ID CDK2_RAT Reviewed; 298 AA. AC Q63699; O09136; DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 174. DE RecName: Full=Cyclin-dependent kinase 2; DE EC=2.7.11.22 {ECO:0000269|PubMed:10542199}; DE AltName: Full=Cell division protein kinase 2; GN Name=Cdk2; Synonyms=Cdkn2; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Thyroid; RX PubMed=7862443; RA Kotani S., Endo T., Kitagawa M., Higashi H., Onaya T.; RT "A variant form of cyclin-dependent kinase 2 (Cdk2) in a malignantly RT transformed rat thyroid (FRTL-Tc) cell line."; RL Oncogene 10:663-669(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] OF 19-124. RX PubMed=8673024; RA Hosokawa Y., Yang M., Kaneko S., Tanaka M., Nakashima K.; RT "Synergistic gene expressions of cyclin E, cdk2, cdk5 and E2F-1 during the RT prolactin-induced G1/S transition in rat Nb2 pre-T lymphoma cells."; RL Biochem. Mol. Biol. Int. 37:393-399(1995). RN [3] RP FUNCTION AS RB1 KINASE, CATALYTIC ACTIVITY, INDUCTION BY TGFB1, AND RP INTERACTION WITH RB1. RX PubMed=10542199; DOI=10.1074/jbc.274.45.31775; RA Choi K.S., Eom Y.W., Kang Y., Ha M.J., Rhee H., Yoon J.-W., Kim S.-J.; RT "Cdc2 and Cdk2 kinase activated by transforming growth factor-beta1 trigger RT apoptosis through the phosphorylation of retinoblastoma protein in FaO RT hepatoma cells."; RL J. Biol. Chem. 274:31775-31783(1999). CC -!- FUNCTION: Serine/threonine-protein kinase involved in the control of CC the cell cycle; essential for meiosis, but dispensable for mitosis. CC Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, CC NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the CC G1-S transition to promote the E2F transcriptional program and the CC initiation of DNA synthesis, and modulates G2 progression; controls the CC timing of entry into mitosis/meiosis by controlling the subsequent CC activation of cyclin B/CDK1 by phosphorylation, and coordinates the CC activation of cyclin B/CDK1 at the centrosome and in the nucleus. CC Crucial role in orchestrating a fine balance between cellular CC proliferation, cell death, and DNA repair in human embryonic stem cells CC (hESCs). Activity of CDK2 is maximal during S phase and G2; activated CC by interaction with cyclin E during the early stages of DNA synthesis CC to permit G1-S transition, and subsequently activated by cyclin A2 CC (cyclin A1 in germ cells) during the late stages of DNA replication to CC drive the transition from S phase to mitosis, the G2 phase. EZH2 CC phosphorylation promotes H3K27me3 maintenance and epigenetic gene CC silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 CC prevents oxidative stress-mediated Ras-induced senescence by CC phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that CC prevents cells with damaged DNA from initiating mitosis; regulates CC homologous recombination-dependent repair by phosphorylating BRCA2, CC this phosphorylation is low in S phase when recombination is active, CC but increases as cells progress towards mitosis. In response to DNA CC damage, double-strand break repair by homologous recombination a CC reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of CC RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin CC E/CDK2 promotes its dissociates from unduplicated centrosomes, thus CC initiating centrosome duplication. Cyclin E/CDK2-mediated CC phosphorylation of NPAT at G1-S transition and until prophase CC stimulates the NPAT-mediated activation of histone gene transcription CC during S phase. Required for vitamin D-mediated growth inhibition by CC being itself inactivated. Involved in the nitric oxide- (NO) mediated CC signaling in a nitrosylation/activation-dependent manner. USP37 is CC activated by phosphorylation and thus triggers G1-S transition. CTNNB1 CC phosphorylation regulates insulin internalization. Phosphorylates FOXP3 CC and negatively regulates its transcriptional activity and protein