Integrin α2-mediated ERK and calpain activation play a critical role in cell adhesion and motility via focal adhesion kinase signaling: Identification of a novel signaling pathway

Rajinder S. Sawhney, Michelle M. Cookson, Yasin Omar, Jennie Hauser, Michael G. Brattain

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

Higher levels of focal adhesion kinase (FAK) are expressed in colon metastatic carcinomas. However, the signaling pathways and their mechanisms that control cell adhesion and motility, important components of cancer metastasis, are not well understood. We sought to identify the integrin-mediated mechanism ofFAKcleavage and downstream signaling as well as its role in motility in human colon cancer GEO cells. Our results demonstrate that phosphorylated FAK (tyrosine 397) is cleaved at distinct sites by integrin signaling when cells attach to collagen IV. Specific blocking antibodies (clone P1E6) to integrin α2 inhibited FAK activation and cell motility (micromotion). Ectopic expression of the FAK C-terminal domain FRNK attenuated FAK and ERK phosphorylation and micromotion. Calpain inhibitor N-acetylleucyl-leucyl- norleucinal blocked FAK cleavage, cell adhesion, and micromotion. Antisense approaches established an important role for μ-calpain in cell motility. Expression of wild type μ-calpain increased cell micromotion, whereas its point mutant reversed the effect. Further, cytochalasin D inhibited FAK phosphorylation and cleavage, cell adhesion, locomotion, and ERK phosphorylation, thus showing FAK activation downstream of actin assembly. We also found a pivotal role for FAK Tyr861 phosphorylation in cell motility and ERK activation. Our results reveal a novel functional connection between integrin α2 engagement, FAK, ERK, and μ-calpain activation in cell motility and a direct link between FAKcleavage and enhanced cell motility. The data suggest that blocking the integrin α2/FAK/ERK/μ-calpain pathway may be an important strategy to reduce cancer progression.

Original languageEnglish (US)
Pages (from-to)8497-8510
Number of pages14
JournalJournal of Biological Chemistry
Volume281
Issue number13
DOIs
StatePublished - Mar 31 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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