HAKAI_HUMAN
ID HAKAI_HUMAN Reviewed; 491 AA.
AC Q75N03; B7ZM03; Q8TAJ4; Q9H5S6;
DT 17-APR-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=E3 ubiquitin-protein ligase Hakai {ECO:0000305};
DE EC=2.3.2.27 {ECO:0000250|UniProtKB:Q9JIY2};
DE AltName: Full=Casitas B-lineage lymphoma-transforming sequence-like protein 1 {ECO:0000250|UniProtKB:Q9JIY2};
DE Short=c-Cbl-like protein 1 {ECO:0000250|UniProtKB:Q9JIY2};
DE AltName: Full=RING finger protein 188;
DE AltName: Full=RING-type E3 ubiquitin transferase Hakai {ECO:0000305};
GN Name=CBLL1 {ECO:0000312|HGNC:HGNC:21225};
GN Synonyms=HAKAI {ECO:0000303|PubMed:29507755}, RNF188;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Testis;
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 [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-201, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-290, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [6]
RP IDENTIFICATION IN A MACOM-LIKE COMPLEX, AND SUBCELLULAR LOCATION.
RX PubMed=24100041; DOI=10.1074/jbc.m113.500397;
RA Horiuchi K., Kawamura T., Iwanari H., Ohashi R., Naito M., Kodama T.,
RA Hamakubo T.;
RT "Identification of Wilms' tumor 1-associating protein complex and its role
RT in alternative splicing and the cell cycle.";
RL J. Biol. Chem. 288:33292-33302(2013).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-285, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [8]
RP FUNCTION, AND IDENTIFICATION IN THE WMM COMPLEX.
RX PubMed=29507755; DOI=10.1038/s41421-018-0019-0;
RA Yue Y., Liu J., Cui X., Cao J., Luo G., Zhang Z., Cheng T., Gao M., Shu X.,
RA Ma H., Wang F., Wang X., Shen B., Wang Y., Feng X., He C., Liu J.;
RT "VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop
RT codon and associates with alternative polyadenylation.";
RL Cell Discov. 4:10-10(2018).
CC -!- FUNCTION: E3 ubiquitin-protein ligase that mediates ubiquitination of
CC several tyrosine-phosphorylated Src substrates, including CDH1, CTTN
CC and DOK1 (By similarity). Targets CDH1 for endocytosis and degradation
CC (By similarity). Associated component of the WMM complex, a complex
CC that mediates N6-methyladenosine (m6A) methylation of RNAs, a
CC modification that plays a role in the efficiency of mRNA splicing and
CC RNA processing (PubMed:29507755). Its function in the WMM complex is
CC unknown (PubMed:29507755). {ECO:0000250|UniProtKB:Q9JIY2,
CC ECO:0000269|PubMed:29507755}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000250|UniProtKB:Q9JIY2};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000250|UniProtKB:Q9JIY2}.
CC -!- SUBUNIT: Homodimer (By similarity). Interacts with tyrosine-
CC phosphorylated SRC substrates (By similarity). Component of the WMM
CC complex, a N6-methyltransferase complex composed of a catalytic
CC subcomplex, named MAC, and of an associated subcomplex, named MACOM
CC (PubMed:29507755). The MAC subcomplex is composed of METTL3 and METTL14
CC (PubMed:29507755). The MACOM subcomplex is composed of WTAP, ZC3H13,
CC CBLL1/HAKAI, VIRMA, and, in some cases of RBM15 (RBM15 or RBM15B)
CC (PubMed:29507755). Also a component of a MACOM-like complex, named WTAP
CC complex, composed of WTAP, ZC3H13, CBLL1, VIRMA, RBM15, BCLAF1 and
CC THRAP3 (PubMed:24100041). {ECO:0000250|UniProtKB:Q9JIY2,
CC ECO:0000269|PubMed:24100041, ECO:0000269|PubMed:29507755}.
CC -!- INTERACTION:
CC Q75N03; P98175: RBM10; NbExp=3; IntAct=EBI-2832762, EBI-721525;
CC -!- SUBCELLULAR LOCATION: Nucleus speckle {ECO:0000269|PubMed:24100041}.
