CUB-domain-containing protein 1 (CDCP1) activates Src to promote melanoma metastasis.

TitleCUB-domain-containing protein 1 (CDCP1) activates Src to promote melanoma metastasis.
Publication TypeJournal Article
Year of Publication2011
AuthorsLiu, H, Ong, S-E, Badu-Nkansah, K, Schindler, J, White, FM, Hynes, RO
JournalProc Natl Acad Sci U S A
Date Published2011 Jan 25
KeywordsAnimals, Antigens, CD, Blotting, Western, Cell Adhesion, Cell Adhesion Molecules, Cell Line, Tumor, Cell Membrane, Cell Movement, Cell Proliferation, Enzyme Activation, Fluorescent Antibody Technique, HEK293 Cells, Humans, Lung Neoplasms, Melanoma, Melanoma, Experimental, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Neoplasm Proteins, Pyrimidines, src-Family Kinases, Tandem Mass Spectrometry, Thiazoles, Transplantation, Heterologous

We report the application of quantitative mass spectrometry to identify plasma membrane proteins differentially expressed in melanoma cells with high vs. low metastatic abilities. Using stable isotope labeling with amino acids in culture (SILAC) coupled with nanospray tandem mass spectrometry, we identified CUB-domain-containing protein 1 (CDCP1) as one such differentially expressed transmembrane protein. CDCP1 is not only a surface marker for cells with higher metastatic potential, but also functionally involved in enhancing tumor metastasis. Overexpression of CDCP1 also correlates with activation of Src. Pharmacological reagents, PP2 and Dasatinib, which block Src family kinase activation, blocked scattered growth of CDCP1-overexpressing cells in 3D Matrigel culture, suggesting that CDCP1 might function through the activation of Src-family kinases (SFKs). This hypothesis was further supported by mutational studies of CDCP1. Whereas wild-type CDCP1 enhances Src activation, point mutation Y734F abolishes in vitro dispersive growth in 3D culture and in vivo metastasis-enhancing activities of CDCP1. In addition, the Y734F mutation also eliminated enhanced Src activation. Thus, this work provides molecular mechanisms for the metastasis-enhancing functions of CDCP1.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID21220330
PubMed Central IDPMC3029734
Grant ListU54-CA112967 / CA / NCI NIH HHS / United States
U54-CA126515 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States