The Cell Surface Glycoprotein CUB Domain-containing Protein 1 (CDCP1) Contributes to Epidermal Growth Factor Receptor-mediated Cell Migration

• Published in: The Journal of biological chemistry Vol. 287; no. 13; pp. 9792 - 9803
• Main Authors: Dong, Ying, He, Yaowu, de Boer, Leonore, Stack, M. Sharon, Lumley, John W., Clements, Judith A., Hooper, John D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.03.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Antigens, CD - biosynthesis; Antigens, CD - genetics; Antigens, Neoplasm; Antineoplastic Agents - pharmacology; CDCP1; Cell Adhesion Molecules - biosynthesis; Cell Adhesion Molecules - genetics; Cell Biology; Cell Line, Tumor; Cell Migration; Cell Movement; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epidermal Growth Factor - genetics; Epidermal Growth Factor - metabolism; Epidermal Growth Factor Receptor (egfr); ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Intercellular Junctions - genetics; Intercellular Junctions - metabolism; Intercellular Junctions - pathology; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Mutation; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Ovarian Cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Protein Structure; Pseudopodia - genetics; Pseudopodia - metabolism; Pseudopodia - pathology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Up-Regulation; Cell Migration; Ovarian Cancer; CDCP1; Protein Structure; Epidermal Growth Factor Receptor (egfr); Cell Biology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.335448

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. Epidermal growth factor (EGF) activates EGF receptor (EGFR) to promote cell migration and cancer. EGF/EGFR up-regulates the cell surface glycoprotein CDCP1, and blockade of CDCP1 reduces EGF/EGFR-induced migration of ovarian cancer cells lines. CDCP1 is expressed by ovarian tumors. CDCP1 contributes to EGF/EGFR-induced cell migration. Targeting of CDCP1 may be a rational approach to inhibit cancers mediated by EGFR.