UniProt functional annotation for P51955



	UniProt functional annotation for P51955

UniProt code: P51955.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and 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 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGO1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Phosphorylates CEP68 and CNTLN directly or indirectly (PubMed:24554434). NEK2-mediated phosphorylation of CEP68 promotes CEP68 dissociation from the centrosome and its degradation at the onset of mitosis (PubMed:25704143). Involved in the regulation of centrosome disjunction (PubMed:26220856). {ECO:0000269|PubMed:11742531, ECO:0000269|PubMed:12857871, ECO:0000269|PubMed:14978040, ECO:0000269|PubMed:15358203, ECO:0000269|PubMed:15388344, ECO:0000269|PubMed:17283141, ECO:0000269|PubMed:17621308, ECO:0000269|PubMed:17626005, ECO:0000269|PubMed:18086858, ECO:0000269|PubMed:18297113, ECO:0000269|PubMed:20034488, ECO:0000269|PubMed:21076410, ECO:0000269|PubMed:24554434, ECO:0000269|PubMed:25704143, ECO:0000269|PubMed:26220856}.

Function: [Isoform 1]: Phosphorylates and activates NEK11 in G1/S- arrested cells. {ECO:0000269|PubMed:15161910}.

Function: [Isoform 2]: Not present in the nucleolus and, in contrast to isoform 1, does not phosphorylate and activate NEK11 in G1/S-arrested cells. {ECO:0000269|PubMed:15161910}.

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420;

Activity regulation: Isoform 1 is inhibited by ionizing radiation in the presence of PPP1CA. Its catalytic activity is inhibited by the inhibitor 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, and blocks the alphaC helix. {ECO:0000269|PubMed:15161910, ECO:0000269|PubMed:17283141, ECO:0000269|PubMed:19941817}.

Subunit: Isoform 1, isoform 2 and isoform 4 form homo- and heterodimers. Interacts with NECAB3 and HMGA2 (By similarity). Isoform 1 interacts with CDC20, CTNB1, MAD1L1, MAPK, NEK11, NPM1, NDC80, PCNT and SGO1 (PubMed:14978040, PubMed:15358203, PubMed:15388344, PubMed:15161910, PubMed:17621308, PubMed:18086858, PubMed:18297113, PubMed:20599736, PubMed:20034488). Isoform 1 interacts with STK3/MST2 (via SARAH domain) and SAV1 (via SARAH domain) (PubMed:21076410). Isoform 1 and isoform 2 interact with MAD2L1 (PubMed:20034488). Isoform 1 and isoform 4 interact with PPP1CA and PPP1CC (PubMed:15659832, PubMed:17283141). Interacts with CEP68; the interaction leads to phosphorylation of CEP68. Interacts with CNTLN; the interaction leads to phosphorylation of CNTLN (PubMed:24554434). Isoform 1 interacts with CEP85 (PubMed:26220856). {ECO:0000250|UniProtKB:O35942, ECO:0000269|PubMed:14978040, ECO:0000269|PubMed:15161910, ECO:0000269|PubMed:15358203, ECO:0000269|PubMed:15388344, ECO:0000269|PubMed:15659832, ECO:0000269|PubMed:17197699, ECO:0000269|PubMed:17283141, ECO:0000269|PubMed:17621308, ECO:0000269|PubMed:17626005, ECO:0000269|PubMed:18086858, ECO:0000269|PubMed:18297113, ECO:0000269|PubMed:20034488, ECO:0000269|PubMed:20599736, ECO:0000269|PubMed:21076410, ECO:0000269|PubMed:24554434, ECO:0000269|PubMed:26220856}.

Subcellular location: [Isoform 1]: Nucleus. Nucleus, nucleolus {ECO:0000269|PubMed:15161910}. Cytoplasm. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:14654843, ECO:0000269|PubMed:26220856}. Cytoplasm, cytoskeleton, spindle pole. Chromosome, centromere, kinetochore. Chromosome, centromere {ECO:0000250}. Note=STK3/MST2 and SAV1 are required for its targeting to the centrosome. Colocalizes with SGO1 and MAD1L1 at the kinetochore. Not associated with kinetochore in the interphase but becomes associated with it upon the breakdown of the nuclear envelope. Has a nucleolar targeting/ retention activity via a coiled-coil domain at the C-terminal end.

