title: VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKC{delta}-driven migration.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Center for Clinical Sciences Research, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Olga V
authors.initials: OV
authors.lastname: Razorenova
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Finger
authors.forename: Renata
authors.initials: R
authors.lastname: Colavitti
authors.forename: Sophia B
authors.initials: SB
authors.lastname: Chernikova
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Boiko
authors.forename: Charles K F
authors.initials: CK
authors.lastname: Chan
authors.forename: Adam
authors.initials: A
authors.lastname: Krieg
authors.forename: Barbara
authors.initials: B
authors.lastname: Bedogni
authors.forename: Edward
authors.initials: E
authors.lastname: LaGory
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.forename: Marianne
authors.initials: M
authors.lastname: Broome-Powell
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D000951:Antigens, Neoplasm; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D009363:Neoplasm Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051745:Protein Kinase C-delta; C497446:VHL protein, human