CC stability (By similarity). Phosphorylates CDK2AP2 (By similarity). CC Phosphorylates ERCC6 which is essential for its chromatin remodeling CC activity at DNA double-strand breaks (By similarity). CC {ECO:0000250|UniProtKB:P24941, ECO:0000250|UniProtKB:P97377, CC ECO:0000269|PubMed:10542199}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.22; CC Evidence={ECO:0000269|PubMed:10542199}; CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; CC EC=2.7.11.22; Evidence={ECO:0000269|PubMed:10542199}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000250|UniProtKB:P24941}; CC Note=Binds 2 Mg(2+) ions. {ECO:0000250|UniProtKB:P24941}; CC -!- ACTIVITY REGULATION: Phosphorylation at Thr-14 or Tyr-15 inactivates CC the enzyme, while phosphorylation at Thr-160 activates it. Stimulated CC by MYC. Inactivated by CDKN1A (p21) (By similarity). CC {ECO:0000250|UniProtKB:P24941}. CC -!- SUBUNIT: Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts CC with CABLES1 (By similarity). Interacts with UHRF2. Part of a complex CC consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo CC proteins SPDYA and SPDYC. Interaction with SPDYA promotes kinase CC activation via a conformation change that alleviates obstruction of the CC substrate-binding cleft by the T-loop. Found in a complex with both CC SPDYA and CDKN1B/KIP1. Binds to RB1 (PubMed:10542199). Binds to CDK7. CC Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S CC phase DNA damage checkpoint, thereby arresting cells at the G1-S CC transition during DNA repair. Associated with PTPN6 and beta- CC catenin/CTNNB1. Interacts with CACUL1. May interact with CEP63. CC Interacts with ANKRD17. Interacts with CEBPA (when phosphorylated). CC Forms a ternary complex with CCNA2 and CDKN1B; CDKN1B inhibits the CC kinase activity of CDK2 through conformational rearrangements. CC Interacts with cyclins A, B1, B3, D, or E. Interacts with CDK2AP2 (By CC similarity). {ECO:0000250|UniProtKB:P24941, CC ECO:0000250|UniProtKB:P97377, ECO:0000269|PubMed:10542199}. CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, microtubule organizing CC center, centrosome {ECO:0000250}. Nucleus, Cajal body {ECO:0000250}. CC Cytoplasm {ECO:0000250}. Endosome {ECO:0000250}. Note=Localized at the CC centrosomes in late G2 phase after separation of the centrosomes but CC before the start of prophase. Nuclear-cytoplasmic trafficking is CC mediated during the inhibition by 1,25-(OH)(2)D(3) (By similarity). CC {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=CDK2-alpha; CC IsoId=Q63699-1; Sequence=Displayed; CC Name=CDK2-beta; CC IsoId=Q63699-2; Sequence=Not described; CC -!- INDUCTION: Induced transiently by TGFB1 at an early phase of TGFB1- CC mediated apoptosis. {ECO:0000269|PubMed:10542199}. CC -!- PTM: Phosphorylated at Thr-160 by CDK7 in a CAK complex. CC Phosphorylation at Thr-160 promotes kinase activity, whereas CC phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. CC Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being CC dephosphorylated by CDC25A. {ECO:0000250|UniProtKB:P24941}. CC -!- PTM: Nitrosylated after treatment with nitric oxide (DETA-NO). CC {ECO:0000250}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr CC protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D28753; BAA05947.1; -; mRNA. DR EMBL; D63162; BAA09638.1; -; mRNA. DR AlphaFoldDB; Q63699; -. DR SMR; Q63699; -. DR ComplexPortal; CPX-2067; Cyclin A1-CDK2 complex. DR ComplexPortal; CPX-2068; Cyclin A2-CDK2 complex. DR ComplexPortal; CPX-2083; Cyclin E1-CDK2 complex. DR ComplexPortal; CPX-2084; Cyclin E2-CDK2 complex. DR DIP; DIP-36536N; -. DR IntAct; Q63699; 2. DR STRING; 10116.ENSRNOP00000032191; -. DR iPTMnet; Q63699; -. DR PhosphoSitePlus; Q63699; -. DR jPOST; Q63699; -. DR PaxDb; 10116-ENSRNOP00000032191; -. DR UCSC; RGD:70486; rat. [Q63699-1] DR AGR; RGD:70486; -. DR RGD; 70486; Cdk2. DR