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Published online March 24, 2008
doi:10.1083/jcb.200708137
The Journal of Cell Biology, Vol. 180, No. 6, 1277-1289
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Shintani et al.
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Article

 Collagen I–mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1

Yasushi Shintani1, Yuri Fukumoto2, Nina Chaika1, Robert Svoboda1, Margaret J. Wheelock1,2,3, and Keith R. Johnson1,2,3

1 Department of Oral Biology, 2 Eppley Institute for Research in Cancer and Allied Diseases, and 3 Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198

Correspondence to Margaret J. Wheelock: mwheelock{at}unmc.edu

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}2β1 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}2β1 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.

Abbreviations used in this paper: CAS, Crk-associated substrate; CRIB, Cdc42-Rac interactive binding; DDR, discoidin domain receptor; EMT, epithelial-to-mesenchymal transition; MKK, MAPK kinase; MLK, mixed lineage kinase; pAb, polyclonal antibody; PAK, p21-activated kinase; PI3K, phosphatidylinositol 3-kinase; RIPA, radioimmunoprecipitation assay; SD, substrate domain; shRNA, short hairpin RNA; TNE, Tris/NP40/EDTA.


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