NIMA-related kinases in cell cycle control and human disease. (360G-Wellcome-082828_Z_07_Z)

NIMA, a serine/threonine kinase, was identified in a genetic screen as an essential regulator of mitotic entry in Aspergillus nidulans. Like other important cell cycle regulators, NIMA-related kinases are conserved across all eukaryotes. The human genome encodes eleven NIMA-related kinases (Nek1-Nek11) that form a distinct family representing about 2% of the entire kinome. We have established an international track record in studying the regulation and function of Nek2, the most closely related sequence to NIMA, demonstrating that it is a cell cycle-dependent kinase that localizes to the centrosome, regulates spindle formation upon mitotic entry and is overexpressed in human cancer. Much less is known about the other human Neks although evidence is emerging from our group and others that Nek6, Nek7 and Nek9 also regulate mitosis. Surprisingly, Nek1 and Nek8 are mutated in mouse models of polycystic kidney disease (PKD), a disease that frequently results from ciliary defects. Hence, an underlying theme for Nek kinase function may be in coordinating cell proliferation and ciliogenesis through microtubule regulation. The aim of this programme of research is to test this hypothesis by undertaking a comprehensive analysis of the regulation and function of human Neks in dividing and differentiated cells.