Full text data of CUL2
CUL2
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Cullin-2; CUL-2
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Cullin-2; CUL-2
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00014311
IPI00014311 Cullin homolog 2 Component of E3 ubiquitin ligase complexes soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00014311 Cullin homolog 2 Component of E3 ubiquitin ligase complexes soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
Q13617
ID CUL2_HUMAN Reviewed; 745 AA.
AC Q13617; B3KT95; B7Z6K8; D3DRY6; G3V1S2; O00200; Q5T2B6; Q9UNF9;
read moreDT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 14-AUG-2001, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Cullin-2;
DE Short=CUL-2;
GN Name=CUL2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT SER-109, AND
RP IDENTIFICATION IN COMPLEX WITH VHL AND ELONGIN BC.
RC TISSUE=Kidney;
RX PubMed=9122164; DOI=10.1073/pnas.94.6.2156;
RA Pause A., Lee S., Worrel R., Chen D.Y.T., Burgess W.H., Linehan W.M.,
RA Klausner R.D.;
RT "The von Hippel-Lindau tumor-suppressor gene product forms a stable
RT complex with human CUL-2, a member of the Cdc53 family of proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:2156-2161(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT SER-109, MUTAGENESIS
RP OF LYS-621; LYS-689 AND LYS-719, AND NEDDYLATION AT LYS-689.
RC TISSUE=Brain;
RX PubMed=10092517; DOI=10.1006/bbrc.1999.0339;
RA Wada H., Yeh E.T.H., Kamitani T.;
RT "Identification of NEDD8-conjugation site in human cullin-2.";
RL Biochem. Biophys. Res. Commun. 257:100-105(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Prostate;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Skin;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 95-745.
RX PubMed=8681378; DOI=10.1016/S0092-8674(00)81267-2;
RA Kipreos E.T., Lander L.E., Wing J.P., He W.W., Hedgecock E.M.;
RT "cul-1 is required for cell cycle exit in C. elegans and identifies a
RT novel gene family.";
RL Cell 85:829-839(1996).
RN [8]
RP INTERACTION WITH RBX1 AND RNF7.
RX PubMed=10230407; DOI=10.1016/S1097-2765(00)80482-7;
RA Ohta T., Michel J.J., Schottelius A.J., Xiong Y.;
RT "ROC1, a homolog of APC11, represents a family of cullin partners with
RT an associated ubiquitin ligase activity.";
RL Mol. Cell 3:535-541(1999).
RN [9]
RP IDENTIFICATION IN CBC(VHL) COMPLEX.
RX PubMed=10973499; DOI=10.1073/pnas.190332597;
RA Kamura T., Sato S., Iwai K., Czyzyk-Krzeska M., Conaway R.C.,
RA Conaway J.W.;
RT "Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-
RT Lindau (VHL) tumor suppressor complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:10430-10435(2000).
RN [10]
RP IDENTIFICATION IN COMPLEX WITH VHL; ELONGIN BC AND RBX1.
RX PubMed=11384984; DOI=10.1074/jbc.M103093200;
RA Kamura T., Burian D., Yan Q., Schmidt S.L., Lane W.S., Querido E.,
RA Branton P.E., Shilatifard A., Conaway R.C., Conaway J.W.;
RT "Muf1, a novel elongin BC-interacting leucine-rich repeat protein that
RT can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase.";
RL J. Biol. Chem. 276:29748-29753(2001).
RN [11]
RP IDENTIFICATION IN E3 UBIQUITIN-PROTEIN LIGASE COMPLEX WITH MED8.
RX PubMed=12149480; DOI=10.1073/pnas.162424199;
RA Brower C.S., Sato S., Tomomori-Sato C., Kamura T., Pause A.,
RA Stearman R., Klausner R.D., Malik S., Lane W.S., Sorokina I.,
RA Roeder R.G., Conaway J.W., Conaway R.C.;
RT "Mammalian mediator subunit mMED8 is an Elongin BC-interacting protein
RT that can assemble with Cul2 and Rbx1 to reconstitute a ubiquitin
RT ligase.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:10353-10358(2002).
RN [12]
RP INTERACTION WITH TIP120A.
RX PubMed=12609982; DOI=10.1074/jbc.M213070200;
RA Min K.-W., Hwang J.-W., Lee J.-S., Park Y., Tamura T.-A., Yoon J.-B.;
RT "TIP120A associates with cullins and modulates ubiquitin ligase
RT activity.";
RL J. Biol. Chem. 278:15905-15910(2003).
RN [13]
RP NEDDYLATION.
RX PubMed=10597293; DOI=10.1038/sj.onc.1203093;
RA Hori T., Osaka F., Chiba T., Miyamoto C., Okabayashi K., Shimbara N.,
RA Kato S., Tanaka K.;
RT "Covalent modification of all members of human cullin family proteins
RT by NEDD8.";
RL Oncogene 18:6829-6834(1999).
RN [14]
RP INTERACTION WITH LRR1 AND FEM1B.
RX PubMed=15601820; DOI=10.1101/gad.1252404;
RA Kamura T., Maenaka K., Kotoshiba S., Matsumoto M., Kohda D.,
RA Conaway R.C., Conaway J.W., Nakayama K.I.;
RT "VHL-box and SOCS-box domains determine binding specificity for Cul2-
RT Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases.";
RL Genes Dev. 18:3055-3065(2004).
RN [15]
RP IDENTIFICATION IN COMPLEX WITH TCEB1 AND ZYG11B, AND IDENTIFICATION IN
RP COMPLEX WITH TCEB1; TCEB2 AND CUL2.
RX PubMed=17304241; DOI=10.1038/sj.embor.7400895;
RA Vasudevan S., Starostina N.G., Kipreos E.T.;
RT "The Caenorhabditis elegans cell-cycle regulator ZYG-11 defines a
RT conserved family of CUL-2 complex components.";
RL EMBO Rep. 8:279-286(2007).
RN [16]
RP INTERACTION WITH HRSV VIRUS PROTEIN NS1.
RX PubMed=17251292; DOI=10.1128/JVI.02303-06;
RA Elliott J., Lynch O.T., Suessmuth Y., Qian P., Boyd C.R.,
RA Burrows J.F., Buick R., Stevenson N.J., Touzelet O., Gadina M.,
RA Power U.F., Johnston J.A.;
RT "Respiratory syncytial virus NS1 protein degrades STAT2 by using the
RT Elongin-Cullin E3 ligase.";
RL J. Virol. 81:3428-3436(2007).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-661, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-393, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP INTERACTS WITH KLHDC10.
RX PubMed=23102700; DOI=10.1016/j.molcel.2012.09.018;
RA Sekine Y., Hatanaka R., Watanabe T., Sono N., Iemura S., Natsume T.,
RA Kuranaga E., Miura M., Takeda K., Ichijo H.;
RT "The Kelch repeat protein KLHDC10 regulates oxidative stress-induced
RT ASK1 activation by suppressing PP5.";
RL Mol. Cell 48:692-704(2012).
RN [21]
RP IDENTIFICATION IN A COMPLEX WITH LIMD1; EGLN1/PHD2; VHL AND TCEB2.
RX PubMed=22286099; DOI=10.1038/ncb2424;
RA Foxler D.E., Bridge K.S., James V., Webb T.M., Mee M., Wong S.C.,
RA Feng Y., Constantin-Teodosiu D., Petursdottir T.E., Bjornsson J.,
RA Ingvarsson S., Ratcliffe P.J., Longmore G.D., Sharp T.V.;
RT "The LIMD1 protein bridges an association between the prolyl
RT hydroxylases and VHL to repress HIF-1 activity.";
RL Nat. Cell Biol. 14:201-208(2012).
CC -!- FUNCTION: Core component of multiple cullin-RING-based ECS
CC (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase
CC complexes, which mediate the ubiquitination of target proteins.
CC May serve as a rigid scaffold in the complex and may contribute to
CC catalysis through positioning of the substrate and the ubiquitin-
CC conjugating enzyme. The E3 ubiquitin-protein ligase activity of
CC the complex is dependent on the neddylation of the cullin subunit
CC and is inhibited by the association of the deneddylated cullin
CC subunit with TIP120A/CAND1 (By similarity). The functional
CC specificity of the ECS complex depends on the substrate
CC recognition component. ECS(VHL) mediates the ubiquitination of
CC hypoxia-inducible factor (HIF).
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Component of multiple ECS (Elongin BC-CUL2/5-SOCS-box
CC protein) E3 ubiquitin-protein ligase complexes formed of CUL2,
CC Elongin BC (TCEB1 and TCEB2), RBX1 and a variable substrate-
CC specific adapter. Component of the ECS(VHL) or CBC(VHL) complex
CC containing VHL. Component of the ECS(MED8) complex with the
CC probable substrate recognition component MED8. Component of the
CC ECS(LRR1) complex with the probable substrate recognition
CC component LRR1. Component of a probable ECS E3 ubiquitin-protein
CC ligase complex containing CUL2, RBX1, TCEB1, TCEB2 and FEM1B. Part
CC of an E3 ubiquitin-protein ligase complex including ZYG11B, CUL2
CC and Elongin BC. Part of an E3 ubiquitin-protein ligase complex
CC including ZYG11BL, CUL2 and Elongin BC. Interacts with RBX1, RNF7,
CC FEM1B and TIP120A/CAND1. Interacts with COPS2, and MED8. Interacts
CC with human respiratory syncytial virus (HRSV) protein NS1. Found
CC in a complex composed of LIMD1, VHL, EGLN1/PHD2, TCEB2 and CUL2.
CC Interacts with KLHDC10; which may be an E3 ubiquitin ligase
CC complex substrate recognition component.
CC -!- INTERACTION:
CC Q86VP6:CAND1; NbExp=3; IntAct=EBI-456179, EBI-456077;
CC Q8N668:COMMD1; NbExp=3; IntAct=EBI-456179, EBI-1550112;
CC P62877:RBX1; NbExp=5; IntAct=EBI-456179, EBI-398523;
CC Q15369:TCEB1; NbExp=5; IntAct=EBI-456179, EBI-301231;
CC P40337:VHL; NbExp=9; IntAct=EBI-456179, EBI-301246;
CC P12504:vif (xeno); NbExp=5; IntAct=EBI-456179, EBI-779991;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q13617-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13617-2; Sequence=VSP_044498;
CC Note=No experimental confirmation available;
CC -!- PTM: CBC(VHL) complex formation seems to promote neddylation.
CC Deneddylated via its interaction with the COP9 signalosome (CSN)
CC complex (By similarity).
CC -!- SIMILARITY: Belongs to the cullin family.
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DR EMBL; U83410; AAC51190.1; -; mRNA.
DR EMBL; AF126404; AAD23581.1; -; mRNA.
DR EMBL; AK095217; BAG53007.1; -; mRNA.
DR EMBL; AK300491; BAH13294.1; -; mRNA.
DR EMBL; AL392046; CAI13163.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW85924.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW85925.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW85926.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW85927.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW85928.1; -; Genomic_DNA.
DR EMBL; BC009591; AAH09591.1; -; mRNA.
DR EMBL; BC110901; AAI10902.1; -; mRNA.
DR EMBL; U58088; AAC50545.1; -; mRNA.
DR RefSeq; NP_001185706.1; NM_001198777.1.
DR RefSeq; NP_001185707.1; NM_001198778.1.
DR RefSeq; NP_001185708.1; NM_001198779.1.
DR RefSeq; NP_003582.2; NM_003591.3.
DR UniGene; Hs.82919; -.
DR ProteinModelPortal; Q13617; -.
DR SMR; Q13617; 8-745.
DR DIP; DIP-31612N; -.
DR IntAct; Q13617; 39.
DR MINT; MINT-1523339; -.
DR STRING; 9606.ENSP00000363880; -.
DR PhosphoSite; Q13617; -.
DR DMDM; 19863260; -.
DR PaxDb; Q13617; -.
DR PRIDE; Q13617; -.
DR DNASU; 8453; -.
DR Ensembl; ENST00000374748; ENSP00000363880; ENSG00000108094.
DR Ensembl; ENST00000374749; ENSP00000363881; ENSG00000108094.
DR Ensembl; ENST00000374751; ENSP00000363883; ENSG00000108094.
DR Ensembl; ENST00000537177; ENSP00000444856; ENSG00000108094.
DR GeneID; 8453; -.
DR KEGG; hsa:8453; -.
DR UCSC; uc001ixv.3; human.
DR CTD; 8453; -.
DR GeneCards; GC10M035338; -.
DR HGNC; HGNC:2552; CUL2.
DR HPA; CAB002677; -.
DR HPA; HPA024578; -.
DR MIM; 603135; gene.
DR neXtProt; NX_Q13617; -.
DR PharmGKB; PA27048; -.
DR eggNOG; COG5647; -.
DR HOVERGEN; HBG106177; -.
DR InParanoid; Q13617; -.
DR KO; K03870; -.
DR OMA; VMLDYVE; -.
DR OrthoDB; EOG7X3QQG; -.
DR PhylomeDB; Q13617; -.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_6900; Immune System.
DR UniPathway; UPA00143; -.
DR ChiTaRS; CUL2; human.
DR GeneWiki; CUL2; -.
DR GenomeRNAi; 8453; -.
DR NextBio; 31634; -.
DR PRO; PR:Q13617; -.
DR ArrayExpress; Q13617; -.
DR Bgee; Q13617; -.
DR CleanEx; HS_CUL2; -.
DR Genevestigator; Q13617; -.
DR GO; GO:0031462; C:Cul2-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB.
DR GO; GO:0007050; P:cell cycle arrest; TAS:ProtInc.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:ProtInc.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:ProtInc.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0008285; P:negative regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR GO; GO:0061418; P:regulation of transcription from RNA polymerase II promoter in response to hypoxia; TAS:Reactome.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR Gene3D; 1.10.10.10; -; 2.
DR InterPro; IPR016157; Cullin_CS.
DR InterPro; IPR016158; Cullin_homology.
DR InterPro; IPR001373; Cullin_N.
DR InterPro; IPR019559; Cullin_neddylation_domain.
DR InterPro; IPR016159; Cullin_repeat-like_dom.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00888; Cullin; 1.
DR Pfam; PF10557; Cullin_Nedd8; 1.
DR SMART; SM00182; CULLIN; 1.
DR SMART; SM00884; Cullin_Nedd8; 1.
DR SUPFAM; SSF74788; SSF74788; 1.
DR SUPFAM; SSF75632; SSF75632; 1.
DR PROSITE; PS01256; CULLIN_1; 1.
DR PROSITE; PS50069; CULLIN_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Complete proteome;
KW Host-virus interaction; Isopeptide bond; Phosphoprotein; Polymorphism;
KW Reference proteome; Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1 745 Cullin-2.
FT /FTId=PRO_0000119790.
FT MOD_RES 393 393 N6-acetyllysine.
FT MOD_RES 661 661 Phosphothreonine.
FT CROSSLNK 689 689 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in NEDD8).
FT VAR_SEQ 1 1 M -> MYRVTWSTFWLRFQHYTCTM (in isoform 2).
FT /FTId=VSP_044498.
FT VARIANT 109 109 N -> S (in dbSNP:rs1131503).
FT /FTId=VAR_011374.
FT MUTAGEN 621 621 K->R: No effect on conjugation with
FT NEDD8.
FT MUTAGEN 689 689 K->R: Loss of conjugation with NEDD8.
FT MUTAGEN 719 719 K->R: No effect on conjugation with
FT NEDD8.
FT CONFLICT 20 20 T -> I (in Ref. 3; BAH13294).
FT CONFLICT 95 98 SKGA -> IRHE (in Ref. 7; AAC50545).
FT CONFLICT 681 681 Q -> H (in Ref. 7; AAC50545).
SQ SEQUENCE 745 AA; 86983 MW; 30647248F671AB0E CRC64;
MSLKPRVVDF DETWNKLLTT IKAVVMLEYV ERATWNDRFS DIYALCVAYP EPLGERLYTE
TKIFLENHVR HLHKRVLESE EQVLVMYHRY WEEYSKGADY MDCLYRYLNT QFIKKNKLTE
ADLQYGYGGV DMNEPLMEIG ELALDMWRKL MVEPLQAILI RMLLREIKND RGGEDPNQKV
IHGVINSFVH VEQYKKKFPL KFYQEIFESP FLTETGEYYK QEASNLLQES NCSQYMEKVL
GRLKDEEIRC RKYLHPSSYT KVIHECQQRM VADHLQFLHA ECHNIIRQEK KNDMANMYVL
LRAVSTGLPH MIQELQNHIH DEGLRATSNL TQENMPTLFV ESVLEVHGKF VQLINTVLNG
DQHFMSALDK ALTSVVNYRE PKSVCKAPEL LAKYCDNLLK KSAKGMTENE VEDRLTSFIT
VFKYIDDKDV FQKFYARMLA KRLIHGLSMS MDSEEAMINK LKQACGYEFT SKLHRMYTDM
SVSADLNNKF NNFIKNQDTV IDLGISFQIY VLQAGAWPLT QAPSSTFAIP QELEKSVQMF
ELFYSQHFSG RKLTWLHYLC TGEVKMNYLG KPYVAMVTTY QMAVLLAFNN SETVSYKELQ
DSTQMNEKEL TKTIKSLLDV KMINHDSEKE DIDAESSFSL NMNFSSKRTK FKITTSMQKD
TPQEMEQTRS AVDEDRKMYL QAAIVRIMKA RKVLRHNALI QEVISQSRAR FNPSISMIKK
CIEVLIDKQY IERSQASADE YSYVA
//
ID CUL2_HUMAN Reviewed; 745 AA.
AC Q13617; B3KT95; B7Z6K8; D3DRY6; G3V1S2; O00200; Q5T2B6; Q9UNF9;
read moreDT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 14-AUG-2001, sequence version 2.
DT 22-JAN-2014, entry version 128.
DE RecName: Full=Cullin-2;
DE Short=CUL-2;
GN Name=CUL2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT SER-109, AND
RP IDENTIFICATION IN COMPLEX WITH VHL AND ELONGIN BC.
RC TISSUE=Kidney;
RX PubMed=9122164; DOI=10.1073/pnas.94.6.2156;
RA Pause A., Lee S., Worrel R., Chen D.Y.T., Burgess W.H., Linehan W.M.,
RA Klausner R.D.;
RT "The von Hippel-Lindau tumor-suppressor gene product forms a stable
RT complex with human CUL-2, a member of the Cdc53 family of proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:2156-2161(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT SER-109, MUTAGENESIS
RP OF LYS-621; LYS-689 AND LYS-719, AND NEDDYLATION AT LYS-689.
RC TISSUE=Brain;
RX PubMed=10092517; DOI=10.1006/bbrc.1999.0339;
RA Wada H., Yeh E.T.H., Kamitani T.;
RT "Identification of NEDD8-conjugation site in human cullin-2.";
RL Biochem. Biophys. Res. Commun. 257:100-105(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Prostate;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Skin;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 95-745.
RX PubMed=8681378; DOI=10.1016/S0092-8674(00)81267-2;
RA Kipreos E.T., Lander L.E., Wing J.P., He W.W., Hedgecock E.M.;
RT "cul-1 is required for cell cycle exit in C. elegans and identifies a
RT novel gene family.";
RL Cell 85:829-839(1996).
RN [8]
RP INTERACTION WITH RBX1 AND RNF7.
RX PubMed=10230407; DOI=10.1016/S1097-2765(00)80482-7;
RA Ohta T., Michel J.J., Schottelius A.J., Xiong Y.;
RT "ROC1, a homolog of APC11, represents a family of cullin partners with
RT an associated ubiquitin ligase activity.";
RL Mol. Cell 3:535-541(1999).
RN [9]
RP IDENTIFICATION IN CBC(VHL) COMPLEX.
RX PubMed=10973499; DOI=10.1073/pnas.190332597;
RA Kamura T., Sato S., Iwai K., Czyzyk-Krzeska M., Conaway R.C.,
RA Conaway J.W.;
RT "Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-
RT Lindau (VHL) tumor suppressor complex.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:10430-10435(2000).
RN [10]
RP IDENTIFICATION IN COMPLEX WITH VHL; ELONGIN BC AND RBX1.
RX PubMed=11384984; DOI=10.1074/jbc.M103093200;
RA Kamura T., Burian D., Yan Q., Schmidt S.L., Lane W.S., Querido E.,
RA Branton P.E., Shilatifard A., Conaway R.C., Conaway J.W.;
RT "Muf1, a novel elongin BC-interacting leucine-rich repeat protein that
RT can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase.";
RL J. Biol. Chem. 276:29748-29753(2001).
RN [11]
RP IDENTIFICATION IN E3 UBIQUITIN-PROTEIN LIGASE COMPLEX WITH MED8.
RX PubMed=12149480; DOI=10.1073/pnas.162424199;
RA Brower C.S., Sato S., Tomomori-Sato C., Kamura T., Pause A.,
RA Stearman R., Klausner R.D., Malik S., Lane W.S., Sorokina I.,
RA Roeder R.G., Conaway J.W., Conaway R.C.;
RT "Mammalian mediator subunit mMED8 is an Elongin BC-interacting protein
RT that can assemble with Cul2 and Rbx1 to reconstitute a ubiquitin
RT ligase.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:10353-10358(2002).
RN [12]
RP INTERACTION WITH TIP120A.
RX PubMed=12609982; DOI=10.1074/jbc.M213070200;
RA Min K.-W., Hwang J.-W., Lee J.-S., Park Y., Tamura T.-A., Yoon J.-B.;
RT "TIP120A associates with cullins and modulates ubiquitin ligase
RT activity.";
RL J. Biol. Chem. 278:15905-15910(2003).
RN [13]
RP NEDDYLATION.
RX PubMed=10597293; DOI=10.1038/sj.onc.1203093;
RA Hori T., Osaka F., Chiba T., Miyamoto C., Okabayashi K., Shimbara N.,
RA Kato S., Tanaka K.;
RT "Covalent modification of all members of human cullin family proteins
RT by NEDD8.";
RL Oncogene 18:6829-6834(1999).
RN [14]
RP INTERACTION WITH LRR1 AND FEM1B.
RX PubMed=15601820; DOI=10.1101/gad.1252404;
RA Kamura T., Maenaka K., Kotoshiba S., Matsumoto M., Kohda D.,
RA Conaway R.C., Conaway J.W., Nakayama K.I.;
RT "VHL-box and SOCS-box domains determine binding specificity for Cul2-
RT Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases.";
RL Genes Dev. 18:3055-3065(2004).
RN [15]
RP IDENTIFICATION IN COMPLEX WITH TCEB1 AND ZYG11B, AND IDENTIFICATION IN
RP COMPLEX WITH TCEB1; TCEB2 AND CUL2.
RX PubMed=17304241; DOI=10.1038/sj.embor.7400895;
RA Vasudevan S., Starostina N.G., Kipreos E.T.;
RT "The Caenorhabditis elegans cell-cycle regulator ZYG-11 defines a
RT conserved family of CUL-2 complex components.";
RL EMBO Rep. 8:279-286(2007).
RN [16]
RP INTERACTION WITH HRSV VIRUS PROTEIN NS1.
RX PubMed=17251292; DOI=10.1128/JVI.02303-06;
RA Elliott J., Lynch O.T., Suessmuth Y., Qian P., Boyd C.R.,
RA Burrows J.F., Buick R., Stevenson N.J., Touzelet O., Gadina M.,
RA Power U.F., Johnston J.A.;
RT "Respiratory syncytial virus NS1 protein degrades STAT2 by using the
RT Elongin-Cullin E3 ligase.";
RL J. Virol. 81:3428-3436(2007).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-661, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-393, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP INTERACTS WITH KLHDC10.
