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

151 Citations (Scopus)

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

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Cadherins
Integrins
Up-Regulation
Collagen
Focal Adhesion Protein-Tyrosine Kinases
Epithelial-Mesenchymal Transition
Pancreatic Neoplasms
Crk-Associated Substrate Protein
Collagen Receptors
Neoplasms
JNK Mitogen-Activated Protein Kinases
Guanosine
Growth
Protein-Tyrosine Kinases
Neoplasm Metastasis
Phenotype
Discoidin Domain Receptors

ASJC Scopus subject areas

  • Cell Biology

Cite this

Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor. / Shintani, Yasushi; Fukumoto, Yuri; Chaika, Nina; Svoboda, Robert; Wheelock, Margaret J.; Johnson, Keith R.

In: Journal of Cell Biology, Vol. 180, No. 6, 24.03.2008, p. 1277-1289.

Research output: Contribution to journalArticle

Shintani, Yasushi ; Fukumoto, Yuri ; Chaika, Nina ; Svoboda, Robert ; Wheelock, Margaret J. ; Johnson, Keith R. / Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor. In: Journal of Cell Biology. 2008 ; Vol. 180, No. 6. pp. 1277-1289.
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