“Stop Ne(c)king around”: How interactomics contributes to functionally characterize Nek family kinases

Abstract

Aside from Polo and Aurora, a third but less studied kinase family involved in mitosis regulation is the never in mitosis-gene A (NIMA)-related kinases (Neks). The founding member of this family is the sole member NIMA of Aspergillus nidulans, which is crucial for the initiation of mitosis in that organism. All 11 human Neks have been functionally assigned to one of the three core functions established for this family in mammals: (1) centrioles/mitosis; (2) primary ciliary function/ciliopathies; and (3) DNA damage response (DDR). Recent findings, especially on Nek 1 and 8, showed however, that several Neks participate in parallel in at least two of these contexts: primary ciliary function and DDR. In the core section of this in-depth review, we report the current detailed functional knowledge on each of the 11 Neks. In the discussion, we return to the cross-connections among Neks and point out how our and other groups’ functional and interactomics studies revealed that most Neks interact with protein partners associated with two if not all three of the functional contexts. We then raise the hypothesis that Neks may be the connecting regulatory elements that allow the cell to fine tune and synchronize the cellular events associated with these three core functions. The new and exciting findings on the Nek family open new perspectives and should allow the Neks to finally claim the attention they deserve in the field of kinases and cell cycle biology.

Keywords: Cell cycle, Mitosis, DNA damage response, Protein interactions, Kinases

Core tip: Never in mitosis-gene A (NIMA)-related kinases (Neks) are a family of 11 human kinases involved in cell cycle regulation. This article represents an in-depth review of the current knowledge on the function of each of the 11 human Nek kinases. Furthermore, we present arguments in the discussion of how systems biology, especially interactomics, helped to uncover that the majority of Neks are involved in more than one of the three Neks core functions: (1) centrioles/mitosis; (2) primary ciliary function/ciliopathies; and (3) the DNA damage response. Possibly, the Neks act on a higher regulatory level which may control the core functions.