RX PubMed=23102700; DOI=10.1016/j.molcel.2012.09.018;
RA Sekine Y., Hatanaka R., Watanabe T., Sono N., Iemura S., Natsume T.,
RA Kuranaga E., Miura M., Takeda K., Ichijo H.;
RT "The Kelch repeat protein KLHDC10 regulates oxidative stress-induced
RT ASK1 activation by suppressing PP5.";
RL Mol. Cell 48:692-704(2012).
RN [21]
RP IDENTIFICATION IN A COMPLEX WITH LIMD1; EGLN1/PHD2; VHL AND TCEB2.
RX PubMed=22286099; DOI=10.1038/ncb2424;
RA Foxler D.E., Bridge K.S., James V., Webb T.M., Mee M., Wong S.C.,
RA Feng Y., Constantin-Teodosiu D., Petursdottir T.E., Bjornsson J.,
RA Ingvarsson S., Ratcliffe P.J., Longmore G.D., Sharp T.V.;
RT "The LIMD1 protein bridges an association between the prolyl
RT hydroxylases and VHL to repress HIF-1 activity.";
RL Nat. Cell Biol. 14:201-208(2012).
CC -!- FUNCTION: Core component of multiple cullin-RING-based ECS
CC (ElonginB/C-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase
CC complexes, which mediate the ubiquitination of target proteins.
CC May serve as a rigid scaffold in the complex and may contribute to
CC catalysis through positioning of the substrate and the ubiquitin-
CC conjugating enzyme. The E3 ubiquitin-protein ligase activity of
CC the complex is dependent on the neddylation of the cullin subunit
CC and is inhibited by the association of the deneddylated cullin
CC subunit with TIP120A/CAND1 (By similarity). The functional
CC specificity of the ECS complex depends on the substrate
CC recognition component. ECS(VHL) mediates the ubiquitination of
CC hypoxia-inducible factor (HIF).
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Component of multiple ECS (Elongin BC-CUL2/5-SOCS-box
CC protein) E3 ubiquitin-protein ligase complexes formed of CUL2,
CC Elongin BC (TCEB1 and TCEB2), RBX1 and a variable substrate-
CC specific adapter. Component of the ECS(VHL) or CBC(VHL) complex
CC containing VHL. Component of the ECS(MED8) complex with the
CC probable substrate recognition component MED8. Component of the
CC ECS(LRR1) complex with the probable substrate recognition
CC component LRR1. Component of a probable ECS E3 ubiquitin-protein
CC ligase complex containing CUL2, RBX1, TCEB1, TCEB2 and FEM1B. Part
CC of an E3 ubiquitin-protein ligase complex including ZYG11B, CUL2
CC and Elongin BC. Part of an E3 ubiquitin-protein ligase complex
CC including ZYG11BL, CUL2 and Elongin BC. Interacts with RBX1, RNF7,
CC FEM1B and TIP120A/CAND1. Interacts with COPS2, and MED8. Interacts
CC with human respiratory syncytial virus (HRSV) protein NS1. Found
CC in a complex composed of LIMD1, VHL, EGLN1/PHD2, TCEB2 and CUL2.
CC Interacts with KLHDC10; which may be an E3 ubiquitin ligase
CC complex substrate recognition component.
CC -!- INTERACTION:
CC Q86VP6:CAND1; NbExp=3; IntAct=EBI-456179, EBI-456077;
CC Q8N668:COMMD1; NbExp=3; IntAct=EBI-456179, EBI-1550112;
CC P62877:RBX1; NbExp=5; IntAct=EBI-456179, EBI-398523;
CC Q15369:TCEB1; NbExp=5; IntAct=EBI-456179, EBI-301231;
CC P40337:VHL; NbExp=9; IntAct=EBI-456179, EBI-301246;
CC P12504:vif (xeno); NbExp=5; IntAct=EBI-456179, EBI-779991;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q13617-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q13617-2; Sequence=VSP_044498;
CC Note=No experimental confirmation available;
CC -!- PTM: CBC(VHL) complex formation seems to promote neddylation.
CC Deneddylated via its interaction with the COP9 signalosome (CSN)
CC complex (By similarity).
CC -!- SIMILARITY: Belongs to the cullin family.
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DR EMBL; U83410; AAC51190.1; -; mRNA.
DR EMBL; AF126404; AAD23581.1; -; mRNA.
DR EMBL; AK095217; BAG53007.1; -; mRNA.
DR EMBL; AK300491; BAH13294.1; -; mRNA.
DR EMBL; AL392046; CAI13163.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW85924.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW85925.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW85926.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW85927.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW85928.1; -; Genomic_DNA.
DR EMBL; BC009591; AAH09591.1; -; mRNA.
DR EMBL; BC110901; AAI10902.1; -; mRNA.
DR EMBL; U58088; AAC50545.1; -; mRNA.
DR RefSeq; NP_001185706.1; NM_001198777.1.
DR RefSeq; NP_001185707.1; NM_001198778.1.
DR RefSeq; NP_001185708.1; NM_001198779.1.
DR RefSeq; NP_003582.2; NM_003591.3.
DR UniGene; Hs.82919; -.
DR ProteinModelPortal; Q13617; -.
DR SMR; Q13617; 8-745.
DR DIP; DIP-31612N; -.
DR IntAct; Q13617; 39.
DR MINT; MINT-1523339; -.
DR STRING; 9606.ENSP00000363880; -.
DR PhosphoSite; Q13617; -.
DR DMDM; 19863260; -.
DR PaxDb; Q13617; -.
DR PRIDE; Q13617; -.
DR DNASU; 8453; -.
DR Ensembl; ENST00000374748; ENSP00000363880; ENSG00000108094.
DR Ensembl; ENST00000374749; ENSP00000363881; ENSG00000108094.
DR Ensembl; ENST00000374751; ENSP00000363883; ENSG00000108094.
DR Ensembl; ENST00000537177; ENSP00000444856; ENSG00000108094.
DR GeneID; 8453; -.
DR KEGG; hsa:8453; -.
DR UCSC; uc001ixv.3; human.
DR CTD; 8453; -.
DR GeneCards; GC10M035338; -.
DR HGNC; HGNC:2552; CUL2.
DR HPA; CAB002677; -.
