UniProt functional annotation for P24941



	UniProt functional annotation for P24941

UniProt code: P24941.

Organism: Homo sapiens (Human).

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

Function: Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). Phosphorylates CDK2AP2 (PubMed:12944431). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878). {ECO:0000250|UniProtKB:P97377, ECO:0000269|PubMed:10499802, ECO:0000269|PubMed:10884347, ECO:0000269|PubMed:10995386, ECO:0000269|PubMed:10995387, ECO:0000269|PubMed:11051553, ECO:0000269|PubMed:11113184, ECO:0000269|PubMed:12944431, ECO:0000269|PubMed:15800615, ECO:0000269|PubMed:17495531, ECO:0000269|PubMed:18372919, ECO:0000269|PubMed:19966300, ECO:0000269|PubMed:20079829, ECO:0000269|PubMed:20147522, ECO:0000269|PubMed:20195506, ECO:0000269|PubMed:20935635, ECO:0000269|PubMed:21262353, ECO:0000269|PubMed:21319273, ECO:0000269|PubMed:21596315, ECO:0000269|PubMed:28666995, ECO:0000269|PubMed:29203878}.

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=2.7.11.22; Evidence={ECO:0000269|PubMed:1396589, ECO:0000269|PubMed:28666995, ECO:0000269|PubMed:9030781};

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=2.7.11.22; Evidence={ECO:0000269|PubMed:1396589, ECO:0000269|PubMed:28666995, ECO:0000269|PubMed:9030781};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:21565702}; Note=Binds 2 Mg(2+) ions. {ECO:0000269|PubMed:21565702};

Activity regulation: Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-160 activates it (PubMed:1396589). Inhibited by 1,25-dihydroxyvitamin D(3) (1,25- (OH)(2)D(3)), AG-024322, N-(4-Piperidinyl)-4-(2,6- dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), R547 (Ro- 4584820), purine, pyrimidine and pyridine derivatives, 2- aminopyrimidines, paullones, thiazo derivatives, macrocyclic quinoxalin-2-one, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5- a]pyrimidine, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9- isopropylpurine (roscovitine, seliciclib and CYC202), SNS-032 (BMS- 387032), triazolo[1,5-a]pyrimidines, staurosporine and olomoucine. Stimulated by MYC. Inactivated by CDKN1A (p21). {ECO:0000269|PubMed:1396589, ECO:0000269|PubMed:20147522, ECO:0000269|PubMed:28666995, ECO:0000269|PubMed:9030781, ECO:0000269|PubMed:9334743}.

Subunit: Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 (By similarity). Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC (PubMed:15611625). Interaction with SPDYA promotes kinase activation via a conformation change that alleviates obstruction of the substrate-binding cleft by the T-loop (PubMed:28666995). Found in a complex with both SPDYA and CDKN1B/KIP1 (PubMed:12972555, PubMed:28666995). Binds to RB1 and CDK7. Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Associated with PTPN6 and beta-catenin/CTNNB1. Interacts with CACUL1. May interact with CEP63. Interacts with ANKRD17. Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Forms a ternary complex with CCNA2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements (PubMed:8684460). Interacts with cyclins A, B1, B3, D, or E (PubMed:10499802, PubMed:10884347, PubMed:12185076, PubMed:23781148). Interacts with CDK2AP2 (PubMed:23781148). {ECO:0000250|UniProtKB:P97377, ECO:0000250|UniProtKB:Q63699, ECO:0000269|PubMed:10499802, ECO:0000269|PubMed:10884347, ECO:0000269|PubMed:11980914, ECO:0000269|PubMed:12185076, ECO:0000269|PubMed:12839962, ECO:0000269|PubMed:12972555, ECO:0000269|PubMed:15107404, ECO:0000269|PubMed:15178429, ECO:0000269|PubMed:15611625, ECO:0000269|PubMed:16325401, ECO:0000269|PubMed:17095507, ECO:0000269|PubMed:17373709, ECO:0000269|PubMed:17495531, ECO:0000269|PubMed:17570665, ECO:0000269|PubMed:17937404, ECO:0000269|PubMed:18656911, ECO:0000269|PubMed:19445729, ECO:0000269|PubMed:19829063, ECO:0000269|PubMed:21262353, ECO:0000269|PubMed:21406398, ECO:0000269|PubMed:21565702, ECO:0000269|PubMed:23711367, ECO:0000269|PubMed:23781148, ECO:0000269|PubMed:28666995, ECO:0000269|PubMed:7630397, ECO:0000269|PubMed:8610110, ECO:0000269|PubMed:8684460, ECO:0000269|PubMed:8756328, ECO:0000269|PubMed:9334743}.

Subcellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Nucleus, Cajal body. Cytoplasm. Endosome. Note=Localized at the centrosomes in late G2 phase after separation of the centrosomes but before the start of prophase. Nuclear-cytoplasmic trafficking is mediated during the inhibition by 1,25-(OH)(2)D(3).

Induction: Induced transiently by TGFB1 at an early phase of TGFB1- mediated apoptosis.

Ptm: Phosphorylated at Thr-160 by CDK7 in a CAK complex (PubMed:28666995). Phosphorylation at Thr-160 promotes kinase activity, whereas phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being dephosphorylated by CDC25A. {ECO:0000269|PubMed:11113184, ECO:0000269|PubMed:1396589, ECO:0000269|PubMed:14597612, ECO:0000269|PubMed:16325401, ECO:0000269|PubMed:17095507, ECO:0000269|PubMed:17373709, ECO:0000269|PubMed:17570665, ECO:0000269|PubMed:20147522, ECO:0000269|PubMed:20360007, ECO:0000269|PubMed:21565702, ECO:0000269|PubMed:23781148, ECO:0000305|PubMed:28666995}.

Ptm: Nitrosylated after treatment with nitric oxide (DETA-NO). {ECO:0000269|PubMed:20079829}.

Similarity: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. {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:		Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). Phosphorylates CDK2AP2 (PubMed:12944431). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878). {ECO:0000250\|UniProtKB:P97377, ECO:0000269\|PubMed:10499802, ECO:0000269\|PubMed:10884347, ECO:0000269\|PubMed:10995386, ECO:0000269\|PubMed:10995387, ECO:0000269\|PubMed:11051553, ECO:0000269\|PubMed:11113184, ECO:0000269\|PubMed:12944431, ECO:0000269\|PubMed:15800615, ECO:0000269\|PubMed:17495531, ECO:0000269\|PubMed:18372919, ECO:0000269\|PubMed:19966300, ECO:0000269\|PubMed:20079829, ECO:0000269\|PubMed:20147522, ECO:0000269\|PubMed:20195506, ECO:0000269\|PubMed:20935635, ECO:0000269\|PubMed:21262353, ECO:0000269\|PubMed:21319273, ECO:0000269\|PubMed:21596315, ECO:0000269\|PubMed:28666995, ECO:0000269\|PubMed:29203878}.


