The VHL tumor suppressor:: Riding tandem with GSK3β in primary cilium maintenance

Amongst other clinical manifestations, patients with the von Hippel - Lindau ( VHL) cancer syndrome are predisposed to develop kidney cysts, which are considered to be precursor lesions of clear cell renal cell carcinoma (ccRCC). Recent evidence has highlighted an unexpected function of the VHL tumor suppressor protein (pVHL) in maintaining the structural integrity of the primary cilium, a microtubule-based cellular antenna important for suppression of uncontrolled proliferation of kidney epithelial cells and cyst formation. Intriguingly, this function of pVHL is directly linked to its capacity to regulate the micro tubule cytoskeleton independent of its well-characterized role in the degradation of hypoxia inducible factor alpha (HIF alpha) subunits. However, loss of pVHL alone does not suffice for a cell to lose the primary cilium. Other pathways need to be additionally inactivated, including one involving glycogen synthase kinase 3 beta (GSK3 beta). These new findings draw attention to a primary cilium maintenance network as new territory for pVHL tumor suppressive activity and have implications for understanding the development of kidney pathology in the setting of VHL disease.