CDK2_CRIGR
ID CDK2_CRIGR Reviewed; 298 AA.
AC O55076;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 129.
DE RecName: Full=Cyclin-dependent kinase 2;
DE EC=2.7.11.22 {ECO:0000269|PubMed:11506705};
DE AltName: Full=Cell division protein kinase 2;
GN Name=CDK2; Synonyms=CDKN7;
OS Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Cricetulus.
OX NCBI_TaxID=10029;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=11506705; DOI=10.1089/104454901750361479;
RA Ellenrieder C., Bartosch B., Lee G.Y., Murphy M., Sweeney C.,
RA Hergersberg M., Carrington M., Jaussi R., Hunt T.;
RT "The long form of CDK2 arises via alternative splicing and forms an active
RT protein kinase with cyclins A and E.";
RL DNA Cell Biol. 20:413-423(2001).
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 -!- 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:11506705};
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:11506705};
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 (By similarity). Inactivated by CDKN1A (p21) (PubMed:11506705).
CC {ECO:0000250|UniProtKB:P24941, ECO:0000269|PubMed:11506705}.
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 and CDK7. Binding to CDKN1A (p21)
CC leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage
CC checkpoint, thereby arresting cells at the G1-S transition during DNA
CC repair. Associated with PTPN6 and beta-catenin/CTNNB1. Interacts with
CC CACUL1. May interact with CEP63. Interacts with ANKRD17. Interacts with
CC CEBPA (when phosphorylated). Forms a ternary complex with CCNA2 and
CC CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through
CC conformational rearrangements. Interacts with cyclins A, B1, B3, D, or
CC E. Interacts with CDK2AP2 (By similarity).
CC {ECO:0000250|UniProtKB:P24941, ECO:0000250|UniProtKB:P97377,
CC ECO:0000250|UniProtKB:Q63699}.
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=O55076-1; Sequence=Displayed;
CC Name=CDK2-beta;
CC IsoId=O55076-2; Sequence=Not described;
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; AJ223949; CAA11680.1; -; mRNA.
DR AlphaFoldDB; O55076; -.
DR SMR; O55076; -.
DR PRIDE; O55076; -.
DR Ensembl; ENSCGRT00001016410; ENSCGRP00001012177; ENSCGRG00001013650. [O55076-1]
DR GeneTree; ENSGT00940000159517; -.
DR BRENDA; 2.7.11.22; 1309.
DR GO; GO:0015030; C:Cajal body; IEA:UniProtKB-SubCell.
DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005815; C:microtubule organizing center; IEA:UniProtKB-SubCell.
DR GO; GO:0030496; C:midbody; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0097472; F:cyclin-dependent protein kinase activity; ISS:UniProtKB.
DR GO; GO:0004693; F:cyclin-dependent protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0051321; P:meiotic cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
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; Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..298
FT /note="Cyclin-dependent kinase 2"
FT /id="PRO_0000085768"
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"
SQ SEQUENCE 298 AA; 33873 MW; 3B580D8C2460CD8E CRC64;
MENFQKVEKI GEGTYGVVYK AKNKLTGEVV ALKKIRLDTE TEGVPSTAIR EISLLKELNH
PNIVKLLDVI HTENKLYLVF EFLHQDLKKF MDASAVTGIP LPLIKSYLFQ LLQGLAFCHS
HRVLHRDLKP QNLLINAEGS IKLADFGLAR AFGVPVRTYT HEVVTLWYRA PEILLGCKYY
STAVDIWSLG CIFAEMVTRR ALFPGDSEID QLFRIFRTLG TPDEVVWPGV TSMPDYKPSF
PKWARQDFSK VVPPLDEDGR SLLSQMLHYD PNKRISAKAA LAHPFFQDVT KPVPHLRL