eggNOG; KOG0594; Eukaryota. DR InParanoid; Q63699; -. DR PhylomeDB; Q63699; -. DR BRENDA; 2.7.11.22; 5301. DR Reactome; R-RNO-1538133; G0 and Early G1. DR Reactome; R-RNO-171319; Telomere Extension By Telomerase. DR Reactome; R-RNO-176187; Activation of ATR in response to replication stress. DR Reactome; R-RNO-176408; Regulation of APC/C activators between G1/S and early anaphase. DR Reactome; R-RNO-187577; SCF(Skp2)-mediated degradation of p27/p21. DR Reactome; R-RNO-2559582; Senescence-Associated Secretory Phenotype (SASP). DR Reactome; R-RNO-2559586; DNA Damage/Telomere Stress Induced Senescence. DR Reactome; R-RNO-5693607; Processing of DNA double-strand break ends. DR Reactome; R-RNO-6804116; TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest. DR Reactome; R-RNO-6804756; Regulation of TP53 Activity through Phosphorylation. DR Reactome; R-RNO-6804757; Regulation of TP53 Degradation. DR Reactome; R-RNO-68911; G2 Phase. DR Reactome; R-RNO-68949; Orc1 removal from chromatin. DR Reactome; R-RNO-68962; Activation of the pre-replicative complex. DR Reactome; R-RNO-69017; CDK-mediated phosphorylation and removal of Cdc6. DR Reactome; R-RNO-69200; Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes. DR Reactome; R-RNO-69202; Cyclin E associated events during G1/S transition. DR Reactome; R-RNO-69231; Cyclin D associated events in G1. DR Reactome; R-RNO-69273; Cyclin A/B1/B2 associated events during G2/M transition. DR Reactome; R-RNO-69563; p53-Dependent G1 DNA Damage Response. DR Reactome; R-RNO-69656; Cyclin A:Cdk2-associated events at S phase entry. DR Reactome; R-RNO-8849470; PTK6 Regulates Cell Cycle. DR Reactome; R-RNO-9616222; Transcriptional regulation of granulopoiesis. DR PRO; PR:Q63699; -. DR Proteomes; UP000002494; Unplaced. DR GO; GO:0015030; C:Cajal body; ISO:RGD. DR GO; GO:0005813; C:centrosome; IEA:UniProtKB-SubCell. DR GO; GO:0000781; C:chromosome, telomeric region; ISO:RGD. DR GO; GO:0000793; C:condensed chromosome; ISO:RGD. DR GO; GO:0097123; C:cyclin A1-CDK2 complex; ISO:RGD. DR GO; GO:0097124; C:cyclin A2-CDK2 complex; ISO:RGD. DR GO; GO:0097134; C:cyclin E1-CDK2 complex; ISO:RGD. DR GO; GO:0097135; C:cyclin E2-CDK2 complex; ISO:RGD. DR GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; ISO:RGD. DR GO; GO:0005737; C:cytoplasm; ISO:RGD. DR GO; GO:0005768; C:endosome; ISO:RGD. DR GO; GO:0001673; C:male germ cell nucleus; ISO:RGD. DR GO; GO:0005635; C:nuclear envelope; ISO:RGD. DR GO; GO:0005654; C:nucleoplasm; ISO:RGD. DR GO; GO:0005634; C:nucleus; ISO:RGD. DR GO; GO:0005667; C:transcription regulator complex; ISO:RGD. DR GO; GO:0000805; C:X chromosome; ISO:RGD. DR GO; GO:0000806; C:Y chromosome; ISO:RGD. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0030332; F:cyclin binding; IPI:RGD. DR GO; GO:0097472; F:cyclin-dependent protein kinase activity; ISO:RGD. DR GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; IDA:RGD. DR GO; GO:0016301; F:kinase activity; ISO:RGD. DR GO; GO:0000287; F:magnesium ion binding; ISO:RGD. DR GO; GO:0019904; F:protein domain specific binding; ISO:RGD. DR GO; GO:0004672; F:protein kinase activity; ISO:RGD. DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA. DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISO:RGD. DR GO; GO:0044877; F:protein-containing complex binding; IPI:RGD. DR GO; GO:0031100; P:animal organ regeneration; IEP:RGD. DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW. DR GO; GO:0032869; P:cellular response to insulin stimulus; IDA:RGD. DR GO; GO:0007099; P:centriole replication; ISO:RGD. DR GO; GO:0006338; P:chromatin remodeling; IEA:GOC. DR GO; GO:0006974; P:DNA damage response; IMP:RGD. DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW. DR GO; GO:0006351; P:DNA-templated transcription; ISO:RGD. DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; ISO:RGD. DR GO; GO:0002088; P:lens development in camera-type eye; IEP:RGD. DR GO; GO:0051321; P:meiotic cell cycle; IEA:UniProtKB-KW. