title: VHL inactivation induces HEF1 and Aurora kinase A.
abstract: 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.
authors.affiliation: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
authors.forename: Jianyong
authors.initials: J
authors.lastname: Xu
authors.forename: Huapeng
authors.initials: H
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Jiayin
authors.initials: J
authors.lastname: Yang
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Harten
authors.forename: Deepa
authors.initials: D
authors.lastname: Shukla
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Duanqing
authors.initials: D
authors.lastname: Pei
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Esteban
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000503:physiopathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000032:analysis; D012680:Sensitivity and Specificity; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099942:NEDD9 protein, human; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases