serine/threonine protein kinase Nek2; HSPK 21; Never in mitosis A-related kinase 2; NimA-related protein kinase 2; NimA-like protein kinase 1 (NEK2, NEK2A, NLK1)
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Function
- serine/threonine protein kinase involved in
- control of centrosome separation & bipolar spindle formation in mitotic cells
- chromatin condensation in meiotic cells
- regulates centrosome separation (essential for the formation of bipolar spindles & high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 & NINL, resulting in their displacement from the centrosomes
- regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80.
- involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 & MAD2L1
- plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2
- phosphorylates: PPP1CC; SGOL1; NECAB3 & NPM1
- essential for localization of MAD2L1 to kinetochore & MAPK1 & NPM1 to the centrosome
- isoform 1 phosphorylates & activates NEK11 in G1/S-arrested cells
- isoform 2, which is not present in the nucleolus, does not
- isoform 1 is inhibited by ionizing radiation in the presence of PPP1CA
- catalytic activity is inhibited by the CCT241950
- in the presence of this inhibitor, displays an autoinhibited conformation: Tyr-70 side chain points into the active site, interacts with the activation loop, & blocks the alphaC helix
- activated by autophosphorylation
- protein phosphatase 1 represses autophosphorylation & activation of isoform 1 by dephosphorylation
- phosphorylation by STK3/MST2 is necessary for its localization to the centrosome
- isoform 1, isoform 2 & isoform 4 form homodimers & heterodimers
- interacts with NECAB3 & HMGA2 (putative)
- isoform 1 interacts with CDC20, CTNB1, MAD1L1, MAPK, NEK11, NPM1, NDC80, PCNT & SGOL1
- isoform 1 interacts with STK3/MST2 (via SARAH domain) & SAV1 (via SARAH domain)
- isoform 1 & isoform 2 interact with MAD2L1.
- isoform 1 & isoform 4 interact with PPP1CA & PPP1CC
Structure
- the leucine-zipper domain is required for its dimerization & activation
- belongs to the protein kinase superfamily, NEK Ser/Thr protein kinase family, NIMA subfamily
- contains 1 protein kinase domain
Compartment
- isoform 1:
- nucleus, nucleolus
- cytoplasm, cytoskeleton
- centrosome, spindle pole, centromere, kinetochore
- STK3/MST2 & SAV1 are required for its targeting to the centrosome
- co-localizes with SGOL1 & MAD1L1 at the kinetochore
- not associated with kinetochore in the interphase but becomes associated with it upon breakdown of the nuclear envelope
- nucleolar targeting/retention activity via a coiled-coil domain at the C-terminal end
- isoform 2: predominantly cytoplasmic
- isoform 4:
- nucleus
- cytoplasm, cytoskeleton, centrosome
- predominantly nuclear
Alternative splicing
named isoforms=4
Expression
- isoform 1 & isoform 2 are expressed in peripheral blood T-cells & a wide variety of transformed cell types
- isoform 1 & isoform 4 are expressed in the testis
- up- regulated in various cancer cell lines, & in breast cancer
- expression & activity peak in G2 phase of the cell cycle & decrease once the cells have entered mitosis due to degradation by the anaphase promoting complex APC/C-CDC20
- in G1 phase, both isoform 1 & isoform 2 are almost undetectable
- at the G1/S transition, expression increases & is sustained throughout S & G2
- at the onset of mitosis
- during the rest of mitosis