CCM2_MOUSE
ID CCM2_MOUSE Reviewed; 453 AA.
AC Q8K2Y9; Q5SUA3;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=Cerebral cavernous malformations protein 2 homolog;
DE AltName: Full=Malcavernin {ECO:0000250|UniProtKB:Q9BSQ5};
DE AltName: Full=Osmosensing scaffold for MEKK3 {ECO:0000303|PubMed:14634666};
GN Name=Ccm2; Synonyms=Osm;
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 [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION,
RP TISSUE SPECIFICITY, AND INTERACTION WITH MAP3K3; MAP2K3 AND RAC1.
RC STRAIN=C57BL/6J; TISSUE=T-cell lymphoma;
RX PubMed=14634666; DOI=10.1038/ncb1071;
RA Uhlik M.T., Abell A.N., Johnson N.L., Sun W., Cuevas B.D., Lobel-Rice K.E.,
RA Horne E.A., Dell'Acqua M.L., Johnson G.L.;
RT "Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic
RT shock.";
RL Nat. Cell Biol. 5:1104-1110(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=NOD; TISSUE=Dendritic cell;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND ALTERNATIVE SPLICING
RP (ISOFORMS 1 AND 2).
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=FVB/N; TISSUE=Mammary tumor;
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 [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [6]
RP FUNCTION, INTERACTION WITH HEG1 AND KRIT1, AND DEVELOPMENTAL STAGE.
RX PubMed=19151727; DOI=10.1038/nm.1918;
RA Kleaveland B., Zheng X., Liu J.J., Blum Y., Tung J.J., Zou Z.,
RA Sweeney S.M., Chen M., Guo L., Lu M.M., Zhou D., Kitajewski J.,
RA Affolter M., Ginsberg M.H., Kahn M.L.;
RT "Regulation of cardiovascular development and integrity by the heart of
RT glass-cerebral cavernous malformation protein pathway.";
RL Nat. Med. 15:169-176(2009).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-393; SER-402; THR-403;
RP SER-405 AND THR-408, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
RP ANALYSIS].
RC TISSUE=Brown adipose tissue, Kidney, Lung, and Spleen;
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).
CC -!- FUNCTION: Component of the CCM signaling pathway which is a crucial
CC regulator of heart and vessel formation and integrity. May act through
CC the stabilization of endothelial cell junctions. May also function as a
CC scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major
CC role in the modulation of MAP3K3-dependent p38 activation induced by
CC hyperosmotic shock. {ECO:0000269|PubMed:14634666,
CC ECO:0000269|PubMed:19151727}.
CC -!- SUBUNIT: Part of a complex with MAP2K3, MAP3K3 and RAC1. Binds RAC1
CC directly and independently of its nucleotide-bound state. Interacts
CC with PDCD10 (By similarity). Interacts with HEG1 and KRIT1; KRIT1
CC greatly facilitates the interaction with HEG1. {ECO:0000250,
CC ECO:0000269|PubMed:14634666, ECO:0000269|PubMed:19151727}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14634666}.
CC Note=Treatment with sorbitol caused relocalization to ruffle-like
CC structures.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8K2Y9-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8K2Y9-2; Sequence=VSP_024404, VSP_024405;
CC -!- TISSUE SPECIFICITY: Highly expressed in heart, lower expression in
CC kidney, lung and liver (at protein level).
CC {ECO:0000269|PubMed:14634666}.
CC -!- DEVELOPMENTAL STAGE: Expressed primarily in the developing neural tube
CC at 10.5 dpc. {ECO:0000269|PubMed:19151727}.
CC -!- DOMAIN: The C-terminal region constitutes an independently folded
CC domain that has structural similarity with the USH1C (harmonin) N-
CC terminus, despite very low sequence similarity. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the CCM2 family. {ECO:0000305}.
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DR EMBL; AY442689; AAR29082.1; -; mRNA.
DR EMBL; AK155145; BAE33075.1; -; mRNA.
DR EMBL; AL603787; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL646047; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC029157; AAH29157.1; -; mRNA.
DR CCDS; CCDS24422.1; -. [Q8K2Y9-1]
DR RefSeq; NP_666126.1; NM_146014.3. [Q8K2Y9-1]
DR AlphaFoldDB; Q8K2Y9; -.
DR SMR; Q8K2Y9; -.
DR BioGRID; 229755; 2.
DR ComplexPortal; CPX-4621; CCM complex.
DR CORUM; Q8K2Y9; -.
DR IntAct; Q8K2Y9; 1.
DR MINT; Q8K2Y9; -.
DR STRING; 10090.ENSMUSP00000000388; -.
DR iPTMnet; Q8K2Y9; -.
DR PhosphoSitePlus; Q8K2Y9; -.
DR EPD; Q8K2Y9; -.
DR jPOST; Q8K2Y9; -.
DR MaxQB; Q8K2Y9; -.
DR PaxDb; Q8K2Y9; -.
DR PRIDE; Q8K2Y9; -.
DR ProteomicsDB; 281124; -. [Q8K2Y9-1]
DR ProteomicsDB; 281125; -. [Q8K2Y9-2]
DR Antibodypedia; 13519; 346 antibodies from 30 providers.
DR DNASU; 216527; -.
DR Ensembl; ENSMUST00000000388; ENSMUSP00000000388; ENSMUSG00000000378. [Q8K2Y9-1]
DR GeneID; 216527; -.
DR KEGG; mmu:216527; -.
DR UCSC; uc007hyv.2; mouse. [Q8K2Y9-1]
DR CTD; 83605; -.
DR MGI; MGI:2384924; Ccm2.
DR VEuPathDB; HostDB:ENSMUSG00000000378; -.
DR eggNOG; ENOG502QSZM; Eukaryota.
DR GeneTree; ENSGT00390000016168; -.
DR HOGENOM; CLU_034621_1_0_1; -.
DR InParanoid; Q8K2Y9; -.
DR OMA; EPYETET; -.
DR OrthoDB; 1446057at2759; -.
DR PhylomeDB; Q8K2Y9; -.
DR TreeFam; TF328517; -.
DR BioGRID-ORCS; 216527; 14 hits in 73 CRISPR screens.
DR ChiTaRS; Ccm2; mouse.
DR PRO; PR:Q8K2Y9; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q8K2Y9; protein.
DR Bgee; ENSMUSG00000000378; Expressed in peripheral lymph node and 289 other tissues.
DR ExpressionAtlas; Q8K2Y9; baseline and differential.
DR Genevisible; Q8K2Y9; MM.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; IDA:MGI.
DR GO; GO:0001568; P:blood vessel development; IMP:MGI.
DR GO; GO:0060837; P:blood vessel endothelial cell differentiation; IMP:MGI.
DR GO; GO:0045216; P:cell-cell junction organization; IMP:MGI.
DR GO; GO:0001885; P:endothelial cell development; IMP:MGI.
DR GO; GO:0061154; P:endothelial tube morphogenesis; ISO:MGI.
DR GO; GO:0003158; P:endothelium development; IC:ComplexPortal.
DR GO; GO:0007507; P:heart development; IMP:MGI.
DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI.
DR GO; GO:0048839; P:inner ear development; IDA:MGI.
DR GO; GO:0035264; P:multicellular organism growth; IMP:MGI.
DR GO; GO:0060039; P:pericardium development; IMP:MGI.
DR GO; GO:0045765; P:regulation of angiogenesis; IC:ComplexPortal.
DR GO; GO:0001944; P:vasculature development; IMP:MGI.
DR GO; GO:0001570; P:vasculogenesis; IGI:MGI.
DR GO; GO:0048845; P:venous blood vessel morphogenesis; IMP:MGI.
DR CDD; cd13516; HHD_CCM2; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR032375; CCM2_C.
DR InterPro; IPR026159; Malcavernin.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR006020; PTB/PI_dom.
DR PANTHER; PTHR21642; PTHR21642; 1.
DR Pfam; PF16545; CCM2_C; 1.
DR PROSITE; PS01179; PID; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cytoplasm; Phosphoprotein; Reference proteome.
FT CHAIN 1..453
FT /note="Cerebral cavernous malformations protein 2 homolog"
FT /id="PRO_0000089425"
FT DOMAIN 59..248
FT /note="PID"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT REGION 1..36
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 292..385
FT /note="Harmonin homology domain"
FT REGION 401..432
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 21..36
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 401..421
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 15
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9BSQ5"
FT MOD_RES 164
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9BSQ5"
FT MOD_RES 393
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 402
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 403
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 405
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 408
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT VAR_SEQ 1..10
FT /note="MEEEGKKGKK -> MENE (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_024404"
FT VAR_SEQ 279..287
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_024405"
SQ SEQUENCE 453 AA; 49917 MW; 51F165291E52691F CRC64;
MEEEGKKGKK PGIVSPFKRV FLKGEKSRDK KAHEKVTERR PLHTVVLALP ERVEPDRLLS
DYIEKEVKYL GQLTSIPGYL NPSSRTEILH FIDKAKRSHQ LPGHLTQEHD AVLSLSAYNV
KLAWRDGEDI ILRVPIHDIA AVSYVRDDAA HLVVLKTAQD PGISPSQSLC AESSRGLSAG
SLSESAVGPV EACCLVIMAT ESKVAAEELC SLLSQVFQIV YTESTIDFLD RAIFDGASTP
THHLSLHSDD SSTKVDMKDS YDADASTFCF PDSGDVGGLP PLPFCMQTSP HSKTVSESEL
STSATELLQD YMLTLRTKLS SQEIQQFAAL LHEYRNGASI HEFCISLRQL YGDSRKFLLL
GLRPFIPEKD SQHFENFLET IGVKDGRGII TDSFGRHRRA LSTTSTSTIN GNRTTGSPDD
RSAPSEGDEW DRMISDISSD IEALGCSMDQ DSA
