Up-regulation of N-cadherin by Collagen I-activated Discoidin Domain Receptor 1 in Pancreatic Cancer Requires the Adaptor Molecule Shc1.
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 epithelial-mesenchymal 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 up-regulation 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.
From the Department of Biochemistry and Molecular Biology, College of Medicine.
Huocong
H
Huang
Department of Oral Biology, College of Dentistry.
Robert A
RA
Svoboda
Department of Pathology and Microbiology, College of Medicine, and.
Audrey J
AJ
Lazenby
Department of Oral Biology, College of Dentistry.
Jintana
J
Saowapa
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha Nebraska 68198.
Nina
N
Chaika
State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China, and.
Ke
K
Ding
From the Department of Biochemistry and Molecular Biology, College of Medicine.|Department of Oral Biology, College of Dentistry.|Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha Nebraska 68198.
Margaret J
MJ
Wheelock
From the Department of Biochemistry and Molecular Biology, College of Medicine, kjohnsonr@unmc.edu.|Department of Oral Biology, College of Dentistry.|Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha Nebraska 68198.|Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198.
Keith R
KR
Johnson
D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D000070819:Discoidin Domain Receptor 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
D015820:Cadherins; D024042:Collagen Type I; D020033:Protein Isoforms; C528024:SHC1 protein, human; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1
DDR1; N-cadherin; Pyk2; Shc1; collagen; epithelial-mesenchymal transition (EMT); pancreatic cancer; receptor-tyrosine kinase