Up-Regulation of N-Cadherin by Collagen I-activated discoidin domain receptor 1 in pancreatic cancer requires the adaptor molecule Shc

Huocong Huang, Robert A. Svoboda, Audrey J. Lazenby, Jintana Saowapa, Nina Chaika, Ke Ding, Margaret J. Wheelock, Keith R. Johnson

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Pancreatic ductal adenocarcinomas are highly malignant cancers characterized by extensive invasion into surrounding tissues, metastasis to distant organs, and a limited response to therapy. A main feature of pancreatic ductal adenocarcinomas is desmoplasia, which leads to extensive deposition of collagen I. We have demonstrated that collagen I can induce epithelialmesenchymal transition (EMT) in pancreatic cancer cells. A hallmark of EMT is an increase in the expression of the mesenchymal cadherin N-cadherin. Previously we showed up-regulation of N-cadherin promotes tumor cell invasion and that collagen I-induced EMT is mediated by two collagen receptors, α2β1-integrin and discoidin domain receptor 1 (DDR1). DDR1 is a receptor-tyrosine kinase widely expressed during embryonic development and in many adult tissues and is also highly expressed in many different cancers. In the signaling pathway initiated by collagen, we have shown proline-rich tyrosine kinase 2 (Pyk2) is downstream of DDR1. In this study we found isoform b of DDR1 is responsible for collagen I-induced up-regulation of N-cadherin and tyrosine 513 of DDR1b is necessary. Knocking down Shc1, which binds to tyrosine 513 of DDR1b via its PTB (phosphotyrosine binding) domain, eliminates the upregulation of N-cadherin. The signaling does not require a functional SH2 domain or the tyrosine residues commonly phosphorylated in Shc1 but is mediated by the interaction between a short segment of the central domain of Shc1 and the proline-rich region of Pyk2. Taken together, these data illustrate DDR1b, but not DDR1a, mediates collagen I-induced N-cadherin up-regulation, and Shc1 is involved in this process by coupling to both DDR1 and Pyk2.

Original languageEnglish (US)
Pages (from-to)23208-23223
Number of pages16
JournalJournal of Biological Chemistry
Volume291
Issue number44
DOIs
StatePublished - Oct 28 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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