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD. DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:RGD. DR GO; GO:0032298; P:positive regulation of DNA-templated DNA replication initiation; ISO:RGD. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISO:RGD. DR GO; GO:0031453; P:positive regulation of heterochromatin formation; ISO:RGD. DR GO; GO:0043687; P:post-translational protein modification; ISO:RGD. DR GO; GO:0006813; P:potassium ion transport; ISO:RGD. DR GO; GO:0007265; P:Ras protein signal transduction; ISO:RGD. DR GO; GO:0010389; P:regulation of G2/M transition of mitotic cell cycle; IBA:GO_Central. DR GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central. DR GO; GO:0046686; P:response to cadmium ion; IEP:RGD. DR GO; GO:0051591; P:response to cAMP; IDA:RGD. DR GO; GO:0051602; P:response to electrical stimulus; IDA:RGD. DR GO; GO:0032355; P:response to estradiol; IEP:RGD. DR GO; GO:0045471; P:response to ethanol; IEP:RGD. DR GO; GO:0010033; P:response to organic substance; IBA:GO_Central. DR GO; GO:0009636; P:response to toxic substance; IEP:RGD. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR CDD; cd07860; STKc_CDK2_3; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR008271; Ser/Thr_kinase_AS. DR PANTHER; PTHR24056; CELL DIVISION PROTEIN KINASE; 1. DR PANTHER; PTHR24056:SF521; CYCLIN-DEPENDENT KINASE 2; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. PE 1: Evidence at protein level; KW Acetylation; Alternative splicing; ATP-binding; Cell cycle; Cell division; KW Cytoplasm; Cytoskeleton; DNA damage; DNA repair; Endosome; Kinase; KW Magnesium; Meiosis; Metal-binding; Mitosis; Nucleotide-binding; Nucleus; KW Phosphoprotein; Reference proteome; Serine/threonine-protein kinase; KW Transferase. FT CHAIN 1..298 FT /note="Cyclin-dependent kinase 2" FT /id="PRO_0000085772" FT DOMAIN 4..286 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT ACT_SITE 127 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" FT BINDING 10..18 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 33 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 81..83 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 86 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 129..132 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 132 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250|UniProtKB:P24941" FT BINDING 145 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 145 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000250|UniProtKB:P24941" FT SITE 9 FT /note="CDK7 binding" FT /evidence="ECO:0000250" FT SITE 88..89 FT /note="CDK7 binding" FT /evidence="ECO:0000250" FT SITE 166 FT /note="CDK7 binding" FT /evidence="ECO:0000250" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000250|UniProtKB:P24941" FT MOD_RES 6 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P24941" FT MOD_RES 14 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P24941" FT MOD_RES 15 FT /note="Phosphotyrosine; by WEE1" FT /evidence="ECO:0000250|UniProtKB:P24941" FT MOD_RES 19 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P24941" FT MOD_RES 160 FT /note="Phosphothreonine; by CAK and CCRK" FT /evidence="ECO:0000250|UniProtKB:P24941" FT CONFLICT 79 FT /note="V -> C (in Ref. 2; BAA09638)" FT /evidence="ECO:0000305" FT CONFLICT 99 FT /note="L -> I (in Ref. 2; BAA09638)" FT /evidence="ECO:0000305" FT CONFLICT 124 FT /note="L -> C (in Ref. 2; BAA09638)" FT /evidence="ECO:0000305" SQ SEQUENCE 298 AA; 33887 MW; C8CB3ADCE9B97F88 CRC64; MENFQKVEKI GEGTYGVVYK AKNKLTGEVV ALKKIRLDTE TEGVPSTAIR EISLLKELNH PNIVKLLDVI HTENKLYLVF EFLHQDLKKF MDASALTGLP LPLIKSYLFQ LLQGLAFCHS HRVLHRDLKP QNLLINAEGS IKLADFGLAR AFGVPVRTYT HEVVTLWYRA PEILLGCKYY STAVDIWSLG CIFAEMVTRR ALFPGDSEID QLFRIFRTLG TPDEVVWPGV TSMPDYKPSF PKWARQDFSK VVPPLDEDGR SLLSQMLHYD PNKRISAKAA LAHPFFQDVT KPVPHLRL //