Domains of the insulin-like growth factor I receptor required for the activation of extracellular signal-regulated kinases

Endocrinology. 2000 Apr;141(4):1289-300. doi: 10.1210/endo.141.4.7414.

Abstract

The type 1 insulin-like growth factor receptor (IGF-IR) activates the extracellular signal-regulated kinases (ERK1 and -2). The two major substrates of the IGF-IR, insulin receptor substrate-1 (IRS-1) and the Shc proteins, are known to contribute to this activation. We investigated the domains of the IGF-IR required for the activation of the ERK proteins. To facilitate this study, we used a cell line (32D cells) that lacks IRS-1. In the absence of IRS-1, ERK activation is inhibited if the IGF-IR is mutated at two domains: tyrosine Y950 and a serine quartet at 1280-1283. Expression of IRS-1 in 32D cells expressing the double mutant IGF-IR restores ERK activation. The importance of the C-terminus of the IGF-IR in ERK activation (in the absence of IRS-1) is confirmed by the failure of the insulin receptor to give a sustained activation of ERK. In this model system, there is a good, but not exact, correlation between ERK activation and cell survival after withdrawal of growth factors.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport*
  • Cell Line / physiology
  • Cell Survival
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Insulin Receptor Substrate Proteins
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphoproteins
  • Phosphorylation
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Proteins / metabolism
  • Proto-Oncogene Proteins / physiology
  • Proto-Oncogene Proteins c-akt
  • Receptor, IGF Type 1 / genetics*
  • Receptor, IGF Type 1 / physiology*
  • Shc Signaling Adaptor Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Enzyme Inhibitors
  • Flavonoids
  • Insulin Receptor Substrate Proteins
  • Phosphoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Shc Signaling Adaptor Proteins
  • Receptor, IGF Type 1
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one