DR HPA; HPA024578; -.
DR MIM; 603135; gene.
DR neXtProt; NX_Q13617; -.
DR PharmGKB; PA27048; -.
DR eggNOG; COG5647; -.
DR HOVERGEN; HBG106177; -.
DR InParanoid; Q13617; -.
DR KO; K03870; -.
DR OMA; VMLDYVE; -.
DR OrthoDB; EOG7X3QQG; -.
DR PhylomeDB; Q13617; -.
DR Reactome; REACT_120956; Cellular responses to stress.
DR Reactome; REACT_6900; Immune System.
DR UniPathway; UPA00143; -.
DR ChiTaRS; CUL2; human.
DR GeneWiki; CUL2; -.
DR GenomeRNAi; 8453; -.
DR NextBio; 31634; -.
DR PRO; PR:Q13617; -.
DR ArrayExpress; Q13617; -.
DR Bgee; Q13617; -.
DR CleanEx; HS_CUL2; -.
DR Genevestigator; Q13617; -.
DR GO; GO:0031462; C:Cul2-RING ubiquitin ligase complex; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IDA:UniProtKB.
DR GO; GO:0007050; P:cell cycle arrest; TAS:ProtInc.
DR GO; GO:0000082; P:G1/S transition of mitotic cell cycle; TAS:ProtInc.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:ProtInc.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0008285; P:negative regulation of cell proliferation; TAS:ProtInc.
DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway.
DR GO; GO:0061418; P:regulation of transcription from RNA polymerase II promoter in response to hypoxia; TAS:Reactome.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR Gene3D; 1.10.10.10; -; 2.
DR InterPro; IPR016157; Cullin_CS.
DR InterPro; IPR016158; Cullin_homology.
DR InterPro; IPR001373; Cullin_N.
DR InterPro; IPR019559; Cullin_neddylation_domain.
DR InterPro; IPR016159; Cullin_repeat-like_dom.
DR InterPro; IPR011991; WHTH_DNA-bd_dom.
DR Pfam; PF00888; Cullin; 1.
DR Pfam; PF10557; Cullin_Nedd8; 1.
DR SMART; SM00182; CULLIN; 1.
DR SMART; SM00884; Cullin_Nedd8; 1.
DR SUPFAM; SSF74788; SSF74788; 1.
DR SUPFAM; SSF75632; SSF75632; 1.
DR PROSITE; PS01256; CULLIN_1; 1.
DR PROSITE; PS50069; CULLIN_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Complete proteome;
KW Host-virus interaction; Isopeptide bond; Phosphoprotein; Polymorphism;
KW Reference proteome; Ubl conjugation; Ubl conjugation pathway.
FT CHAIN 1 745 Cullin-2.
FT /FTId=PRO_0000119790.
FT MOD_RES 393 393 N6-acetyllysine.
FT MOD_RES 661 661 Phosphothreonine.
FT CROSSLNK 689 689 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in NEDD8).
FT VAR_SEQ 1 1 M -> MYRVTWSTFWLRFQHYTCTM (in isoform 2).
FT /FTId=VSP_044498.
FT VARIANT 109 109 N -> S (in dbSNP:rs1131503).
FT /FTId=VAR_011374.
FT MUTAGEN 621 621 K->R: No effect on conjugation with
FT NEDD8.
FT MUTAGEN 689 689 K->R: Loss of conjugation with NEDD8.
FT MUTAGEN 719 719 K->R: No effect on conjugation with
FT NEDD8.
FT CONFLICT 20 20 T -> I (in Ref. 3; BAH13294).
FT CONFLICT 95 98 SKGA -> IRHE (in Ref. 7; AAC50545).
FT CONFLICT 681 681 Q -> H (in Ref. 7; AAC50545).
SQ SEQUENCE 745 AA; 86983 MW; 30647248F671AB0E CRC64;
MSLKPRVVDF DETWNKLLTT IKAVVMLEYV ERATWNDRFS DIYALCVAYP EPLGERLYTE
TKIFLENHVR HLHKRVLESE EQVLVMYHRY WEEYSKGADY MDCLYRYLNT QFIKKNKLTE
ADLQYGYGGV DMNEPLMEIG ELALDMWRKL MVEPLQAILI RMLLREIKND RGGEDPNQKV
IHGVINSFVH VEQYKKKFPL KFYQEIFESP FLTETGEYYK QEASNLLQES NCSQYMEKVL
GRLKDEEIRC RKYLHPSSYT KVIHECQQRM VADHLQFLHA ECHNIIRQEK KNDMANMYVL
LRAVSTGLPH MIQELQNHIH DEGLRATSNL TQENMPTLFV ESVLEVHGKF VQLINTVLNG
DQHFMSALDK ALTSVVNYRE PKSVCKAPEL LAKYCDNLLK KSAKGMTENE VEDRLTSFIT
VFKYIDDKDV FQKFYARMLA KRLIHGLSMS MDSEEAMINK LKQACGYEFT SKLHRMYTDM
SVSADLNNKF NNFIKNQDTV IDLGISFQIY VLQAGAWPLT QAPSSTFAIP QELEKSVQMF
ELFYSQHFSG RKLTWLHYLC TGEVKMNYLG KPYVAMVTTY QMAVLLAFNN SETVSYKELQ
DSTQMNEKEL TKTIKSLLDV KMINHDSEKE DIDAESSFSL NMNFSSKRTK FKITTSMQKD
TPQEMEQTRS AVDEDRKMYL QAAIVRIMKA RKVLRHNALI QEVISQSRAR FNPSISMIKK
CIEVLIDKQY IERSQASADE YSYVA
//
MIM
603135
*RECORD*
*FIELD* NO
603135
*FIELD* TI
*603135 CULLIN 2; CUL2
*FIELD* TX
CLONING
Kipreos et al. (1996) identified a conserved gene family, designated
read morecullins, with at least 5 members in nematodes, 6 in humans, and 3 in S.
cerevisiae. Human CUL2 is an ortholog of nematode cul2. Michel and Xiong
(1998) identified human CUL2 cDNAs and reported that the predicted
protein is 745 amino acids long.
Pause et al. (1997) reported that the protein sequences of human and C.
elegans cul2 are 45% identical. Using immunofluorescence, they showed
that CUL2 is a cytosolic protein that can be translocated to the nucleus
by VHL (608537).
GENE FUNCTION
Both Pause et al. (1997) and Lonergan et al. (1998) found that CUL2
specifically associates with the trimeric VHL-elongin B (600787)-elongin
C (600788), or VBC, complex in vitro and in vivo. This association was
disrupted by mutations in VHL that disrupt elongin binding. Nearly 70%
of the naturally-occurring cancer-disposing mutations in VHL abrogate
elongin binding, suggesting that binding to elongin-CUL2 complexes
contributes to the ability of VHL to suppress tumor growth in vivo.
Pause et al. (1997) suggested that CUL2 is a candidate tumor suppressor
gene, as has been proposed for CUL1 (603134). Lonergan et al. (1998)
demonstrated that formation of the VBC-CUL2 complexes is linked to the
regulation of hypoxia-inducible mRNAs by VHL. They proposed a model for
this regulation based on the similarity of elongin C and CUL2 to SKP1
(601434) and CUL1, which have been shown in yeast to form complexes that
target specific proteins for ubiquitin-dependent proteolysis.
In C. elegans, DeRenzo et al. (2003) found that Cul2 was one of several
proteins required for degradation of a class of RNA-binding germline
proteins in somatic cells of the early blastomere.
GENE STRUCTURE
Clifford et al. (1999) showed that the CUL2 gene contains 21 exons
ranging between 50 and 570 bp, separated by 20 introns that follow the
usual GT/AG rule at the splice sites.
MAPPING
By fluorescence in situ hybridization, Clifford et al. (1999) mapped the
CUL2 gene to 10p11.2-p11.1, a region reported to show loss of
heterozygosity (LOH) in several forms of human cancer, including
non-clear cell renal cell carcinoma.
MOLECULAR GENETICS
Clifford et al. (1999) could demonstrate no pathogenic CUL2 mutations in
89 sporadic renal cell carcinomas analyzed.
To examine whether CUL2 plays a role in pheochromocytoma pathogenesis,
Duerr et al. (1999) analyzed a series of 26 distinct tumor samples for
mutations in the coding segments of the CUL2 gene. They identified no
somatic pathogenic mutations in CUL2, except for 1 sporadic tumor that
had a hemizygous gene deletion. The authors also identified 3 novel
polymorphisms in the gene. Two variants, IVS5-6C/T and 2057G/A were
overrepresented in pheochromocytoma patients compared to controls (P
less than 0.005 and P less than 0.01, respectively). Although these
findings suggested that CUL2 does not play a major role in the
pathogenesis of pheochromocytomas, the authors concluded that further
studies are needed to determine if epigenetic mechanisms are involved in
its inactivation in VHL-associated tumors and the potential role for the
overrepresented alleles in the pheochromocytoma group.
*FIELD* RF
1. Clifford, S. C.; Walsh, S.; Hewson, K.; Green, E. K.; Brinke, A.;
Green, P. M.; Gianelli, F.; Eng, C.; Maher, E. R.: Genomic organization
and chromosomal localization of the human CUL2 gene and the role of
von Hippel-Lindau tumor suppressor-binding protein (CUL2 and VBP1)
mutation and loss in renal-cell carcinoma development. Genes Chromosomes
Cancer 26: 20-28, 1999.
2. DeRenzo, C.; Reese, K. J.; Seydoux, G.: Exclusion of germ plasm
proteins from somatic lineages by cullin-dependent degradation. Nature 424:
685-689, 2003.
3. Duerr, E.-M.; Gimm, O.; Neuberg, D. S.; Kum, J. B.; Clifford, S.
C.; Toledo, S. P. A.; Maher, E. R.; Dahia, P. L. M.; Eng, C.: Differences
in allelic distribution of two polymorphisms in the VHL-associated
gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations. J.
Clin. Endocr. Metab. 84: 3207-3211, 1999.
4. Kipreos, E. T.; Lander, L. E.; Wing, J. P.; He, W. W.; Hedgecock,
E. M.: cul-1 is required for cell cycle exit in C. elegans and identifies
a novel gene family. Cell 85: 829-839, 1996.
5. Lonergan, K. M.; Iliopoulos, O.; Ohh, M.; Kamura, T.; Conaway,
R. C.; Conaway, J. W.; Kaelin, W. G., Jr.: Regulation of hypoxia-inducible
mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding
to complexes containing elongins B/C and Cul2. Molec. Cell. Biol. 18:
732-741, 1998.
6. Michel, J. J.; Xiong, Y.: Human CUL-1, but not other cullin family
members, selectively interacts with SKP1 to form a complex with SKP2
and cyclin A. Cell Growth Differ. 9: 435-449, 1998.
7. Pause, A.; Lee, S.; Worrell, R. A.; Chen, D. Y. T.; Burgess, W.
H.; Linehan, W. M.; Klausner, R. D.: The von Hippel-Lindau tumor-suppressor
gene product forms a stable complex with human CUL-2, a member of
the Cdc53 family of proteins. Proc. Nat. Acad. Sci. 94: 2156-2161,
1997.
*FIELD* CN
Patricia A. Hartz - updated: 1/26/2006
John A. Phillips, III - updated: 3/20/2000
Victor A. McKusick - updated: 11/1/1999
*FIELD* CD
Rebekah S. Rasooly: 10/13/1998
*FIELD* ED
mgross: 02/02/2006
terry: 1/26/2006
ckniffin: 3/23/2004
mgross: 3/31/2000
terry: 3/20/2000
carol: 11/10/1999
carol: 11/9/1999
terry: 11/1/1999
alopez: 10/30/1998
dkim: 10/28/1998
alopez: 10/13/1998
*RECORD*
*FIELD* NO
603135
*FIELD* TI
*603135 CULLIN 2; CUL2
*FIELD* TX
CLONING
Kipreos et al. (1996) identified a conserved gene family, designated
read morecullins, with at least 5 members in nematodes, 6 in humans, and 3 in S.
cerevisiae. Human CUL2 is an ortholog of nematode cul2. Michel and Xiong
(1998) identified human CUL2 cDNAs and reported that the predicted
protein is 745 amino acids long.