Subcellular location: [Isoform 2]: Cytoplasm. Note=Predominantly cytoplasmic.

Subcellular location: [Isoform 4]: Nucleus. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Note=Predominantly nuclear.

Tissue specificity: Isoform 1 and isoform 2 are expressed in peripheral blood T-cells and a wide variety of transformed cell types. Isoform 1 and isoform 4 are expressed in the testis. Up-regulated in various cancer cell lines, as well as primary breast tumors. {ECO:0000269|PubMed:11742531, ECO:0000269|PubMed:15659832}.

Induction: Expression and activity peak in the G2 phase of the mitotic cycle and decrease once the cells have entered mitosis due to degradation by the anaphase promoting complex APC/C-CDC20. In G1 phase, both isoform 1 and isoform 2 are almost undetectable. However, at the G1/S transition, there is an increase in expression of both isoforms which then remain at this increased level throughout S and G2. At the onset of mitosis, isoform 1 undergoes a rapid disappearance whereas isoform 2 continues to be present at about the same level as in G2. During the rest of mitosis, isoform 1 remains absent, while isoform 2 only begins to decline upon re-entry into the next G1 phase. {ECO:0000269|PubMed:11742531, ECO:0000269|PubMed:26220856}.

Domain: The leucine-zipper domain is required for its dimerization and activation. {ECO:0000269|PubMed:21669869}.

Ptm: Activated by autophosphorylation. Protein phosphatase 1 represses autophosphorylation and activation of isoform 1 by dephosphorylation. Phosphorylation by STK3/MST2 is necessary for its localization to the centrosome. {ECO:0000269|PubMed:17197699, ECO:0000269|PubMed:21076410}.

Disease: Retinitis pigmentosa 67 (RP67) [MIM:615565]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:24043777}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the protein kinase superfamily. NEK Ser/Thr protein kinase family. NIMA subfamily. {ECO:0000305}.

Sequence caution: Sequence=AAH65932.1; Type=Frameshift; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and 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 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGO1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Phosphorylates CEP68 and CNTLN directly or indirectly (PubMed:24554434). NEK2-mediated phosphorylation of CEP68 promotes CEP68 dissociation from the centrosome and its degradation at the onset of mitosis (PubMed:25704143). Involved in the regulation of centrosome disjunction (PubMed:26220856). {ECO:0000269\|PubMed:11742531, ECO:0000269\|PubMed:12857871, ECO:0000269\|PubMed:14978040, ECO:0000269\|PubMed:15358203, ECO:0000269\|PubMed:15388344, ECO:0000269\|PubMed:17283141, ECO:0000269\|PubMed:17621308, ECO:0000269\|PubMed:17626005, ECO:0000269\|PubMed:18086858, ECO:0000269\|PubMed:18297113, ECO:0000269\|PubMed:20034488, ECO:0000269\|PubMed:21076410, ECO:0000269\|PubMed:24554434, ECO:0000269\|PubMed:25704143, ECO:0000269\|PubMed:26220856}.



Function:		[Isoform 1]: Phosphorylates and activates NEK11 in G1/S- arrested cells. {ECO:0000269\|PubMed:15161910}.



Function:		[Isoform 2]: Not present in the nucleolus and, in contrast to isoform 1, does not phosphorylate and activate NEK11 in G1/S-arrested cells. {ECO:0000269\|PubMed:15161910}.


Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1;
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
Activity regulation:		Isoform 1 is inhibited by ionizing radiation in the presence of PPP1CA. Its catalytic activity is inhibited by the inhibitor 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, and blocks the alphaC helix. {ECO:0000269\|PubMed:15161910, ECO:0000269\|PubMed:17283141, ECO:0000269\|PubMed:19941817}.
Subunit:		Isoform 1, isoform 2 and isoform 4 form homo- and heterodimers. Interacts with NECAB3 and HMGA2 (By similarity). Isoform 1 interacts with CDC20, CTNB1, MAD1L1, MAPK, NEK11, NPM1, NDC80, PCNT and SGO1 (PubMed:14978040, PubMed:15358203, PubMed:15388344, PubMed:15161910, PubMed:17621308, PubMed:18086858, PubMed:18297113, PubMed:20599736, PubMed:20034488). Isoform 1 interacts with STK3/MST2 (via SARAH domain) and SAV1 (via SARAH domain) (PubMed:21076410). Isoform 1 and isoform 2 interact with MAD2L1 (PubMed:20034488). Isoform 1 and isoform 4 interact with PPP1CA and PPP1CC (PubMed:15659832, PubMed:17283141). Interacts with CEP68; the interaction leads to phosphorylation of CEP68. Interacts with CNTLN; the interaction leads to phosphorylation of CNTLN (PubMed:24554434). Isoform 1 interacts with CEP85 (PubMed:26220856). {ECO:0000250\|UniProtKB:O35942, ECO:0000269\|PubMed:14978040, ECO:0000269\|PubMed:15161910, ECO:0000269\|PubMed:15358203, ECO:0000269\|PubMed:15388344, ECO:0000269\|PubMed:15659832, ECO:0000269\|PubMed:17197699, ECO:0000269\|PubMed:17283141, ECO:0000269\|PubMed:17621308, ECO:0000269\|PubMed:17626005, ECO:0000269\|PubMed:18086858, ECO:0000269\|PubMed:18297113, ECO:0000269\|PubMed:20034488, ECO:0000269\|PubMed:20599736, ECO:0000269\|PubMed:21076410, ECO:0000269\|PubMed:24554434, ECO:0000269\|PubMed:26220856}.
Subcellular location:		[Isoform 1]: Nucleus. Nucleus, nucleolus {ECO:0000269\|PubMed:15161910}. Cytoplasm. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269\|PubMed:14654843, ECO:0000269\|PubMed:26220856}. Cytoplasm, cytoskeleton, spindle pole. Chromosome, centromere, kinetochore. Chromosome, centromere {ECO:0000250}. Note=STK3/MST2 and SAV1 are required for its targeting to the centrosome. Colocalizes with SGO1 and MAD1L1 at the kinetochore. Not associated with kinetochore in the interphase but becomes associated with it upon the breakdown of the nuclear envelope. Has a nucleolar targeting/ retention activity via a coiled-coil domain at the C-terminal end.
Subcellular location:		[Isoform 2]: Cytoplasm. Note=Predominantly cytoplasmic.
Subcellular location:		[Isoform 4]: Nucleus. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Note=Predominantly nuclear.
Tissue specificity:		Isoform 1 and isoform 2 are expressed in peripheral blood T-cells and a wide variety of transformed cell types. Isoform 1 and isoform 4 are expressed in the testis. Up-regulated in various cancer cell lines, as well as primary breast tumors. {ECO:0000269\|PubMed:11742531, ECO:0000269\|PubMed:15659832}.
Induction:		Expression and activity peak in the G2 phase of the mitotic cycle and decrease once the cells have entered mitosis due to degradation by the anaphase promoting complex APC/C-CDC20. In G1 phase, both isoform 1 and isoform 2 are almost undetectable. However, at the G1/S transition, there is an increase in expression of both isoforms which then remain at this increased level throughout S and G2. At the onset of mitosis, isoform 1 undergoes a rapid disappearance whereas isoform 2 continues to be present at about the same level as in G2. During the rest of mitosis, isoform 1 remains absent, while isoform 2 only begins to decline upon re-entry into the next G1 phase. {ECO:0000269\|PubMed:11742531, ECO:0000269\|PubMed:26220856}.
Domain:		The leucine-zipper domain is required for its dimerization and activation. {ECO:0000269\|PubMed:21669869}.
Ptm:		Activated by autophosphorylation. Protein phosphatase 1 represses autophosphorylation and activation of isoform 1 by dephosphorylation. Phosphorylation by STK3/MST2 is necessary for its localization to the centrosome. {ECO:0000269\|PubMed:17197699, ECO:0000269\|PubMed:21076410}.
Disease:		Retinitis pigmentosa 67 (RP67) [MIM:615565]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269\|PubMed:24043777}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the protein kinase superfamily. NEK Ser/Thr protein kinase family. NIMA subfamily. {ECO:0000305}.
Sequence caution:		Sequence=AAH65932.1; Type=Frameshift; Evidence={ECO:0000305};