VHL Inactivation Induces HEF1 and Aurora Kinase A

• Published in: Journal of the American Society of Nephrology 2010-12, Vol.21 (12), p.2041-2046
• Main Authors: JIANYONG XU, HUAPENG LI, ESTEBAN, Miguel A, BO WANG, YAN XU, JIAYIN YANG, XIAOFEI ZHANG, HARTEN, Sarah K, SHUKLA, Deepa, MAXWELL, Patrick H, DUANQING PEI
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Aurora Kinase A; Aurora Kinases; Biological and medical sciences; Brief Communications; 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; Kidneys; Male; Medical sciences; Nephrology. Urinary tract diseases; Phosphoproteins - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; RNA, Small Interfering - analysis; Sensitivity and Specificity; Tumors of the urinary system; Von Hippel-Lindau Tumor Suppressor Protein - drug effects; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2010040345

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.