Early studies in lower eukaryotes have identified the role of members of the NimA-associated kinase (Nek) protein kinase family in cell cycle control. The expansion of the Nek family throughout evolution has been accompanied by their extensive involvement in checkpoint regulation and ciliary biology. In addition, mutations in members of the Nek family have been identified as driving forces for cilia and cancer development. Recent advances in using mouse genetics and RNAi-mediated knockout to study the physiological roles of members of the Nek family have revealed the complex links of Nek family members to basic biological processes.
The filamentous fungus Aspergillus nidulans (Apergillus nidulans) is a founding member of the serine-threonine kinase (NEK) family and an important regulator of mitosis. NimA is necessary for the transport of active CDC2 into the nucleus, so it can initiate mitosis. In addition, NimA promotes mitotic chromosome condensation by phosphorylating histone H3 at serine 10 and may regulate nuclear membrane fission during mitotic withdrawal. The key role of NimA in promoting the cell cycle progression of Aspergillus nidulans increases the likelihood that NimA homologues will be present in higher eukaryotes. Consistent with this, overexpression of NimA in S.pombe and human HeLa cells induces chromosome agglutination in the absence of other mitotic events, such as microtubule spindle assembly or Cdc2 activation. In fact, NimA-related kinases have been identified throughout higher eukaryotes, and the family has significantly expanded through evolution. Despite the presence of a single NimA homologue in yeast, 2, 4, and 11 NimA-related kinases were identified in Drosophila melanogaster, nematodes, and mammals, respectively. NimA consists of an N-terminal catalytic domain, a helical coiled domain that mediates oligomerization, and a PEST sequence that participates in ubiquitin-dependent proteolysis, which may be the process necessary for A. nidulans to exit mitosis. NimA kinase activity shows preference for phosphorylated residues (FR/KR/KS/T, underlined target residues) for N-terminal hydrophobic residues and phenylalanine at the -3 position. Despite the low overall sequence homology, the tissue characteristics of NimA are widely retained in mammalian Nek kinases. For example, except Nek10, all Nek kinases contain an N-terminal catalytic domain, while Nek4, 6 and 7 are the only family members that do not contain a coiled-coil motif. In addition, 6 of the 11 mammalian Nek kinases have putative PEST sequences.
In addition to established functions during mitosis, certain Nek kinases also participate in cell cycle regulation after genotoxic stress. All eukaryotic cells have multiple molecular mechanisms to identify and repair damaged DNA and maintain genomic integrity. An important aspect of this process is activating checkpoints and inducing cell cycle arrest to give cells time to repair the damage. Cell cycle arrest can be triggered during the G1/S, S and S2/G2/M phases of the cell cycle due to endogenous (such as a stalled replication fork) or exogenous agents (including ultraviolet (UV) radiation, ionizing radiation) Damage (IR), reactive oxygen species (ROS) and certain chemotherapeutic agents. After successful repair, the cells will re-enter the cell cycle.
Early phenotypic analysis of the mutant fungus of the prototype Nek kinase revealed that it is involved in cell cycle regulation. Subsequent research in yeast and frogs, and more recently in mice, found that members of the Nek family have fascinating complexity in controlling the cell cycle and its checkpoints. In addition, mutations in members of the Nek family have been identified as drivers of cilia and cancer development. Recent emergence of the comprehensive cancer genome highlights that certain members of the Nek family are targets for frequent mutations. Despite significant advances in understanding the biology of the Nek family, the most interesting work has not been completed due to gene knockouts, RNAi-mediated knockouts, naturally occurring mutations, and the emergence of xenograft tumor models.
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