The cell surface glycoprotein CUB domain-containing protein 1 (CDCP1) contributes to epidermal growth factor receptor-mediated cell migration.
Epidermal growth factor (EGF) activation of the EGF receptor (EGFR) is an important mediator of cell migration, and aberrant signaling via this system promotes a number of malignancies including ovarian cancer. We have identified the cell surface glycoprotein CDCP1 as a key regulator of EGF/EGFR-induced cell migration. We show that signaling via EGF/EGFR induces migration of ovarian cancer Caov3 and OVCA420 cells with concomitant up-regulation of CDCP1 mRNA and protein. Consistent with a role in cell migration CDCP1 relocates from cell-cell junctions to punctate structures on filopodia after activation of EGFR. Significantly, disruption of CDCP1 either by silencing or the use of a function blocking antibody efficiently reduces EGF/EGFR-induced cell migration of Caov3 and OVCA420 cells. We also show that up-regulation of CDCP1 is inhibited by pharmacological agents blocking ERK but not Src signaling, indicating that the RAS/RAF/MEK/ERK pathway is required downstream of EGF/EGFR to induce increased expression of CDCP1. Our immunohistochemical analysis of benign, primary, and metastatic serous epithelial ovarian tumors demonstrates that CDCP1 is expressed during progression of this cancer. These data highlight a novel role for CDCP1 in EGF/EGFR-induced cell migration and indicate that targeting of CDCP1 may be a rational approach to inhibit progression of cancers driven by EGFR signaling including those resistant to anti-EGFR drugs because of activating mutations in the RAS/RAF/MEK/ERK pathway.
Cancer Research Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia.
Ying
Y
Dong
Mater Medical Research Institute, South Brisbane, Queensland 4101, Australia.
Yaowu
Y
He
Cancer Research Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia.
Leonore
L
de Boer
Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri 65212, and.
M Sharon
MS
Stack
Wesley Medical Centre, Auchenflower, Queensland 4066, Australia.
John W
JW
Lumley
Cancer Research Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Kelvin Grove, Queensland 4059, Australia.
Judith A
JA
Clements
Mater Medical Research Institute, South Brisbane, Queensland 4101, Australia,. Electronic address: jhooper@mmri.mater.org.au.
John D
JD
Hooper
D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007365:Intercellular Junctions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors