Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor

Yasushi Shintani, Yuri Fukumoto, Nina Chaika, Robert Svoboda, Margaret J. Wheelock, Keith R. Johnson

Research output: Contribution to journalArticle

156 Scopus citations

Abstract

Tumor cells undergo epithelial-to-mesenchymal transition (EMT) to convert from a benign to a malignant phenotype. Our recent focus has been signaling pathways that promote EMT in response to collagen. We have shown that human pancreatic cancer cells respond to collagen by up-regulating N-cadherin, which promotes tumor growth, invasion, and metastasis. Initial characterization showed that knocking down c-Jun NH2-terminal kinase prevented N-cadherin up-regulation and limited tumor growth and invasion in a mouse model for pancreatic cancer. The current study was designed to understand the pathway from collagen to N-cadherin up-regulation. Initiation of the signal requires two collagen receptors, α2β1 integrin and discoidin domain receptor (DDR) 1. Each receptor propagates signals through separate pathways that converge to up-regulate N-cadherin. Focal adhesion kinase (FAK)-related protein tyrosine kinase (Pyk2) is downstream of DDR1, whereas FAK is downstream of α2β1 integrin. Both receptor complexes rely on the p130 Crk-associated substrate scaffold. Interestingly, Rap1, but not Rho family guanosine triphosphatases, is required for the response to collagen I.

Original languageEnglish (US)
Pages (from-to)1277-1289
Number of pages13
JournalJournal of Cell Biology
Volume180
Issue number6
DOIs
StatePublished - Mar 24 2008

    Fingerprint

ASJC Scopus subject areas

  • Cell Biology

Cite this