Details

Autor(en) / Beteiligte

• Skolnik, E. Y.
• Batzer, A.
• Li, N.
• C.-H. Lee
• Lowenstein, E.
• Mohammadi, M.
• Margolis, B.
• Schlessinger, J.

Titel

The Function of GRB2 in Linking the Insulin Receptor to Ras Signaling Pathways

Ist Teil von

• Science (American Association for the Advancement of Science), 1993-06, Vol.260 (5116), p.1953-1955

Ort / Verlag

Washington, DC: American Society for the Advancement of Science

Erscheinungsjahr

1993

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 Ser$^{17}$ 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.