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=2.7.11.22; Evidence={ECO:0000269\|PubMed:1396589, ECO:0000269\|PubMed:28666995, ECO:0000269\|PubMed:9030781};
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=2.7.11.22; Evidence={ECO:0000269\|PubMed:1396589, ECO:0000269\|PubMed:28666995, ECO:0000269\|PubMed:9030781};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:21565702}; Note=Binds 2 Mg(2+) ions. {ECO:0000269\|PubMed:21565702};
Activity regulation:		Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-160 activates it (PubMed:1396589). Inhibited by 1,25-dihydroxyvitamin D(3) (1,25- (OH)(2)D(3)), AG-024322, N-(4-Piperidinyl)-4-(2,6- dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), R547 (Ro- 4584820), purine, pyrimidine and pyridine derivatives, 2- aminopyrimidines, paullones, thiazo derivatives, macrocyclic quinoxalin-2-one, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5- a]pyrimidine, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9- isopropylpurine (roscovitine, seliciclib and CYC202), SNS-032 (BMS- 387032), triazolo[1,5-a]pyrimidines, staurosporine and olomoucine. Stimulated by MYC. Inactivated by CDKN1A (p21). {ECO:0000269\|PubMed:1396589, ECO:0000269\|PubMed:20147522, ECO:0000269\|PubMed:28666995, ECO:0000269\|PubMed:9030781, ECO:0000269\|PubMed:9334743}.
Subunit:		Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 (By similarity). Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC (PubMed:15611625). Interaction with SPDYA promotes kinase activation via a conformation change that alleviates obstruction of the substrate-binding cleft by the T-loop (PubMed:28666995). Found in a complex with both SPDYA and CDKN1B/KIP1 (PubMed:12972555, PubMed:28666995). Binds to RB1 and CDK7. Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Associated with PTPN6 and beta-catenin/CTNNB1. Interacts with CACUL1. May interact with CEP63. Interacts with ANKRD17. Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Forms a ternary complex with CCNA2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements (PubMed:8684460). Interacts with cyclins A, B1, B3, D, or E (PubMed:10499802, PubMed:10884347, PubMed:12185076, PubMed:23781148). Interacts with CDK2AP2 (PubMed:23781148). {ECO:0000250\|UniProtKB:P97377, ECO:0000250\|UniProtKB:Q63699, ECO:0000269\|PubMed:10499802, ECO:0000269\|PubMed:10884347, ECO:0000269\|PubMed:11980914, ECO:0000269\|PubMed:12185076, ECO:0000269\|PubMed:12839962, ECO:0000269\|PubMed:12972555, ECO:0000269\|PubMed:15107404, ECO:0000269\|PubMed:15178429, ECO:0000269\|PubMed:15611625, ECO:0000269\|PubMed:16325401, ECO:0000269\|PubMed:17095507, ECO:0000269\|PubMed:17373709, ECO:0000269\|PubMed:17495531, ECO:0000269\|PubMed:17570665, ECO:0000269\|PubMed:17937404, ECO:0000269\|PubMed:18656911, ECO:0000269\|PubMed:19445729, ECO:0000269\|PubMed:19829063, ECO:0000269\|PubMed:21262353, ECO:0000269\|PubMed:21406398, ECO:0000269\|PubMed:21565702, ECO:0000269\|PubMed:23711367, ECO:0000269\|PubMed:23781148, ECO:0000269\|PubMed:28666995, ECO:0000269\|PubMed:7630397, ECO:0000269\|PubMed:8610110, ECO:0000269\|PubMed:8684460, ECO:0000269\|PubMed:8756328, ECO:0000269\|PubMed:9334743}.
Subcellular location:		Cytoplasm, cytoskeleton, microtubule organizing center, centrosome. Nucleus, Cajal body. Cytoplasm. Endosome. Note=Localized at the centrosomes in late G2 phase after separation of the centrosomes but before the start of prophase. Nuclear-cytoplasmic trafficking is mediated during the inhibition by 1,25-(OH)(2)D(3).
Induction:		Induced transiently by TGFB1 at an early phase of TGFB1- mediated apoptosis.
Ptm:		Phosphorylated at Thr-160 by CDK7 in a CAK complex (PubMed:28666995). Phosphorylation at Thr-160 promotes kinase activity, whereas phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being dephosphorylated by CDC25A. {ECO:0000269\|PubMed:11113184, ECO:0000269\|PubMed:1396589, ECO:0000269\|PubMed:14597612, ECO:0000269\|PubMed:16325401, ECO:0000269\|PubMed:17095507, ECO:0000269\|PubMed:17373709, ECO:0000269\|PubMed:17570665, ECO:0000269\|PubMed:20147522, ECO:0000269\|PubMed:20360007, ECO:0000269\|PubMed:21565702, ECO:0000269\|PubMed:23781148, ECO:0000305\|PubMed:28666995}.
Ptm:		Nitrosylated after treatment with nitric oxide (DETA-NO). {ECO:0000269\|PubMed:20079829}.
Similarity:		Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}.