VHL inactivation induces HEF1 and Aurora kinase A

J Am Soc Nephrol. 2010 Dec;21(12):2041-6. doi: 10.1681/ASN.2010040345. Epub 2010 Sep 23.


The ciliary hypothesis for cystic renal diseases postulates that most of these conditions result from abnormalities in the primary cilium, a microtubule-based structure that acts as a sensor for extracellular cues. Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes to renal cysts and clear cell renal cell carcinoma. VHL plays a critical role in the formation of primary cilia in kidney epithelium, but the underlying mechanisms are poorly understood. Here, we demonstrate that VHL inactivation induces HEF1/Cas-L/NEDD9 and Aurora kinase A via the stabilization of hypoxia-inducible factors 1 and 2. Aurora kinase A is a mitotic kinase commonly upregulated in cancer that causes regression of the primary cilium by promoting histone deacetylase-dependent tubulin depolymerization of the ciliary axoneme. HEF1/Cas-L/NEDD9 is a component of focal adhesions that has a prominent role in inducing metastasis and that colocalizes with Aurora kinase A at the centrosome, thereby enhancing the harmful effect of Aurora kinase A on the cilium. Suppression of this pathway improved the formation of primary cilia and reduced cell motility in VHL-defective renal cancer cells. Our results highlight the gatekeeper role of VHL in the kidney epithelium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aurora Kinase A
  • Aurora Kinases
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / physiopathology
  • Cell Line, Tumor
  • Cells, Cultured
  • Cilia / metabolism
  • Cilia / physiology
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Humans
  • Kidney Diseases, Cystic / genetics*
  • Kidney Diseases, Cystic / physiopathology
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / physiopathology
  • Male
  • Phosphoproteins / metabolism*
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA, Small Interfering / analysis
  • Sensitivity and Specificity
  • Von Hippel-Lindau Tumor Suppressor Protein / drug effects
  • Von Hippel-Lindau Tumor Suppressor Protein / genetics*
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism


  • Adaptor Proteins, Signal Transducing
  • NEDD9 protein, human
  • Phosphoproteins
  • RNA, Small Interfering
  • Von Hippel-Lindau Tumor Suppressor Protein
  • AURKA protein, human
  • Aurora Kinase A
  • Aurora Kinases
  • Protein Serine-Threonine Kinases