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Protein

Cell cycle and apoptosis regulator protein 2

Gene

Ccar2

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Core component of the DBIRD complex, a multiprotein complex that acts at the interface between core mRNP particles and RNA polymerase II (RNAPII) and integrates transcript elongation with the regulation of alternative splicing: the DBIRD complex affects local transcript elongation rates and alternative splicing of a large set of exons embedded in (A + T)-rich DNA regions. Inhibits SIRT1 deacetylase activity leading to increasing levels of p53/TP53 acetylation and p53-mediated apoptosis (By similarity). As part of a histone H3-specific methyltransferase complex may mediate ligand-dependent transcriptional activation by nuclear hormone receptors (By similarity). Inhibits SUV39H1 methyltransferase activity. Plays a critical role in maintaining genomic stability and cellular integrity following UV-induced genotoxic stress (By similarity) Regulates the circadian expression of the core clock components NR1D1 and ARNTL/BMAL1. Enhances the transcriptional repressor activity of NR1D1 through stabilization of NR1D1 protein levels by preventing its ubiquitination and subsequent degradation. Acts as a regulator of PCK1 expression and gluconeogenesis by a mechanism that involves, at least in part, both NR1D1 and SIRT1 (PubMed:24415752). Negatively regulates the deacetylase activity of HDAC3 and can alter its subcellular localization (PubMed:21030595). Plays an important role in tumor suppression through p53/TP53 regulation; stabilizes p53/TP53 by affecting its interaction with ubiquitin ligase MDM2 (PubMed:25732823). Represses the ligand-dependent transcriptional activation function of ESR2. Positively regulates the beta-catenin pathway (canonical Wnt signaling pathway) and is required for MCC-mediated repression of the beta-catenin pathway. Represses ligand-dependent transcriptional activation function of NR1H2 and NR1H3 and inhibits the interaction of SIRT1 with NR1H3. Represses the transcriptional activator activity of BRCA1. Inhibits SIRT1 in a CHEK2 and PSEM3-dependent manner and inhibits the activity of CHEK2 in vitro (By similarity).By similarity1 Publication

GO - Molecular functioni

  • enzyme binding Source: MGI
  • enzyme inhibitor activity Source: UniProtKB
  • nuclear receptor transcription coactivator activity Source: GO_Central
  • RNA polymerase II complex binding Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionActivator, Metalloenzyme inhibitor, Repressor
Biological processApoptosis, Biological rhythms, Cell cycle, DNA damage, mRNA processing, mRNA splicing, Transcription, Transcription regulation, Wnt signaling pathway

Enzyme and pathway databases

ReactomeiR-MMU-3371453 Regulation of HSF1-mediated heat shock response

Names & Taxonomyi

Protein namesi
Recommended name:
Cell cycle and apoptosis regulator protein 2
Alternative name(s):
Cell division cycle and apoptosis regulator protein 2
Gene namesi
Name:Ccar2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 14

Organism-specific databases

MGIiMGI:2444228 Ccar2

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

Mice mimic a fasted state and therefore, display an increased production of glucose. Display elevated levels of PCK1 and are glucose-intolerant in both a normal and a high-fat diet (PubMed:24415752). Mice develop more tumors including lymphomas, liver tumors, lung tumors (PubMed:25732823).2 Publications

Keywords - Diseasei

Tumor suppressor

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000508141 – 922Cell cycle and apoptosis regulator protein 2Add BLAST922

