Journal
JOURNAL OF CELL BIOLOGY
Volume 180, Issue 6, Pages 1277-1289Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200708137
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Funding
- NCI NIH HHS [P30 CA036727, P30 CA36727] Funding Source: Medline
- NIDCR NIH HHS [R01 DE012308, R01-DE12308] Funding Source: Medline
- NIGMS NIH HHS [R01-GM51188, R01 GM051188] Funding Source: Medline
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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, alpha 2 beta 1 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 alpha 2 beta 1 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.
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