Pause et al. (1997) reported that the protein sequences of human and C.
elegans cul2 are 45% identical. Using immunofluorescence, they showed
that CUL2 is a cytosolic protein that can be translocated to the nucleus
by VHL (608537).
GENE FUNCTION
Both Pause et al. (1997) and Lonergan et al. (1998) found that CUL2
specifically associates with the trimeric VHL-elongin B (600787)-elongin
C (600788), or VBC, complex in vitro and in vivo. This association was
disrupted by mutations in VHL that disrupt elongin binding. Nearly 70%
of the naturally-occurring cancer-disposing mutations in VHL abrogate
elongin binding, suggesting that binding to elongin-CUL2 complexes
contributes to the ability of VHL to suppress tumor growth in vivo.
Pause et al. (1997) suggested that CUL2 is a candidate tumor suppressor
gene, as has been proposed for CUL1 (603134). Lonergan et al. (1998)
demonstrated that formation of the VBC-CUL2 complexes is linked to the
regulation of hypoxia-inducible mRNAs by VHL. They proposed a model for
this regulation based on the similarity of elongin C and CUL2 to SKP1
(601434) and CUL1, which have been shown in yeast to form complexes that
target specific proteins for ubiquitin-dependent proteolysis.
In C. elegans, DeRenzo et al. (2003) found that Cul2 was one of several
proteins required for degradation of a class of RNA-binding germline
proteins in somatic cells of the early blastomere.
GENE STRUCTURE
Clifford et al. (1999) showed that the CUL2 gene contains 21 exons
ranging between 50 and 570 bp, separated by 20 introns that follow the
usual GT/AG rule at the splice sites.
MAPPING
By fluorescence in situ hybridization, Clifford et al. (1999) mapped the
CUL2 gene to 10p11.2-p11.1, a region reported to show loss of
heterozygosity (LOH) in several forms of human cancer, including
non-clear cell renal cell carcinoma.
MOLECULAR GENETICS
Clifford et al. (1999) could demonstrate no pathogenic CUL2 mutations in
89 sporadic renal cell carcinomas analyzed.
To examine whether CUL2 plays a role in pheochromocytoma pathogenesis,
Duerr et al. (1999) analyzed a series of 26 distinct tumor samples for
mutations in the coding segments of the CUL2 gene. They identified no
somatic pathogenic mutations in CUL2, except for 1 sporadic tumor that
had a hemizygous gene deletion. The authors also identified 3 novel
polymorphisms in the gene. Two variants, IVS5-6C/T and 2057G/A were
overrepresented in pheochromocytoma patients compared to controls (P
less than 0.005 and P less than 0.01, respectively). Although these
findings suggested that CUL2 does not play a major role in the
pathogenesis of pheochromocytomas, the authors concluded that further
studies are needed to determine if epigenetic mechanisms are involved in
its inactivation in VHL-associated tumors and the potential role for the
overrepresented alleles in the pheochromocytoma group.
*FIELD* RF
1. Clifford, S. C.; Walsh, S.; Hewson, K.; Green, E. K.; Brinke, A.;
Green, P. M.; Gianelli, F.; Eng, C.; Maher, E. R.: Genomic organization
and chromosomal localization of the human CUL2 gene and the role of
von Hippel-Lindau tumor suppressor-binding protein (CUL2 and VBP1)
mutation and loss in renal-cell carcinoma development. Genes Chromosomes
Cancer 26: 20-28, 1999.
2. DeRenzo, C.; Reese, K. J.; Seydoux, G.: Exclusion of germ plasm
proteins from somatic lineages by cullin-dependent degradation. Nature 424:
685-689, 2003.
3. Duerr, E.-M.; Gimm, O.; Neuberg, D. S.; Kum, J. B.; Clifford, S.
C.; Toledo, S. P. A.; Maher, E. R.; Dahia, P. L. M.; Eng, C.: Differences
in allelic distribution of two polymorphisms in the VHL-associated
gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations. J.
Clin. Endocr. Metab. 84: 3207-3211, 1999.
4. Kipreos, E. T.; Lander, L. E.; Wing, J. P.; He, W. W.; Hedgecock,
E. M.: cul-1 is required for cell cycle exit in C. elegans and identifies
a novel gene family. Cell 85: 829-839, 1996.
5. Lonergan, K. M.; Iliopoulos, O.; Ohh, M.; Kamura, T.; Conaway,
R. C.; Conaway, J. W.; Kaelin, W. G., Jr.: Regulation of hypoxia-inducible
mRNAs by the von Hippel-Lindau tumor suppressor protein requires binding
to complexes containing elongins B/C and Cul2. Molec. Cell. Biol. 18:
732-741, 1998.
6. Michel, J. J.; Xiong, Y.: Human CUL-1, but not other cullin family
members, selectively interacts with SKP1 to form a complex with SKP2
and cyclin A. Cell Growth Differ. 9: 435-449, 1998.
7. Pause, A.; Lee, S.; Worrell, R. A.; Chen, D. Y. T.; Burgess, W.
H.; Linehan, W. M.; Klausner, R. D.: The von Hippel-Lindau tumor-suppressor
gene product forms a stable complex with human CUL-2, a member of
the Cdc53 family of proteins. Proc. Nat. Acad. Sci. 94: 2156-2161,
1997.
*FIELD* CN
Patricia A. Hartz - updated: 1/26/2006
John A. Phillips, III - updated: 3/20/2000
Victor A. McKusick - updated: 11/1/1999
*FIELD* CD
Rebekah S. Rasooly: 10/13/1998
*FIELD* ED
mgross: 02/02/2006
terry: 1/26/2006
ckniffin: 3/23/2004
mgross: 3/31/2000
terry: 3/20/2000
carol: 11/10/1999
carol: 11/9/1999
terry: 11/1/1999
alopez: 10/30/1998
dkim: 10/28/1998
alopez: 10/13/1998