Nek family of kinases in cell cycle, checkpoint control and cancer

Deregulation of the cell cycle is a hallmark of neoplastic transformation and plays a central role in the initiation and progression of cancer. The fidelity of the cell cycle is tightly maintained by numerous regulatory proteins, most notably kinases. Cyclin dependent kinases (CDK), in complex with their partner cyclins, are considered the master regulators of the cell cycle. Members of the Aurora and Polo families are also critical components of the cell cycle machinery. More recently, the NimA related kinase (Nek) family protein kinases begun to emerge as important players in regulation of the eukaryotic cell cycle both during normal cell cycle progression and in response to genotoxic stress. This review aims to provide a systematic account of our understanding of Nek kinase biology and their involvement in disease drawn from biochemical, cell biology, animal model and genetic studies.The filamentous fungus Aspergillus nidulans Never in mitosis A (NimA) is the founding member of the (NEK) family of serine-threonine kinases, and an essential regulator of mitosis [1,2]. NimA is required for transport of active CDC2 into the nucleus thus allowing initiation of mitosis [3]. Moreover, NimA promotes mitotic chromosome condensation through phosphorylation of histone H3 at serine 10 and may regulate nuclear membrane fission during mitotic exit [4,5].The critical role for NimA in promoting cell cycle progression in A.nidulans raised the possibility that homologues of NimA existed in higher eukaryotes. Consistent with this, overexpression of NimA in S.pombe and in human HeLa cells induced chromosome condensation in the absence of other mitotic events, such as the microtubule spindle assembly or Cdc2 activation [6,7]. Indeed, NimA-related kinases have been identified throughout higher eukaryotes with a significant expansion of the family through evolution. While a single NimA homologue exists in yeast, 2, 4 and 11 NimA-related kinases were identified in D.melanogaster, C.ele