CRTC3_MOUSE
ID CRTC3_MOUSE Reviewed; 619 AA.
AC Q91X84;
DT 05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 05-FEB-2008, sequence version 2.
DT 03-AUG-2022, entry version 133.
DE RecName: Full=CREB-regulated transcription coactivator 3;
DE AltName: Full=Transducer of regulated cAMP response element-binding protein 3;
DE Short=TORC-3;
DE Short=Transducer of CREB protein 3;
GN Name=Crtc3; Synonyms=Torc3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=FVB/N; TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62 AND SER-370, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Kidney, Lung, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [4]
RP FUNCTION, AND PHOSPHORYLATION AT SER-273.
RX PubMed=29211348; DOI=10.1111/febs.14351;
RA Sonntag T., Vaughan J.M., Montminy M.;
RT "14-3-3 proteins mediate inhibitory effects of cAMP on salt-inducible
RT kinases (SIKs).";
RL FEBS J. 285:467-480(2018).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY, PHOSPHORYLATION AT SER-62; THR-160;
RP SER-162 AND SER-273, MUTAGENESIS OF SER-162 AND SER-273, AND INTERACTION
RP WITH 14-3-3 PROTEINS.
RX PubMed=28235073; DOI=10.1371/journal.pone.0173013;
RA Sonntag T., Moresco J.J., Vaughan J.M., Matsumura S., Yates J.R. III,
RA Montminy M.;
RT "Analysis of a cAMP regulated coactivator family reveals an alternative
RT phosphorylation motif for AMPK family members.";
RL PLoS ONE 12:E0173013-E0173013(2017).
RN [6]
RP FUNCTION, INTERACTION WITH YWHAE; PPP2CA; PPP2R1A AND PPP2R2A, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, PHOSPHORYLATION AT SER-162; SER-273; SER-391
RP AND SER-396, AND MUTAGENESIS OF SER-62; SER-162; SER-273; SER-329; SER-370;
RP SER-391; PRO-392; THR-394 AND SER-396.
RX PubMed=30611118; DOI=10.1016/j.isci.2018.12.012;
RA Sonntag T., Ostojic J., Vaughan J.M., Moresco J.J., Yoon Y.S.,
RA Yates J.R. III, Montminy M.;
RT "Mitogenic Signals Stimulate the CREB Coactivator CRTC3 through PP2A
RT Recruitment.";
RL IScience 11:134-145(2018).
CC -!- FUNCTION: Transcriptional coactivator for CREB1 which activates
CC transcription through both consensus and variant cAMP response element
CC (CRE) sites (PubMed:29211348, PubMed:30611118). Acts as a coactivator,
CC in the SIK/TORC signaling pathway, being active when dephosphorylated
CC (PubMed:29211348). Acts independently of CREB1 'Ser-133'
CC phosphorylation (By similarity). Enhances the interaction of CREB1 with
CC TAF4 (By similarity). Regulates the expression of specific CREB-
CC activated genes such as the steroidogenic gene, StAR (By similarity).
CC Potent coactivator of PPARGC1A and inducer of mitochondrial biogenesis
CC in muscle cells (By similarity). {ECO:0000250|UniProtKB:Q6UUV7,
CC ECO:0000269|PubMed:29211348, ECO:0000269|PubMed:30611118}.
CC -!- SUBUNIT: Binding, as a tetramer, through its N-terminal region, with
CC the bZIP domain of CREB1 enhances recruitment of TAF4 to the promoter
CC (By similarity). 'Arg-314' in the bZIP domain of CREB1 is essential for
CC this interaction (By similarity). Interacts (when phosphorylated at
CC Ser-162 and Se-273) with 14-3-3 proteins (PubMed:28235073,
CC PubMed:30611118). Interacts with YWHAE (PubMed:30611118). Interacts
CC (when phosphorylated at Ser-391) with phosphatase PP2A catalytic
CC subunit PPP2CA and regulatory subunits PPP2R1A and PPP2R2A
CC (PubMed:30611118). {ECO:0000250|UniProtKB:Q6UUV7,
CC ECO:0000269|PubMed:28235073, ECO:0000269|PubMed:30611118}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:30611118}. Cytoplasm
CC {ECO:0000269|PubMed:30611118}. Note=Appears to be mainly nuclear.
CC Translocates to the nucleus following adenylyl cyclase or MAP kinase
CC activation (PubMed:30611118). {ECO:0000250|UniProtKB:Q6UUV7,
CC ECO:0000269|PubMed:30611118}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q91X84-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q91X84-2; Sequence=VSP_031221;
CC -!- TISSUE SPECIFICITY: Expressed in brown adipose tissues.
CC {ECO:0000269|PubMed:30611118}.
CC -!- PTM: Phosphorylation/dephosphorylation states of Ser-273 are required
CC for regulating transduction of CREB activity (PubMed:29211348).
