The function of GRB2 in linking the insulin receptor to Ras signaling pathways.
Insulin-induced activation of extracellular signal-regulated kinases [ERKs, also known as mitogen-activated protein (MAP) kinases] is mediated by Ras. Insulin activates Ras primarily by increasing the rate of guanine nucleotide-releasing activity. Here, we show that insulin-induced activation of ERKs was enhanced by stable overexpression of growth factor receptor-bound protein 2 (GRB2) but not by overexpression of GRB2 proteins with point mutations in the Src homology 2 and 3 domains. Moreover, a dominant negative form of Ras (with Ser17 substituted with Asn) blocked insulin-induced activation of ERKs in cells that overexpressed GRB2. GRB2 overexpression led to increased formation of a complex between the guanine nucleotide-releasing factor Sos (the product of the mammalian homolog of son of sevenless gene) and GRB2. In response to insulin stimulation, this complex bound to tyrosine-phosphorylated IRS-1 (insulin receptor substrate-1) and Shc. In contrast to the activated epidermal growth factor receptor that binds the GRB2-Sos complex directly, activation of the insulin receptor results in the interaction of GRB2-Sos with IRS-1 and Shc, thus linking the insulin receptor to Ras signaling pathways.
Skolnik
E Y
EY
Department of Pharmacology, New York University Medical Center, NY 10016.
Batzer
A
A
Li
N
N
Lee
C H
CH
Lowenstein
E
E
Mohammadi
M
M
Margolis
B
B
Schlessinger
J
J
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D008565:Membrane Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D020664:Son of Sevenless Proteins
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011506:Proteins; D020664:Son of Sevenless Proteins; D004815:Epidermal Growth Factor; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases