, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Morris
authors.forename: S S
authors.initials: SS
authors.lastname: Martin
authors.forename: T
authors.initials: T
authors.lastname: Haruta
authors.forename: J G
authors.initials: JG
authors.lastname: Nelson
authors.forename: P
authors.initials: P
authors.lastname: Vollenweider
authors.forename: T A
authors.initials: TA
authors.lastname: Gustafson
authors.forename: M
authors.initials: M
authors.lastname: Mueckler
authors.forename: D W
authors.initials: DW
authors.lastname: Rose
authors.forename: J M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000648:ultrastructure; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D008856:Microscopy, Fluorescence; D008938:Mitosis; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D009842:Oligopeptides / Q000737:chemistry; D010750:Phosphoproteins / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D009842:Oligopeptides; D010750:Phosphoproteins; C495693:Slc2a4 protein, mouse; C495694:Slc2a4 protein, rat