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei35PhosphothreonineBy similarity1
Modified residuei112N6-acetyllysine; by KAT8By similarity1
Modified residuei123N6-methyllysineBy similarity1
Modified residuei124PhosphoserineBy similarity1
Modified residuei180Omega-N-methylarginineBy similarity1
Modified residuei215N6-acetyllysine; by KAT8By similarity1
Modified residuei483PhosphothreonineBy similarity1
Modified residuei568PhosphoserineBy similarity1
Cross-linki590Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2 and SUMO3); alternateBy similarity
Cross-linki590Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateBy similarity
Modified residuei612PhosphoserineCombined sources1
Modified residuei626PhosphoserineBy similarity1
Modified residuei674PhosphoserineCombined sources1
Modified residuei677PhosphoserineCombined sources1
Modified residuei680PhosphoserineCombined sources1
Modified residuei684PhosphotyrosineCombined sources1
Modified residuei686PhosphoserineCombined sources1
Modified residuei807PhosphoserineBy similarity1
Modified residuei896PhosphothreonineBy similarity1

Post-translational modificationi

Acetylation at Lys-112 and Lys-215 by KAT8 prevents inhibitory binding to SIRT1 and increases its deacetylase activity.By similarity
Genotoxic stress induces its sumoylation and sumoylation promotes the SIRT1-CCAR2 interaction which in turn inhibits SIRT1-mediated deacetylation of p53/TP53. Sumoylation leads to transcriptional activation of p53/TP53 by sequestering SIRT1 from p53/TP53. Desumoylated by SENP1.By similarity

Keywords - PTMi

Acetylation, Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ8VDP4
MaxQBiQ8VDP4
PaxDbiQ8VDP4
PeptideAtlasiQ8VDP4
PRIDEiQ8VDP4

PTM databases

iPTMnetiQ8VDP4
PhosphoSitePlusiQ8VDP4

Expressioni

Gene expression databases

BgeeiENSMUSG00000033712 Expressed in 251 organ(s), highest expression level in dorsal pancreas
CleanExiMM_2610301G19RIK
GenevisibleiQ8VDP4 MM

Interactioni

Subunit structurei

Component of the DBIRD complex. Interacts with ZNF326/ZIRD; the interaction is direct. Interacts (via N-terminus) with SIRT1, which inhibits the deacetylation of substrates. Interacts (via N-terminus) with SUV39H1; this interaction abolishes the interaction with SIRT1. Part of a complex composed at least of ASCL2, EMSY, HCFC1, HSPA8, CCAR2, MATR3, MKI67, RBBP5, TUBB2A, WDR5 and ZNF335; this complex may have a histone H3-specific methyltransferase activity. Interacts with NR1D1. Interacts (via N-terminus) with ESR1 and ESR2. Interacts (via N-terminus) with HDAC3 (via C-terminus). Interacts with HDAC1 and MED2F. Interacts with MCC. Interacts (via N-terminus) with NR1H2 and NR1H3 in a ligand-independent manner. Interacts with CSNK2A1. Interacts (via N-terminus) with p53/TP53. Interacts (via N-terminus) with BRCA1 (via the BRCT domains). Interacts (via N-terminus) with CHEK2 (via protein kinase domain). Interacts with PSEM3. Interacts (via N-terminus) with PSIA3 and SENP1. The sumoylated form shows a preferential interaction with SIRT1 as compared to its unmodified form (By similarity).By similarity5 Publications

GO - Molecular functioni

Protein-protein interaction databases

BioGridi230123, 5 interactors
IntActiQ8VDP4, 10 interactors
MINTiQ8VDP4
STRINGi10090.ENSMUSP00000036924

Structurei

3D structure databases

ProteinModelPortaliQ8VDP4
SMRiQ8VDP4
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni609 – 669Interaction with MCCBy similarityAdd BLAST61
Regioni703 – 922Interaction with NR1D1By similarityAdd BLAST220

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili573 – 596Sequence analysisAdd BLAST24
Coiled coili828 – 898Sequence analysisAdd BLAST71

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG4246 Eukaryota
ENOG4111FW4 LUCA
GeneTreeiENSGT00530000063672
HOGENOMiHOG000113184
HOVERGENiHBG081843
InParanoidiQ8VDP4
OMAiPLQLEMQ
OrthoDBiEOG091G03QV
PhylomeDBiQ8VDP4
TreeFamiTF316387

