CDK2_RAT
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 03-AUG-2022, entry version 165.
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}.
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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; Q63699; -.
DR PRIDE; Q63699; -.
DR UCSC; RGD:70486; rat. [Q63699-1]
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: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:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0005768; C:endosome; ISO:RGD.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
DR GO; GO:0005815; C:microtubule organizing center; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA: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:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; ISO:RGD.
DR GO; GO:0016572; P:histone phosphorylation; 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:0018105; P:peptidyl-serine phosphorylation; ISO:RGD.
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:0031453; P:positive regulation of heterochromatin assembly; ISO:RGD.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:0006813; P:potassium ion transport; ISO:RGD.
DR GO; GO:0006468; P:protein phosphorylation; 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: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 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 Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 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