CC CRTCs/TORCs are inactive when phosphorylated, and active when
CC dephosphorylated at this site (PubMed:29211348). May be phosphorylated
CC at Ser-391 by MAPK3/ERK1 and/or MAPK1/ERK2 or by some cyclin-dependent
CC kinases such as CDK1,CDK2 or CDK5 (PubMed:30611118). Following adenylyl
CC cyclase activation, dephosphorylated at Ser-162 and Ser-273 resulting
CC in its dissociation from 14-3-3 proteins probably promoting CRTC3
CC translocation into the nucleus (PubMed:30611118).
CC {ECO:0000269|PubMed:29211348, ECO:0000269|PubMed:30611118}.
CC -!- SIMILARITY: Belongs to the TORC family. {ECO:0000305}.
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DR EMBL; AK144840; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC011210; AAH11210.1; -; mRNA.
DR CCDS; CCDS21398.2; -. [Q91X84-1]
DR RefSeq; NP_776288.2; NM_173863.2. [Q91X84-1]
DR RefSeq; XP_006541259.1; XM_006541196.1.
DR AlphaFoldDB; Q91X84; -.
DR SMR; Q91X84; -.
DR STRING; 10090.ENSMUSP00000113540; -.
DR iPTMnet; Q91X84; -.
DR PhosphoSitePlus; Q91X84; -.
DR EPD; Q91X84; -.
DR jPOST; Q91X84; -.
DR MaxQB; Q91X84; -.
DR PaxDb; Q91X84; -.
DR PeptideAtlas; Q91X84; -.
DR PRIDE; Q91X84; -.
DR ProteomicsDB; 285366; -. [Q91X84-1]
DR ProteomicsDB; 285367; -. [Q91X84-2]
DR Antibodypedia; 37539; 147 antibodies from 27 providers.
DR Ensembl; ENSMUST00000122255; ENSMUSP00000113540; ENSMUSG00000030527. [Q91X84-1]
DR GeneID; 70461; -.
DR KEGG; mmu:70461; -.
DR UCSC; uc009iaz.1; mouse. [Q91X84-1]
DR CTD; 64784; -.
DR MGI; MGI:1917711; Crtc3.
DR VEuPathDB; HostDB:ENSMUSG00000030527; -.
DR eggNOG; ENOG502QV9G; Eukaryota.
DR GeneTree; ENSGT00390000010652; -.
DR HOGENOM; CLU_019357_3_0_1; -.
DR InParanoid; Q91X84; -.
DR OMA; EAQDSFH; -.
DR OrthoDB; 1118500at2759; -.
DR PhylomeDB; Q91X84; -.
DR TreeFam; TF321571; -.
DR BioGRID-ORCS; 70461; 2 hits in 75 CRISPR screens.
DR ChiTaRS; Crtc3; mouse.
DR PRO; PR:Q91X84; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q91X84; protein.
DR Bgee; ENSMUSG00000030527; Expressed in animal zygote and 217 other tissues.
DR ExpressionAtlas; Q91X84; baseline and differential.
DR Genevisible; Q91X84; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0008140; F:cAMP response element binding protein binding; IBA:GO_Central.
DR GO; GO:0097009; P:energy homeostasis; IMP:MGI.
DR GO; GO:0016042; P:lipid catabolic process; IMP:MGI.
DR GO; GO:0042116; P:macrophage activation; ISO:MGI.
DR GO; GO:0071878; P:negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway; IDA:MGI.
DR GO; GO:0050995; P:negative regulation of lipid catabolic process; IMP:MGI.
DR GO; GO:0032793; P:positive regulation of CREB transcription factor activity; IMP:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0051289; P:protein homotetramerization; IEA:InterPro.
DR InterPro; IPR024786; TORC.
DR InterPro; IPR024785; TORC_C.
DR InterPro; IPR024784; TORC_M.
DR InterPro; IPR024783; TORC_N.
DR PANTHER; PTHR13589; PTHR13589; 1.
DR Pfam; PF12886; TORC_C; 1.
DR Pfam; PF12885; TORC_M; 1.
DR Pfam; PF12884; TORC_N; 1.