CC Nucleus, nucleoplasm {ECO:0000269|PubMed:24100041}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q9JIY2}. Note=Mainly nuclear with some fraction
CC located in the cytoplasm. ZC3H13 is required to anchor component of the
CC MACOM subcomplex, such as VIRMA, in the nucleus.
CC {ECO:0000250|UniProtKB:Q9JIY2}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q75N03-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q75N03-2; Sequence=VSP_054879;
CC -!- DOMAIN: The HYB domain forms a phosphotyrosine-binding pocket upon
CC dimerization, and mediates as well the recognition of its flanking
CC acidic amino acids. {ECO:0000250|UniProtKB:Q9JIY2}.
CC -!- PTM: Phosphorylated on tyrosine residues.
CC {ECO:0000250|UniProtKB:Q9JIY2}.
CC -!- SIMILARITY: Belongs to the Hakai family. {ECO:0000305}.
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DR EMBL; AK026762; BAB15544.1; -; mRNA.
DR EMBL; AC002467; AAS07390.1; -; Genomic_DNA.
DR EMBL; BC027460; AAH27460.2; -; mRNA.
DR EMBL; BC130529; AAI30530.1; -; mRNA.
DR EMBL; BC130531; AAI30532.1; -; mRNA.
DR EMBL; BC144176; AAI44177.1; -; mRNA.
DR CCDS; CCDS5747.1; -. [Q75N03-1]
DR CCDS; CCDS64754.1; -. [Q75N03-2]
DR RefSeq; NP_001271220.1; NM_001284291.1. [Q75N03-2]
DR RefSeq; NP_079090.2; NM_024814.3. [Q75N03-1]
DR AlphaFoldDB; Q75N03; -.
DR BMRB; Q75N03; -.
DR SMR; Q75N03; -.
DR BioGRID; 122960; 33.
DR ComplexPortal; CPX-1605; WMM N6-adenosine-methyltransferase complex.
DR IntAct; Q75N03; 14.
DR MINT; Q75N03; -.
DR STRING; 9606.ENSP00000401277; -.
DR GlyGen; Q75N03; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; Q75N03; -.
DR MetOSite; Q75N03; -.
DR PhosphoSitePlus; Q75N03; -.
DR BioMuta; CBLL1; -.
DR DMDM; 74762414; -.
DR EPD; Q75N03; -.
DR jPOST; Q75N03; -.
DR MassIVE; Q75N03; -.
DR MaxQB; Q75N03; -.
DR PaxDb; Q75N03; -.
DR PeptideAtlas; Q75N03; -.
DR PRIDE; Q75N03; -.
DR ProteomicsDB; 68642; -. [Q75N03-1]
DR ProteomicsDB; 7243; -.
DR Antibodypedia; 17227; 208 antibodies from 30 providers.
DR DNASU; 79872; -.
DR Ensembl; ENST00000222597.6; ENSP00000222597.2; ENSG00000105879.12. [Q75N03-2]
DR Ensembl; ENST00000440859.8; ENSP00000401277.2; ENSG00000105879.12. [Q75N03-1]
DR GeneID; 79872; -.
DR KEGG; hsa:79872; -.
DR MANE-Select; ENST00000440859.8; ENSP00000401277.2; NM_024814.4; NP_079090.2.
DR UCSC; uc003veq.4; human. [Q75N03-1]
DR CTD; 79872; -.
DR DisGeNET; 79872; -.
DR GeneCards; CBLL1; -.
DR HGNC; HGNC:21225; CBLL1.
DR HPA; ENSG00000105879; Low tissue specificity.
DR MIM; 606872; gene.
DR neXtProt; NX_Q75N03; -.
DR OpenTargets; ENSG00000105879; -.
DR PharmGKB; PA134960329; -.
DR VEuPathDB; HostDB:ENSG00000105879; -.
DR eggNOG; KOG2932; Eukaryota.
DR GeneTree; ENSGT00510000047522; -.
