Specificity of insulin-like growth factor I and insulin on Shc phosphorylation and Grb2 recruitment in caveolae

Endocrinology. 2003 Dec;144(12):5497-503. doi: 10.1210/en.2003-0417. Epub 2003 Aug 21.


Caveolae are lipid raft microdomains that regulate endocytosis and signal transduction. IGF-I receptor (IGF-IR) localizes in caveolae and tyrosine phosphorylates caveolin 1, supporting a role for these subcellular regions in the compartmentalization of IGF-I signaling. Src homology 2/alpha-collagen related protein (Shc) is the main mediator of IGF-I mitogenic action, coupling IGF-IR phosphorylation to Ras-MAPK activation. Here we show that IGF-I induces Shc tyrosine phosphorylation in the caveolae with a time course significantly different from that observed in the nonraft cellular fractions. In the same time, IGF-I recruits growth factor receptor bound protein 2 (Grb2) to caveolae and activates p42/p44 MAPKs in these microdomains. Src family kinases regulate IGF-I action through an Shc-dependent mechanism. In R-IGF-IRWT cells, IGF-I causes Fyn enrichment in the caveolae with a time course consistent with Shc phosphorylation and Grb2 recruitment in these regions. Finally, we have observed that after IGF-I stimulation, IGF-IR and Fyn colocalize in lipid raft caveolin 1-enriched microdomains. As insulin and IGF-I share common substrates, the effect of insulin on these cellular processes was measured. Here we show that insulin also induces Shc phosphorylation and Grb2 recruitment to caveolae, but with a significantly different time course compared with IGF-I. Our results suggest that 1) IGF-I causes the colocalization of signaling proteins in caveolae through a phosphorylation-regulated mechanism; and 2) the time course of phosphorylation and recruitment of substrates in caveolae by insulin receptor and IGF-IR could determine the specific actions of these receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Caveolae / drug effects
  • Caveolae / metabolism*
  • Cells, Cultured
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • GRB2 Adaptor Protein
  • Hypoglycemic Agents / pharmacology*
  • Insulin / pharmacology*
  • Insulin-Like Growth Factor I / pharmacology*
  • Mice
  • Phosphorylation
  • Proteins / metabolism*
  • Receptor Aggregation / drug effects
  • Receptor Aggregation / physiology
  • Receptor, IGF Type 1 / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • src Homology Domains / physiology*


  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • Grb2 protein, mouse
  • Hypoglycemic Agents
  • Insulin
  • Proteins
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1