VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration

Olga V. Razorenova, Elizabeth C. Finger, Renata Colavitti, Sophia B. Chernikova, Alexander D. Boiko, Charles K.F. Chan, Adam Krieg, Barbara Bedogni, Edward LaGory, Irving L. Weissman, Marianne Broome-Powell, Amato J. Giaccia

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1931-1936
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number5
DOIs
StatePublished - Feb 1 2011
Externally publishedYes

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Renal Cell Carcinoma
Up-Regulation
Hypoxia-Inducible Factor 1
Crk-Associated Substrate Protein
Scirrhous Adenocarcinoma
Neoplasm Metastasis
Focal Adhesion Protein-Tyrosine Kinases
Kidney Neoplasms
Protein Domains
Genes
Signal Transduction
Neoplasms
Prostatic Neoplasms
Proteins
Phosphorylation
Mutation
Survival

ASJC Scopus subject areas

  • General

Cite this

VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration. / Razorenova, Olga V.; Finger, Elizabeth C.; Colavitti, Renata; Chernikova, Sophia B.; Boiko, Alexander D.; Chan, Charles K.F.; Krieg, Adam; Bedogni, Barbara; LaGory, Edward; Weissman, Irving L.; Broome-Powell, Marianne; Giaccia, Amato J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 5, 01.02.2011, p. 1931-1936.

Research output: Contribution to journalArticle

Razorenova, OV, Finger, EC, Colavitti, R, Chernikova, SB, Boiko, AD, Chan, CKF, Krieg, A, Bedogni, B, LaGory, E, Weissman, IL, Broome-Powell, M & Giaccia, AJ 2011, 'VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 5, pp. 1931-1936. https://doi.org/10.1073/pnas.1011777108
Razorenova, Olga V. ; Finger, Elizabeth C. ; Colavitti, Renata ; Chernikova, Sophia B. ; Boiko, Alexander D. ; Chan, Charles K.F. ; Krieg, Adam ; Bedogni, Barbara ; LaGory, Edward ; Weissman, Irving L. ; Broome-Powell, Marianne ; Giaccia, Amato J. / VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 5. pp. 1931-1936.
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AU - Broome-Powell, Marianne

AU - Giaccia, Amato J.

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