Mechanisms of regulation of cell adhesion and motility by insulin receptor substrate-1 in prostate cancer cells

Oncogene. 2001 Jan 25;20(4):490-500. doi: 10.1038/sj.onc.1204112.


LNCaP cells are human prostatic cancer cells that have a frame-shift mutation of the tumor suppressor gene PTEN and do not express the insulin receptor substrate-1 (IRS-1), a major substrate of the type 1 insulin-like growth factor receptor (IGF-IR). Ectopic expression of IRS-1 in LNCaP cells increases cell adhesion and decreases cell motility by an IGF-I-independent mechanism. We show now that these effects of IRS-1 are accompanied by serine phosphorylation of IRS-1 and are inhibited by inhibitors of phosphatidylinositol 3-kinase (PI3K). We have confirmed the requirement for PI3K activity and serine phosphorylation by the use of IRS-1 mutants, expressed in LNCaP cells. Serine phosphorylation inhibits IGF-I-induced tyrosyl phosphorylation of IRS-1, which is restored by the expression of wild-type PTEN or by inhibition of PI3K activity. Finally, IRS-1 in LNCaP cells co-immunoprecipitates with integrin alpha 5 beta 1, and the association is again IGF-I-independent. We conclude that in LNCaP cells, IRS-1 is serine phosphorylated by PI3K, generating effects that are different, and even opposite, from those generated by IGF-I.

Publication types

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

MeSH terms

  • Adenocarcinoma / pathology
  • Adenocarcinoma / physiopathology
  • Adenocarcinoma / secondary
  • Cell Adhesion* / drug effects
  • Cell Movement*
  • Collagen / metabolism
  • Fibronectins / metabolism
  • Humans
  • Insulin Receptor Substrate Proteins
  • Male
  • Mutation
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / physiopathology*
  • Prostatic Neoplasms / secondary
  • Protein Binding
  • Receptors, Fibronectin / metabolism


  • Fibronectins
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • Receptors, Fibronectin
  • Collagen