DR HOGENOM; CLU_031291_1_0_1; -.
DR InParanoid; Q75N03; -.
DR OMA; EFDYNKE; -.
DR OrthoDB; 765364at2759; -.
DR PhylomeDB; Q75N03; -.
DR TreeFam; TF332910; -.
DR PathwayCommons; Q75N03; -.
DR Reactome; R-HSA-8876493; InlA-mediated entry of Listeria monocytogenes into host cells.
DR SignaLink; Q75N03; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 79872; 177 hits in 1119 CRISPR screens.
DR GeneWiki; CBLL1; -.
DR GenomeRNAi; 79872; -.
DR Pharos; Q75N03; Tbio.
DR PRO; PR:Q75N03; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; Q75N03; protein.
DR Bgee; ENSG00000105879; Expressed in calcaneal tendon and 176 other tissues.
DR ExpressionAtlas; Q75N03; baseline and differential.
DR Genevisible; Q75N03; HS.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0016607; C:nuclear speck; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IC:ComplexPortal.
DR GO; GO:0036396; C:RNA N6-methyladenosine methyltransferase complex; IDA:UniProtKB.
DR GO; GO:0000151; C:ubiquitin ligase complex; IC:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0098609; P:cell-cell adhesion; IDA:UniProtKB.
DR GO; GO:0080009; P:mRNA methylation; IMP:UniProtKB.
DR GO; GO:0007162; P:negative regulation of cell adhesion; ISS:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; ISS:UniProtKB.
DR GO; GO:0045807; P:positive regulation of endocytosis; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
DR GO; GO:0030155; P:regulation of cell adhesion; IBA:GO_Central.
DR CDD; cd16508; RING-HC_HAKAI_like; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR040380; HAKAI-like_RING-HC.
DR InterPro; IPR040383; HAKAI/CBLL2.
DR InterPro; IPR041042; Znf_Hakai.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR PANTHER; PTHR13480; PTHR13480; 1.
DR Pfam; PF18408; zf_Hakai; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cytoplasm; Developmental protein; Metal-binding;
KW Nucleus; Phosphoprotein; Reference proteome; Transferase;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..491
FT /note="E3 ubiquitin-protein ligase Hakai"
FT /id="PRO_0000284048"
FT ZN_FING 109..149
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 164..190
FT /note="C2H2-type"
FT REGION 1..61
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 148..206
FT /note="HYB domain"
FT /evidence="ECO:0000250|UniProtKB:Q9JIY2"
FT REGION 255..491
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 274..301
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 337..361
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 369..426
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 427..445
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 453..477
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 201
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 285
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 290
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT VAR_SEQ 60
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054879"
FT CONFLICT 439
FT /note="L -> P (in Ref. 1; BAB15544)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 491 AA; 54519 MW; 1A733A8CC28F3AA0 CRC64;
MDHTDNELQG TNSSGSLGGL DVRRRIPIKL ISKQANKAKP APRTQRTINR MPAKAPPGDE
EGFDYNEEER YDCKGGELFA NQRRFPGHLF WDFQINILGE KDDTPVHFCD KCGLPIKIYG
RMIPCKHVFC YDCAILHEKK GDKMCPGCSD PVQRIEQCTR GSLFMCSIVQ GCKRTYLSQR
DLQAHINHRH MRAGKPVTRA SLENVHPPIA PPPTEIPERF IMPPDKHHMS HIPPKQHIMM
PPPPLQHVPH EHYNQPHEDI RAPPAELSMA PPPPRSVSQE TFRISTRKHS NLITVPIQDD
SNSGAREPPP PAPAPAHHHP EYQGQPVVSH PHHIMPPQQH YAPPPPPPPP ISHPMPHPPQ
AAGTPHLVYS QAPPPPMTSA PPPITPPPGH IIAQMPPYMN HPPPGPPPPQ HGGPPVTAPP
PHHYNPNSLP QFTEDQGTLS PPFTQPGGMS PGIWPAPRGP PPPPRLQGPP SQTPLPGPHH
PDQTRYRPYY Q
