EGFR-dependent pancreatic carcinoma cell metastasis through Rap1 activation

M. Huang, S. Anand, E. A. Murphy, J. S. Desgrosellier, D. G. Stupack, S. J. Shattil, D. D. Schlaepfer, D. A. Cheresh

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Tyrosine kinase receptors have an essential role in various aspects of tumor progression. In particular, epidermal growth factor receptor (EGFR) and its ligands have been implicated in the growth and dissemination of a wide array of human carcinomas. Here, we describe an EGFR-mediated signaling pathway that regulates human pancreatic carcinoma cell invasion and metastasis, yet does not influence the growth of primary tumors. In fact, ligation/activation of EGFR induces Src-dependent phosphorylation of two critical tyrosine residues of p130CAS, leading to the assembly of a Crk-associated substrate (CAS)/Nck1 complex that promotes Ras-associated protein-1 (Rap1) signaling. Importantly, GTP loading of Rap1 is specifically required for pancreatic carcinoma cell migration on vitronectin but not on collagen. Furthermore, Rap1 activation is required for EGFR-mediated metastasis in vivo without impacting primary tumor growth. These findings identify a molecular pathway that promotes the invasive/metastatic properties of human pancreatic carcinomas driven by EGFR.

Original languageEnglish (US)
Pages (from-to)2783-2793
Number of pages11
JournalOncogene
Volume31
Issue number22
DOIs
StatePublished - May 31 2012

Keywords

  • CAS
  • EGFR
  • Metastasis
  • Pancreatic cancer
  • Rap1
  • Tyrosine phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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