Multiple signaling pathways are activated during insulin-like growth factor-I (IGF-I) stimulated breast cancer cell migration

Xihong Zhang, Min Lin, Kenneth L. Van Golen, Kiyoko Yoshioka, Kazuyuki Itoh, Douglas Yee

Research output: Contribution to journalArticlepeer-review

60 Scopus citations


In order to display the full metastatic phenotype, the cancer cell must acquire the ability to migrate. In breast cancer, we have previously shown that insulin-like growth factor I (IGF-I) enhances cell motility in the highly metastatic MDA-231BO cell line by activating the type I IGF receptor (IGF1R). This motility response requires activation of IRS-2 and integrin ligation. In order to identify the key molecules downstream of IRS-2, we examined several signaling pathways known to be involved in cell motility. Focal adhesion kinase (FAK) was not activated by IGF-I, but IGF-I caused redistribution of FAK away from focal adhesion plaques. IGF-I treatment of MDA-231BO cells activated RhoA and inhibition of Rho-kinase (ROCK) inhibited the IGF-mediated motility response. The mitogen activated protein kinase (MAPK), p38, was also activated by IGF-I and inhibition of p38 by SB203580 blocked IGF-I induced cell motility. ROCK inhibition with Y-27632 also inhibited p38 phosphorylation suggesting that p38 lies downstream of ROCK. Both Erk1,2 and phosphatidyl-3 kinase (PI3K) were required for IGF-I stimulated cell motility, but only PI3K appeared to be directly downstream of IGF-I. Thus, IGF-I activation of its receptor coordinates multiple signaling pathways required for cell motility. Defining the key molecules downstream of the type I IGF receptor may provide a basis for optimizing therapies directed at this target.

Original languageEnglish (US)
Pages (from-to)159-168
Number of pages10
JournalBreast Cancer Research and Treatment
Issue number2
StatePublished - Sep 2005

Bibliographical note

Funding Information:
This work was supported by NIH Grant R01 CA74285 and PHS Cancer Center Support Grant P30 CA77398.


  • Breast neoplasms
  • Cell motility
  • Focal adhesion kinase
  • Insulin-like growth factor-I
  • Mitogen activated protein kinase
  • Rho
  • Type I IGF receptor


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