Protein: Cyclin-dependent kinase 2 (EC 2.7.11.22) (Cell division protein kinase 2) (Q63699)
Organism: Rattus norvegicus (Rat)
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 (By similarity). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (By similarity).
Subcellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000250}. Nucleus, Cajal body {ECO:0000250}. Cytoplasm {ECO:0000250}. Endosome {ECO:0000250}. 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) (By similarity). {ECO:0000250}.
Sequence: MENFQKVEKIGEGTYGVVYKAKNKLTGEVVALKKIRLDTETEGVPSTAIREISLLKELNHPNIVKLLDVIHTENKLYLVFEFLHQDLKKFMDASALTGLPLPLIKSYLFQLLQGLAFCHSHRVLHRDLKPQNLLINAEGSIKLADFGLARAFGVPVRTYTHEVVTLWYRAPEILLGCKYYSTAVDIWSLGCIFAEMVTRRALFPGDSEIDQLFRIFRTLGTPDEVVWPGVTSMPDYKPSFPKWARQDFSKVVPPLDEDGRSLLSQMLHYDPNKRISAKAALAHPFFQDVTKPVPHLRL
InterPro domains: - IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [1-292]
- IPR008271: Serine/threonine-protein kinase, active site (active_site) [123-135]
- IPR050108: Cyclin-dependent kinase (family) [2-287]
- IPR017441: Protein kinase, ATP binding site (binding_site) [10-33]
- IPR000719: Protein kinase domain (domain) [4-286]
Interaction partners: - Cyclin-A1
- Cyclin-A2
- G1/S-specific cyclin-E1
- Forkhead box O3
- Cyclin-dependent kinase inhibitor 1B
- Cyclin-dependent kinase inhibitor 1
- G1/S-specific cyclin-D1
- Cyclin E2
- G1/S-specific cyclin-D3
- S-phase kinase-associated protein 2
Gene Ontology annotations:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0016740 (transferase activity), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0016772 (transferase activity, transferring phosphorus-containing groups), GO:0030332 (cyclin binding), GO:0004672 (protein kinase activity), GO:0035173 (histone kinase activity), GO:0004674 (protein serine/threonine kinase activity), GO:0097472 (cyclin-dependent protein kinase activity), GO:0016301 (kinase activity), GO:0016773 (phosphotransferase activity, alcohol group as acceptor), GO:0004693 (cyclin-dependent protein serine/threonine kinase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0008152 (metabolic process), GO:0048519 (negative regulation of biological process), GO:0048856 (anatomical structure development), GO:0042221 (response to chemical), GO:0051240 (positive regulation of multicellular organismal process), GO:0006807 (nitrogen compound metabolic process), GO:0071840 (cellular component organization or biogenesis), GO:0051239 (regulation of multicellular organismal process), GO:0045927 (positive regulation of growth), GO:0051050 (positive regulation of transport), GO:0009892 (negative regulation of metabolic process), GO:0050793 (regulation of developmental process), GO:0050794 (regulation of cellular process), GO:0051716 (cellular response to stimulus), GO:0048869 (cellular developmental process), GO:0007275 (multicellular organism development), GO:0019222 (regulation of metabolic process), GO:0032879 (regulation of localization), GO:0007049 (cell cycle), GO:0071704 (organic substance metabolic process), GO:0014823 (response to activity), GO:0044237 (cellular metabolic process), GO:0009893 (positive regulation of metabolic process), GO:0006950 (response to stress), GO:0051094 (positive regulation of developmental process), GO:0040008 (regulation of growth), GO:0044238 (primary metabolic process), GO:0048522 (positive regulation of cellular process), GO:0044085 (cellular component biogenesis), GO:0032388 (positive regulation of intracellular transport), GO:0048468 (cell development), GO:0009410 (response to xenobiotic stimulus), GO:0030154 (cell differentiation), GO:0048731 (system development), GO:0048513 (animal organ development), GO:0060255 (regulation of macromolecule metabolic process), GO:0046620 (regulation of organ growth), GO:0045787 (positive regulation of cell cycle), GO:0006793 (phosphorus metabolic process), GO:0051726 (regulation of cell cycle), GO:0010035 (response to inorganic substance), GO:0010605 (negative regulation of macromolecule metabolic process), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0016043 (cellular component organization), GO:0048638 (regulation of developmental growth), GO:0008284 (positive regulation of cell population proliferation), GO:0051173 (positive regulation of nitrogen compound metabolic process), GO:0048639 (positive regulation of developmental growth), GO:1903829 (positive regulation of protein localization), GO:0051049 (regulation of transport), GO:1901564 (organonitrogen compound metabolic process), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0009611 (response to wounding), GO:0006979 (response to oxidative stress), GO:0060341 (regulation of cellular localization), GO:0019538 (protein metabolic process), GO:0009636 (response to toxic substance), GO:0046622 (positive regulation of organ growth), GO:1901700 (response to oxygen-containing compound), GO:0043170 (macromolecule metabolic process), GO:0010033 (response to organic substance), GO:0061061 (muscle structure development), GO:2000026 (regulation of multicellular organismal development), GO:0042127 (regulation of cell population proliferation), GO:0009888 (tissue development), GO:1901698 (response to nitrogen compound), GO:0031325 (positive regulation of cellular metabolic process), GO:0070887 (cellular response to chemical stimulus), GO:0033554 (cellular response to stress), GO:0031323 (regulation of cellular metabolic process), GO:0080090 (regulation of primary metabolic process), GO:0051222 (positive regulation of protein transport), GO:0031099 (regeneration), GO:0000278 (mitotic cell cycle), GO:0034599 (cellular response to oxidative stress), GO:0097305 (response to alcohol), GO:0055006 (cardiac cell development), GO:0007346 (regulation of mitotic cell cycle), GO:1904951 (positive regulation of establishment of protein localization), GO:0070201 (regulation of establishment of protein localization), GO:0046824 (positive regulation of nucleocytoplasmic transport), GO:0060045 (positive regulation of cardiac muscle cell proliferation), GO:0010468 (regulation of gene expression), GO:0022607 (cellular component assembly), GO:0031100 (animal organ regeneration), GO:0055021 (regulation of cardiac muscle tissue growth), GO:0060420 (regulation of heart growth), GO:0043412 (macromolecule modification), GO:0051223 (regulation of protein transport), GO:0042692 (muscle cell differentiation), GO:0072359 (circulatory system development), GO:0055023 (positive regulation of cardiac muscle tissue growth), GO:1900182 (positive regulation of protein localization to nucleus), GO:0043933 (protein-containing complex organization), GO:1901701 (cellular response to oxygen-containing compound), GO:0022411 (cellular component disassembly), GO:0010629 (negative regulation of gene expression), GO:0060043 (regulation of cardiac muscle cell proliferation), GO:0007507 (heart development), GO:0032386 (regulation of intracellular transport), GO:0010038 (response to metal ion), GO:0060421 (positive regulation of heart growth), GO:0090316 (positive regulation of intracellular protein transport), GO:0051052 (regulation of DNA metabolic process), GO:0051054 (positive regulation of DNA metabolic process), GO:0010256 (endomembrane system organization), GO:0071310 (cellular response to organic substance), GO:0055001 (muscle cell development), GO:0062197 (cellular response to chemical stress), GO:0010628 (positive regulation of gene expression), GO:0006796 (phosphate-containing compound metabolic process), GO:0032880 (regulation of protein localization), GO:0045931 (positive regulation of mitotic cell cycle), GO:0048678 (response to axon injury), GO:0036211 (protein modification process), GO:0045935 (positive regulation of nucleobase-containing compound metabolic process), GO:0010243 (response to organonitrogen compound), GO:0060537 (muscle tissue development), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0014070 (response to organic cyclic compound), GO:0042542 (response to hydrogen peroxide), GO:0006996 (organelle organization), GO:0035051 (cardiocyte differentiation), GO:0000302 (response to reactive oxygen species), GO:0045471 (response to ethanol), GO:0014706 (striated muscle tissue development), GO:0065003 (protein-containing complex assembly), GO:0018193 (peptidyl-amino acid modification), GO:0046822 (regulation of nucleocytoplasmic transport), GO:0016310 (phosphorylation), GO:0055007 (cardiac muscle cell differentiation), GO:0006275 (regulation of DNA replication), GO:0046686 (response to cadmium ion), GO:0034614 (cellular response to reactive oxygen species), GO:1900180 (regulation of protein localization to nucleus), GO:0048738 (cardiac muscle tissue development), GO:0045740 (positive regulation of DNA replication), GO:0014075 (response to amine), GO:0006468 (protein phosphorylation), GO:0033157 (regulation of intracellular protein transport), GO:0071407 (cellular response to organic cyclic compound), GO:0051276 (chromosome organization), GO:0055013 (cardiac muscle cell development), GO:1903008 (organelle disassembly), GO:0007030 (Golgi organization), GO:0051146 (striated muscle cell differentiation), GO:0048308 (organelle inheritance), GO:0046688 (response to copper ion), GO:0042307 (positive regulation of protein import into nucleus), GO:0070301 (cellular response to hydrogen peroxide), GO:0042306 (regulation of protein import into nucleus), GO:0055012 (ventricular cardiac muscle cell differentiation), GO:0018105 (peptidyl-serine phosphorylation), GO:0018209 (peptidyl-serine modification), GO:0030261 (chromosome condensation)
Cellular Component (CC): GO:0005575 (cellular component), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0005737 (cytoplasm), GO:0043229 (intracellular organelle), GO:0043227 (membrane-bounded organelle), GO:0043231 (intracellular membrane-bounded organelle), GO:0005634 (nucleus)