CR3L2_MOUSE
ID CR3L2_MOUSE Reviewed; 521 AA.
AC Q8BH52; B2RRL0; Q8CB61; Q8CBN2;
DT 29-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=Cyclic AMP-responsive element-binding protein 3-like protein 2;
DE Short=cAMP-responsive element-binding protein 3-like protein 2;
DE Contains:
DE RecName: Full=Processed cyclic AMP-responsive element-binding protein 3-like protein 2;
GN Name=Creb3l2; Synonyms=Bbf2h7;
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].
RC STRAIN=C57BL/6J; TISSUE=Blood vessel, Bone, Thymus, and Urinary bladder;
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].
RC STRAIN=FVB/N; TISSUE=Brain, and 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 FUNCTION AS TRANSCRIPTION FACTOR, SUBCELLULAR LOCATION, GLYCOSYLATION,
RP INDUCTION BY ER STRESS, PROTEOLYTIC CLEAVAGE, TISSUE SPECIFICITY, AND
RP MUTAGENESIS OF ARG-427 AND LEU-430.
RX PubMed=17178827; DOI=10.1128/mcb.01552-06;
RA Kondo S., Saito A., Hino S., Murakami T., Ogata M., Kanemoto S., Nara S.,
RA Yamashita A., Yoshinaga K., Hara H., Imaizumi K.;
RT "BBF2H7, a novel transmembrane bZIP transcription factor, is a new type of
RT endoplasmic reticulum stress transducer.";
RL Mol. Cell. Biol. 27:1716-1729(2007).
RN [4]
RP FUNCTION IN CHONDROGENESIS, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE, AND
RP INDUCTION BY ER STRESS AND SOX9.
RX PubMed=19767744; DOI=10.1038/ncb1962;
RA Saito A., Hino S., Murakami T., Kanemoto S., Kondo S., Saitoh M.,
RA Nishimura R., Yoneda T., Furuichi T., Ikegawa S., Ikawa M., Okabe M.,
RA Imaizumi K.;
RT "Regulation of endoplasmic reticulum stress response by a BBF2H7-mediated
RT Sec23a pathway is essential for chondrogenesis.";
RL Nat. Cell Biol. 11:1197-1204(2009).
RN [5]
RP UBIQUITINATION.
RX PubMed=22705851; DOI=10.1038/cdd.2012.77;
RA Kondo S., Hino S.I., Saito A., Kanemoto S., Kawasaki N., Asada R.,
RA Izumi S., Iwamoto H., Oki M., Miyagi H., Kaneko M., Nomura Y., Urano F.,
RA Imaizumi K.;
RT "Activation of OASIS family, ER stress transducers, is dependent on its
RT stabilization.";
RL Cell Death Differ. 19:1939-1949(2012).
CC -!- FUNCTION: Transcription factor involved in unfolded protein response
CC (UPR). In the absence of endoplasmic reticulum (ER) stress, inserted
CC into ER membranes, with N-terminal DNA-binding and transcription
CC activation domains oriented toward the cytosolic face of the membrane.
CC In response to ER stress, transported to the Golgi, where it is cleaved
CC in a site-specific manner by resident proteases S1P/MBTPS1 and
CC S2P/MBTPS2. The released N-terminal cytosolic domain is translocated to
CC the nucleus to effect transcription of specific target genes. Plays a
CC critical role in chondrogenesis by activating the transcription of
CC SEC23A, which promotes the transport and secretion of cartilage matrix
CC proteins, and possibly that of ER biogenesis-related genes
CC (PubMed:19767744). In a neuroblastoma cell line, protects cells from ER
CC stress-induced death (PubMed:17178827). In vitro activates
CC transcription of target genes via direct binding to the CRE site
CC (PubMed:17178827). {ECO:0000269|PubMed:17178827,
CC ECO:0000269|PubMed:19767744}.
CC -!- SUBUNIT: Binds DNA as a dimer. {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:17178827}; Single-pass type II membrane protein.
CC Note=ER membrane resident protein. Upon ER stress, translocated to the
CC Golgi apparatus where it is cleaved. The cytosolic N-terminal fragment
CC (processed cyclic AMP-responsive element-binding protein 3-like protein
CC 1) is transported into the nucleus. {ECO:0000269|PubMed:17178827}.
CC -!- SUBCELLULAR LOCATION: [Processed cyclic AMP-responsive element-binding
CC protein 3-like protein 2]: Nucleus {ECO:0000269|PubMed:17178827}.
CC Note=Upon ER stress, translocated into the nucleus.
CC {ECO:0000269|PubMed:17178827}.
CC -!- TISSUE SPECIFICITY: Widely expressed, including in lung, bladder,
CC ovary, testis and spleen (PubMed:17178827). Highly expressed in
CC chondrocytes (PubMed:19767744). {ECO:0000269|PubMed:17178827,
CC ECO:0000269|PubMed:19767744}.
CC -!- INDUCTION: Up-regulated by ER stress at the transcript and protein
CC levels, the increase at the protein level is much higher than at the
CC transcript level. This induction is accompanied by increased
CC proteolytic cleavage that releases the N-terminal transcription factor
CC domain. Up-regulated in brain areas undergoing ischemic injury, in
CC neurons, but not astrocytes. Up-regulated by SOX9 during chondrocyte
CC differentiation, possibly through SOX9-induced mild ER stress
CC (PubMed:19767744). {ECO:0000269|PubMed:17178827,
CC ECO:0000269|PubMed:19767744}.
CC -!- PTM: Upon ER stress, translocated to the Golgi apparatus, where it is
CC processed by regulated intramembrane proteolysis (RIP) to release the
CC cytosol-facing N-terminal transcription factor domain. The cleavage is
CC performed sequentially by site-1 and site-2 proteases (S1P/MBTPS1 and
CC S2P/MBTPS2). {ECO:0000269|PubMed:17178827}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:17178827}.
CC -!- PTM: Ubiquitinated by HRD1/SYVN1; undergoes 'Lys-48'-linked
CC ubiquitination, followed by rapid proteasomal degradation under normal
CC conditions. Upon ER stress, SYVN1 E3 ubiquitin-protein ligase
CC dissociates from its substrate, ubiquitination does not occur and
CC CREB3L2 is stabilized. {ECO:0000269|PubMed:22705851}.
CC -!- DISRUPTION PHENOTYPE: Mutant mice are born at the expected Mendelian
CC rate, but die by suffocation shortly after birth because of an immature
CC chest cavity. They exhibit severe chondrodysplasia. The cartilage shows
CC a lack of typical columnar structure in the proliferating zone and a
CC decrease in the size of the hypertrophic zone, resulting in a
CC significant reduction of extracellular matrix proteins. Proliferating
CC chondrocytes show abnormally expanded ER, containing aggregated type II
CC collagen and cartilage oligomeric matrix protein (COMP). Displays
CC significant decrease in Sec23a levels. {ECO:0000269|PubMed:19767744}.
CC -!- SIMILARITY: Belongs to the bZIP family. ATF subfamily. {ECO:0000305}.
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DR EMBL; AK035695; BAC29155.1; -; mRNA.
DR EMBL; AK036712; BAC29547.1; -; mRNA.
DR EMBL; AK041050; BAC30798.1; -; mRNA.
DR EMBL; AK041669; BAC31028.1; -; mRNA.
DR EMBL; BC043466; AAH43466.1; -; mRNA.
DR EMBL; BC138470; AAI38471.1; -; mRNA.
DR EMBL; BC138471; AAI38472.1; -; mRNA.
DR CCDS; CCDS20006.1; -.
DR RefSeq; NP_848776.2; NM_178661.4.
DR AlphaFoldDB; Q8BH52; -.
DR SMR; Q8BH52; -.
DR BioGRID; 229000; 2.
DR STRING; 10090.ENSMUSP00000040208; -.
DR GlyGen; Q8BH52; 3 sites.
DR iPTMnet; Q8BH52; -.
DR PhosphoSitePlus; Q8BH52; -.
DR jPOST; Q8BH52; -.
DR MaxQB; Q8BH52; -.
DR PaxDb; Q8BH52; -.
DR PeptideAtlas; Q8BH52; -.
DR PRIDE; Q8BH52; -.
DR ProteomicsDB; 284166; -.
DR Antibodypedia; 18186; 255 antibodies from 32 providers.
DR DNASU; 208647; -.
DR Ensembl; ENSMUST00000041093; ENSMUSP00000040208; ENSMUSG00000038648.
DR GeneID; 208647; -.
DR KEGG; mmu:208647; -.
DR UCSC; uc009bjf.2; mouse.
DR CTD; 64764; -.
DR MGI; MGI:2442695; Creb3l2.
DR VEuPathDB; HostDB:ENSMUSG00000038648; -.
DR eggNOG; KOG0709; Eukaryota.
DR GeneTree; ENSGT00940000157659; -.
DR HOGENOM; CLU_037638_0_0_1; -.
DR InParanoid; Q8BH52; -.
DR OMA; TDALMKP; -.
DR OrthoDB; 644485at2759; -.
DR PhylomeDB; Q8BH52; -.
DR TreeFam; TF316079; -.
DR BioGRID-ORCS; 208647; 4 hits in 77 CRISPR screens.
DR ChiTaRS; Creb3l2; mouse.
DR PRO; PR:Q8BH52; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; Q8BH52; protein.
