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   27-MAR-2024, entry version 142.
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; 10090-ENSMUSP00000113540; -.
DR   PeptideAtlas; Q91X84; -.
DR   ProteomicsDB; 285366; -. [Q91X84-1]
DR   ProteomicsDB; 285367; -. [Q91X84-2]
DR   Pumba; Q91X84; -.
DR   Antibodypedia; 37539; 177 antibodies from 27 providers.
DR   Ensembl; ENSMUST00000122255.8; ENSMUSP00000113540.2; ENSMUSG00000030527.16. [Q91X84-1]
DR   GeneID; 70461; -.
DR   KEGG; mmu:70461; -.
DR   UCSC; uc009iaz.1; mouse. [Q91X84-1]
DR   AGR; MGI:1917711; -.
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; PYPMPQE; -.
DR   OrthoDB; 2906223at2759; -.
DR   PhylomeDB; Q91X84; -.
DR   TreeFam; TF321571; -.
DR   BioGRID-ORCS; 70461; 2 hits in 80 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 219 other cell types or tissues.
DR   ExpressionAtlas; Q91X84; baseline and differential.
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; CREB-REGULATED TRANSCRIPTION COACTIVATOR; 1.
DR   PANTHER; PTHR13589:SF4; CREB-REGULATED TRANSCRIPTION COACTIVATOR 3; 1.
DR   Pfam; PF12886; TORC_C; 1.
DR   Pfam; PF12885; TORC_M; 1.
DR   Pfam; PF12884; TORC_N; 1.
DR   Genevisible; Q91X84; MM.
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
FT                   14-3-3 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
//