Family and domain databases

InterProiView protein in InterPro
IPR025224 CCAR1/CCAR2
IPR028811 CCAR2
IPR025954 DBC1/CARP1_inactive_NUDIX_dom
IPR011992 EF-hand-dom_pair
IPR025223 S1-like_RNA-bd_dom
PANTHERiPTHR14304 PTHR14304, 1 hit
PTHR14304:SF12 PTHR14304:SF12, 1 hit
PfamiView protein in Pfam
PF14443 DBC1, 1 hit
PF14444 S1-like, 1 hit
SMARTiView protein in SMART
SM01122 DBC1, 1 hit
SUPFAMiSSF47473 SSF47473, 1 hit

Sequencei

Sequence statusi: Complete.

Q8VDP4-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MSQFKRQRIN PLPGGRNFSG AASTSLLGPP PGLLTPPVAT DLSQNARHLQ
60 70 80 90 100
SGEKQRVFTG IVTSLHDYFG VVDEEVFFQL SVVKGRLPQL GEKVLVKAAY
110 120 130 140 150
NPGQAVPWNA VKVQTLSNQP LLKSPAPPLL HVAALGQKQG ILGAQPQLIF
160 170 180 190 200
QPHRIPPLFP QKPLSLFQTS HTLHLSHLNR FPARGPHGRL DQGRSDDYDS
210 220 230 240 250
KKRKQRAGGE PWGAKKPRHD LSPYRVHLTP YTVDSPTCDF LELQRRYRSL
260 270 280 290 300
LVPSDFLSVH LSWLSAFPLG QPFSLHHPSR IQVSSEKEAA PDTGAEPSPE
310 320 330 340 350
DSDPTYSSKV LLLSSPGLEE FYRCCMLFVD DMAEPRETPE HPLKQLKFLL
360 370 380 390 400
GRKEEEAVLV GGEWSPSLDG LDPQADPQVL VRTAIRCAQA QTGIDLSTCT
410 420 430 440 450
KWWRFAEFQY LQPGPPRQLH TVVVYLPDVW TIMPTLEEWE ALCQQKATEA
460 470 480 490 500
APQPHEASGE AEATEQAPDV SEQADTSKQN TETMEATTQQ DVDTDLPEAP
510 520 530 540 550
PPPLEPAVMA RPRCVNLSLY GIVEDRRPKE RISFEVVVLA ELFVEMLQRD
560 570 580 590 600
FGYRIYKTLL SLPEKVVSPP EPEKEEAAKE DAVKEEEAVK EEAVKVSKDE
610 620 630 640 650
VQNEGTAAES DSPLKEDGLL PKRPSSGGEE EEKARGEAAE DLCEMALDPD
660 670 680 690 700
LLLLRDDGED EFAGAKLEET EVRSVASNQS EMEYSSLQDM PKELDPSTVL
710 720 730 740 750
PLDCLLAFVF FDANWCGYLH RRDLERVLLT LGIRLSAEQA KQLVSRVVAQ
760 770 780 790 800
NICQYRSLQY SRAEVLDDGL PEDVLFGNLD LLPPSGKSTK PGAAPTEHKG
810 820 830 840 850
LVPHNGSLIN VGSLLQRAEQ QDSGRLYLEN KIHTLELKLE ESHNRFSATE
860 870 880 890 900
VTNKTLAAEM QELRARLAEA EETARTAERQ KNQLQRQMQD FRRRLTPLHL
910 920
EMQRIVEKAD SWVEKEEPTP SN
Length:922
Mass (Da):103,002
Last modified:March 1, 2004 - v2
Checksum:i19F43ECEE58F461C
GO