DR Bgee; ENSMUSG00000038648; Expressed in humerus cartilage element and 218 other tissues.
DR Genevisible; Q8BH52; MM.
DR GO; GO:0000785; C:chromatin; ISO:MGI.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0097038; C:perinuclear endoplasmic reticulum; ISO:MGI.
DR GO; GO:0035497; F:cAMP response element binding; IMP:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IDA:NTNU_SB.
DR GO; GO:0000981; F:DNA-binding transcription factor activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:NTNU_SB.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IMP:UniProtKB.
DR GO; GO:0051216; P:cartilage development; IMP:UniProtKB.
DR GO; GO:0002062; P:chondrocyte differentiation; IMP:UniProtKB.
DR GO; GO:0006888; P:endoplasmic reticulum to Golgi vesicle-mediated transport; IMP:UniProtKB.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IEA:InterPro.
DR GO; GO:0010628; P:positive regulation of gene expression; ISO:MGI.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISO:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:NTNU_SB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0009611; P:response to wounding; IEA:Ensembl.
DR InterPro; IPR029804; BBF2H7.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR046347; bZIP_sf.
DR PANTHER; PTHR46004:SF2; PTHR46004:SF2; 1.
DR Pfam; PF00170; bZIP_1; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF57959; SSF57959; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
PE 1: Evidence at protein level;
KW Activator; Developmental protein; DNA-binding; Endoplasmic reticulum;
KW Glycoprotein; Isopeptide bond; Membrane; Nucleus; Phosphoprotein;
KW Reference proteome; Signal-anchor; Transcription; Transcription regulation;
KW Transmembrane; Transmembrane helix; Ubl conjugation;
KW Unfolded protein response.
FT CHAIN 1..521
FT /note="Cyclic AMP-responsive element-binding protein 3-like
FT protein 2"
FT /id="PRO_0000288068"
FT CHAIN 1..?
FT /note="Processed cyclic AMP-responsive element-binding
FT protein 3-like protein 2"
FT /id="PRO_0000296210"
FT TOPO_DOM 1..378
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 379..399
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 400..521
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT DOMAIN 294..357
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 83..106
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 196..264
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 296..325
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 336..357
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT MOTIF 427..430
FT /note="S1P recognition"
FT /evidence="ECO:0000250|UniProtKB:Q70SY1"
FT COMPBIAS 83..102
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 202..228
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 93
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q70SY1"
FT MOD_RES 191
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q70SY1"
FT CARBOHYD 481
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 505
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 518
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CROSSLNK 178
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q70SY1"
FT MUTAGEN 427
FT /note="R->A: Loss of S1P cleavage."
FT /evidence="ECO:0000269|PubMed:17178827"
FT MUTAGEN 427
FT /note="R->A: Loss of S1P cleavage; when associated with V-
FT 430."
FT /evidence="ECO:0000269|PubMed:17178827"
FT MUTAGEN 430
FT /note="L->V: Loss of S1P cleavage."
FT /evidence="ECO:0000269|PubMed:17178827"
FT MUTAGEN 430
FT /note="L->V: Loss of S1P cleavage; when associated with A-
FT 427."
FT /evidence="ECO:0000269|PubMed:17178827"
FT CONFLICT 264
FT /note="L -> R (in Ref. 1; BAC29155)"
FT /evidence="ECO:0000305"
FT CONFLICT 345
FT /note="N -> D (in Ref. 1; BAC29547)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 521 AA; 57469 MW; 4BDC49112F56F8BE CRC64;
MEVLESGEQS VLQWDRKLSE LSEPGETEAL MYHTHFSELL DEFSQNVLGQ LLSDPFLSEK
SESMEVEPSP TSPAPLIQAE HSYSLSEEPR TQSPFTHAAT SDSFNDEEVE SEKWYLSTEF
PSATIKTEPI TEEQPPGLVP SVTLTITAIS TPFEKEESPL DMNAGGDSSC QTLIPKIKLE
PHEVDQFLNF SPKEASVDQL HLPPTPPSSH SSDSEGSLSP NPRLHPFSLS QAHSPARAMP
RGPSALSTSP LLTAPHKLQG SGPLVLTEEE KRTLVAEGYP IPTKLPLTKS EEKALKKIRR
KIKNKISAQE SRRKKKEYMD SLEKKVESCS TENLELRKKV EVLENTNRTL LQQLQKLQTL
VMGKVSRTCK LAGTQTGTCL MVVVLCFAVA FGSFFQGYGP YPSATKMALP SQHPLSEPYT
ASVVRSRNLL IYEEHAPLEE SSSPASAGEL GGWDRGSSLL RASSGLEALP EVDLPHFLIS
NETSLEKSVL LELQQHLVSS KLEGNETLKV VELERRVNAT F