PE 1: Evidence at protein level;
KW Activator; Alternative splicing; Cytoplasm; Isopeptide bond; Nucleus;
KW Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..619
FT /note="CREB-regulated transcription coactivator 3"
FT /id="PRO_0000318532"
FT REGION 129..148
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 375..478
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 380..401
FT /note="Required for interaction with PPP2CA and PPP2R1A"
FT /evidence="ECO:0000269|PubMed:30611118"
FT COMPBIAS 375..390
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 401..439
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 440..456
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 457..478
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 4
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6UUV7"
FT MOD_RES 62
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:28235073,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 160
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:28235073"
FT MOD_RES 162
FT /note="Phosphoserine; by SIK2"
FT /evidence="ECO:0000269|PubMed:28235073,
FT ECO:0000269|PubMed:30611118"
FT MOD_RES 273
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:28235073,
FT ECO:0000269|PubMed:29211348, ECO:0000269|PubMed:30611118"
FT MOD_RES 329
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6UUV7"
FT MOD_RES 332
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6UUV7"
FT MOD_RES 370
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 391
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:30611118"
FT MOD_RES 396
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:30611118"
FT MOD_RES 410
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6UUV7"
FT MOD_RES 443
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6UUV7"
FT CROSSLNK 232
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q6UUV7"
FT VAR_SEQ 1..299
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_031221"
FT MUTAGEN 62
FT /note="S->A: Reduces interaction with 14-3-3 proteins
FT without affecting the interaction with PPP2R1A; when
FT associated with A-329 and A-370."
FT /evidence="ECO:0000269|PubMed:30611118"
FT MUTAGEN 162
FT /note="S->A: Up-regulates CREB transcription factor
FT activity. Reduces interaction with 14-3-3 proteins.
FT Abolishes interaction with 14-3-3 proteins without
FT affecting the interaction with PPP2R1A; when associated
FT with A-273."
FT /evidence="ECO:0000269|PubMed:28235073,
FT ECO:0000269|PubMed:30611118"
FT MUTAGEN 273
FT /note="S->A: Reduces interaction with 14-3-3 proteins.
FT Abolishes interaction with 14-3-3 proteins without
FT affecting the interaction with PPP2R1A; when associated
FT with A-162."
FT /evidence="ECO:0000269|PubMed:28235073,
FT ECO:0000269|PubMed:30611118"
FT MUTAGEN 329
FT /note="S->A: Reduces interaction with 14-3-3 proteins
FT without affecting the interaction with PPP2R1A; when
FT associated with A-62 and A-370."
FT /evidence="ECO:0000269|PubMed:30611118"
FT MUTAGEN 370
FT /note="S->A: Reduces interaction with 14-3-3 proteins
FT without affecting the interaction with PPP2R1A; when
FT associated with A-62 and A-329."
FT /evidence="ECO:0000269|PubMed:30611118"
FT MUTAGEN 391
FT /note="S->A,E: Abolishes phosphorylation. Abolishes
FT interaction with PPP2CA and PPP2R1A. Slight increase in
FT phosphorylation at Ser-273 and in the interaction with 14-
FT 3-3 proteins."
FT /evidence="ECO:0000269|PubMed:30611118"
FT MUTAGEN 392
FT /note="P->A: Abolishes phosphorylation at Ser-391.
FT Abolishes interaction with PPP2CA and PPP2R1A."
FT /evidence="ECO:0000269|PubMed:30611118"
FT MUTAGEN 394
FT /note="T->A: Does not affect phosphorylation at Ser-391 or
FT the interaction with PPP2CA and PPP2R1A."
FT /evidence="ECO:0000269|PubMed:30611118"
FT MUTAGEN 396
FT /note="S->A: Does not affect phosphorylation at Ser-391 or
FT the interaction with PPP2CA and PPP2R1A."
FT /evidence="ECO:0000269|PubMed:30611118"
SQ SEQUENCE 619 AA; 67027 MW; FBBE723F186CD60E CRC64;
MAASPGSGSA NPRKFSEKIA LHTQRQAEET RAFEQLMTDL TLSRVQFQKL QQLRLTQYHG
GSLPNVSQLR NSAPEFQPSL HQADNVRGTR HHGLVERPAR NRFHPLHRRS GDKPGRQFDG
NAFAASYSSQ HLDESWPRQQ PPWKEEKHPG FRLTSALNRT NSDSALHTSA LSTKPQDPYG
GGGQSAWPAP YMGFCDGEND GHAEVAAFPG PLKEENLLNV PKPLPKHLWE SKEIQSLSGR
PRSCDVGGGN AFPHNGQNTG LSPFLGTLNT GGSLPDLTNL HYSAPLPASL DTSDHLFGSM
SVGNSVGNLP AAMTHLGIRT SSGLQSSRSN PSIQATLSKM ALSSSLKCHP QPSVANASAL
HPSLRLFSLS NPSLSTTNLS GPSRRRQPPV SPLTLSPGPE AHQGFSRQLS ATSPLNPYPA
SQMVTSEQSP LSFLPTDAQA QVSPPPPYPT PQELPQPLLQ QPHAQEPPTQ QPQAAPSLPQ
SDFQLLTAQG SALTSFFPDV RFDQQPMRPS PAFPQQVPLV QQSHREPQDS FHLRPNPYSS
CGSFPGTILT EDTNSNLFKG LSGGLSGMPE VSLDMDTPFP LEEELQIEPL SLDGLNMLSD
SSMGLLDPSV EETFRADRL
