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)

Function: - serine/threonine protein kinase involved in a) control of centrosome separation & bipolar spindle formation in mitotic cells b) 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 Cofactor: Mg⁺² 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 - isoform 1 disappears rapidly - isoform 2 is expression remains at about the same level as in G2 - during the rest of mitosis - isoform 1 remains absent - isoform 2 begins to decline upon re-entry into the next G1 phase

Properties

SIZE: entity length = 445 aa MW = 52 kD COMPARTMENT: cytoplasm nuclear membrane STATE: active state MOTIF: kinase domain SITE: 8-271 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 14-22 ATP-binding site NAME: ATP-binding site SITE: 37-37 aspartate residue {D141} Thr phosphorylation site {T170} Ser phosphorylation site {S171} Thr phosphorylation site {T175} Thr phosphorylation site {T179} Ser phosphorylation site {S184} Ser phosphorylation site {S241} PCNT interaction {264-445} MOTIF: Ser phosphorylation site {S296} Ser phosphorylation site {S299} Ser phosphorylation site {S300} coiled coil {303-362} leucine zipper SITE: 306-334 FOR-BINDING-VIA: leucine zipper domain {329-445} domain {333-370} Ser phosphorylation site {S356} Ser phosphorylation site {S365} Ser phosphorylation site {S387} Ser phosphorylation site {S390} Ser phosphorylation site {S397} Ser phosphorylation site {S402} domain {403-439} coiled coil {406-430} Ser phosphorylation site {S406} Ser phosphorylation site {S428} Ser phosphorylation site {S438}

Database Correlations

OMIM 604043 UniProt P51955 Pfam PF00069 Entrez Gene 4751 Kegg hsa:4751 ENZYME 2.7.11.1

References

UniProt :accession P51955