serine/threonine protein kinase Nek6; never in mitosis A-related kinase 6; NimA-related protein kinase 6; protein kinase SID6-1512 (NEK6)

Function: - protein kinase plays an important role in mitotic cell cycle progression - required for chromosome segregation at metaphase-anaphase transition, robust mitotic spindle formation & cytokinesis - phosphorylates ATF4, CIR1, PTN, RAD26L, RBBP6, RPS7, RPS6KB1, TRIP4, STAT3 & histones H1 & H3 - phosphorylates KIF11 to promote mitotic spindle formation - role in G2/M phase cell cycle arrest induced by DNA damage - inhibition of activity results in apoptosis - may contribute to tumorigenesis by suppressing p53/TP53- induced cancer cell senescence - binding to NEK9 stimulates its activity by releasing the autoinhibitory function of Tyr-108 - autophosphorylated - phosphorylation at Ser-206 is required for its activation - phosphorylated upon IR or UV-induced DNA damage - phosphorylated by CHK1 & CHK2 - interaction with APBB1 - down-regulates phosphorylation at Thr-210 - interacts with STAT3 & RPS6KB1 (putative) - interacts with NEK9, predominantly in mitosis - interacts with KIF11 (via C-terminus) - interacts with APBB1 (via WW domain) - interacts with ANKRA2, ATF4, ARHGAP33, CDC42, CIR1, PRAM1, PTN, PRDX3, PIN1, RAD26L, RBBP6, RPS7 & TRIP4 Cofactor: Mg⁺² Structure: - displays an autoinhibited conformation: Tyr-108 side chain points into the active site, interacts with the activation loop, & blocks the alphaC helix - the autoinhibitory conformation is released upon binding with NEK9 - belongs to the protein kinase superfamily, NEK Ser/Thr protein kinase family, NIMA subfamily - contains 1 protein kinase domain Compartment: - cytoplasm, nucleus, nuclear speckle - cytoskeleton, centrosome, spindle pole - colocalizes with APBB1 at the nuclear speckles - colocalizes with PIN1 in the nucleus - colocalizes with ATF4, CIR1, ARHGAP33, ANKRA2, CDC42, NEK9, RAD26L, RBBP6, RPS7, TRIP4, RELB & PHF1 in the centrosome - localizes to spindle microtubules in metaphase & anaphase & to the midbody during cytokinesis Alternative splicing: named isoforms=4 Expression: - ubiquitous - highest expression in heart & skeletal muscle - up-regulated during the M phase of cell cycle progression - down-regulated in both replicative senescence & premature senescence of cancer cells Pathology: - up-regulated in a variety of malignant cancers, such as breast cancer, colorectal carcinoma, lung carcinoma, & gastric cancers

Properties

SIZE: entity length = 313 aa MW = 36 kD COMPARTMENT: cytoplasm cell nucleus STATE: active state MOTIF: multiple interactions {1-44} MOTIF: Thr phosphorylation site {T35} Ser phosphorylation site {S37} kinase domain SITE: 45-310 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 51-59 ATP-binding site NAME: ATP-binding site SITE: 74-74 tyrosine residue {108} aspartate residue {D172} Ser phosphorylation site {S198} Ser phosphorylation site {S199} Thr phosphorylation site {T201} Thr phosphorylation site {T202} Ser phosphorylation site {S206} Thr phosphorylation site {T210} APBB1 interaction {267-270}

Database Correlations

OMIM 604884 UniProt Q9HC98 Pfam PF00069 Entrez Gene 10783 Kegg hsa:10783 ENZYME 2.7.11.1

References

UniProt :accession Q9HC98