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A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCδ, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.

Original publication

DOI

10.1073/pnas.1011777108

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

01/02/2011

Volume

108

Pages

1931 - 1936

Keywords

Antigens, CD, Carcinoma, Renal Cell, Cell Adhesion Molecules, Humans, Kidney Neoplasms, Mutation, Neoplasm Proteins, Phosphorylation, Protein Kinase C-delta, Signal Transduction, Up-Regulation, Von Hippel-Lindau Tumor Suppressor Protein