Sequence cautioni

The sequence BAC27420 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
The sequence BAC34139 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti527 – 529RPK → HAS in AAH25471 (PubMed:15489334).Curated3
Sequence conflicti720H → L in AAH38346 (PubMed:15489334).Curated1
Sequence conflicti812G → R in BAC27420 (PubMed:16141072).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK031472 mRNA Translation: BAC27420.1 Different initiation.
AK050238 mRNA Translation: BAC34139.2 Different initiation.
BC021475 mRNA Translation: AAH21475.2
BC025471 mRNA Translation: AAH25471.1
BC038346 mRNA Translation: AAH38346.1
CCDSiCCDS49534.1
RefSeqiNP_666167.3, NM_146055.3
XP_006518959.1, XM_006518896.3
UniGeneiMm.218284

Genome annotation databases

EnsembliENSMUST00000035612; ENSMUSP00000036924; ENSMUSG00000033712
GeneIDi219158
KEGGimmu:219158
UCSCiuc007unf.1 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK031472 mRNA Translation: BAC27420.1 Different initiation.
AK050238 mRNA Translation: BAC34139.2 Different initiation.
BC021475 mRNA Translation: AAH21475.2
BC025471 mRNA Translation: AAH25471.1
BC038346 mRNA Translation: AAH38346.1
CCDSiCCDS49534.1
RefSeqiNP_666167.3, NM_146055.3
XP_006518959.1, XM_006518896.3
UniGeneiMm.218284

3D structure databases

ProteinModelPortaliQ8VDP4
SMRiQ8VDP4
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi230123, 5 interactors
IntActiQ8VDP4, 10 interactors
MINTiQ8VDP4
STRINGi10090.ENSMUSP00000036924

PTM databases

iPTMnetiQ8VDP4
PhosphoSitePlusiQ8VDP4

Proteomic databases

EPDiQ8VDP4
MaxQBiQ8VDP4
PaxDbiQ8VDP4
PeptideAtlasiQ8VDP4
PRIDEiQ8VDP4

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000035612; ENSMUSP00000036924; ENSMUSG00000033712
GeneIDi219158
KEGGimmu:219158
UCSCiuc007unf.1 mouse

Organism-specific databases

CTDi57805
MGIiMGI:2444228 Ccar2

Phylogenomic databases

eggNOGiKOG4246 Eukaryota
ENOG4111FW4 LUCA
GeneTreeiENSGT00530000063672
HOGENOMiHOG000113184
HOVERGENiHBG081843
InParanoidiQ8VDP4
OMAiPLQLEMQ
OrthoDBiEOG091G03QV
PhylomeDBiQ8VDP4
TreeFamiTF316387

Enzyme and pathway databases

ReactomeiR-MMU-3371453 Regulation of HSF1-mediated heat shock response

Miscellaneous databases

ChiTaRSiCcar2 mouse
PROiPR:Q8VDP4
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000033712 Expressed in 251 organ(s), highest expression level in dorsal pancreas
CleanExiMM_2610301G19RIK
GenevisibleiQ8VDP4 MM

Family and domain databases

InterProiView protein in InterPro
IPR025224 CCAR1/CCAR2
IPR028811 CCAR2
IPR025954 DBC1/CARP1_inactive_NUDIX_dom
IPR011992 EF-hand-dom_pair
IPR025223 S1-like_RNA-bd_dom
PANTHERiPTHR14304 PTHR14304, 1 hit
PTHR14304:SF12 PTHR14304:SF12, 1 hit
PfamiView protein in Pfam
PF14443 DBC1, 1 hit
PF14444 S1-like, 1 hit
SMARTiView protein in SMART
SM01122 DBC1, 1 hit
SUPFAMiSSF47473 SSF47473, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiCCAR2_MOUSE
AccessioniPrimary (citable) accession number: Q8VDP4
Secondary accession number(s): Q6PIB1
, Q8BWR5, Q8C0F0, Q8R3G6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 24, 2006
Last sequence update: March 1, 2004
Last modified: November 7, 2018
This is version 132 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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