NEK2: Human never in mitosis gene A-related kinase 2
PDB Code: 2JAV
Nek2 was first identified as a cell cycle mutant (nimA) which arrested in late G2 phase in the multicellular filamentous fungus Aspergillus nidulans. The protein has later been cloned and identified as a Ser/Thr kinase called NIMA (Never in Mitosis). Surprisingly deletion of NIMA function leads to G2 arrest even in the presence of fully active Cdc2 kinase and mutational analysis subsequently also showed that activation of NIMA is Cdc2 dependent.
Nek2, a human NIMA homolog, is a 48-kDa protein with a catalytic kinase domain localized at the N-terminus of the molecule and a regulatory domain at the C-terminus. Two coiled coils regions are present within the regulatory domain. Nek2 regulation involves homodimerization through a leucine zipper coiled-coil motif which probably facilitates autophosphorylation in trans resulting in enzymatic activation. Autophosphorylation is however not the only mode of kinase activation: A study investigating meiotic progression in mouse spermatocytes showed that the MAPK/p90Rsk2 pathway is required to control Nek2 activation. Nek2 protein level is low in G1 and increases throughout S and G2. The protein is rapidly degraded at the pro-metaphase to metaphase transition of mitosis in an APC/C-Cdc20-dependent manner and with kinetics similar to Cyclin A.
Nek2 is a centrosomal protein that upon overexpression causes centrosome splitting, an event that is different from the physiological separation of centrosomes occurring at G2/M. During centrosome splitting mother and daughter centrioles are separated by > 2 mm, but this event is not followed by recruitment of motor proteins at centrosomes and assembly of a functional mitotic spindle. Nek2-driven centrosome splitting is likely accomplished through phosphorylation of C-Nap1, a protein interacting with Nek2 and associated with the proximal ends of mother and daughter centrioles.
Depletion of Nek2 by RNAi in mouse embryos revealed defects beginning at the second mitotic division. Many blastomeres arrested during M phase with abnormal spindle structures suggesting that Nek2 is essential for embryonic mitosis, especially for proper segregation of chromosomes.
Nek2 is overexpressed in a number of tumour cells including cell lines derived from Ewing ’s tumours (a paediatric osteosarcoma), non-Hodgkin lymphoma, breast, cervical and prostate carcinomas, lymphomas and invasive ductal carcinoma (IDC). In addition there is a correlation of increased Nek2 expression and poor prognosis of the patients. The role of Nek2 in tumour development makes this protein an interesting target for the development of inhibitors for the treatment of cancer.
We determined the structure of Nek2 in complex with the pyrrole-indolinone compound ( 5-[(Z)- (5-Chloro- 2-oxo-1,2- dihydro-3H- indol-3-ylidene) methyl]-N- [2-(diethylamino) ethyl]-2,4- dimethyl-1H- pyrrole-3-carboxamide ). This inhibitor has been described as a cell-permeable compound that acts as a potent and ATP-competitive tyrosine kinase receptor and angiogenic inhibitor that exhibits activity for PDGFRβ (IC50 = 3 nM), VEGFR2 (IC50 = 27 nM), FGFR1 (IC50 = 170 nM), and Kit family members (IC50 ~ 10-500 nM) over EGFR (IC50>20 µM). The inhibitor has been reported to display anti-proliferative and pro-apoptotic properties in tumor cells and a related compound (SU11248, sunitinib malate) has been recently approved for the treatment of metastatic renal cancer.
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