ID CBL_HUMAN Reviewed; 906 AA. AC P22681; DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1991, sequence version 1. DT 04-NOV-2008, entry version 111. DE RecName: Full=E3 ubiquitin-protein ligase CBL; DE EC=6.3.2.-; DE AltName: Full=Signal transduction protein CBL; DE AltName: Full=Proto-oncogene c-CBL; DE AltName: Full=Casitas B-lineage lymphoma proto-oncogene; DE AltName: Full=RING finger protein 55; GN Name=CBL; Synonyms=CBL2, RNF55; 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]. RX MEDLINE=91232862; PubMed=2030914; RA Blake T.J., Shapiro M., Morse H.C. III, Langdon W.Y.; RT "The sequences of the human and mouse c-cbl proto-oncogenes show v-cbl RT was generated by a large truncation encompassing a proline-rich domain RT and a leucine zipper-like motif."; RL Oncogene 6:653-657(1991). RN [2] RP FUNCTION. RX MEDLINE=99445925; PubMed=10514377; DOI=10.1126/science.286.5438.309; RA Joazeiro C.A., Wing S.S., Huang H.-K., Leverson J.D., Hunter T., RA Liu Y.-C.; RT "The tyrosine kinase negative regulator c-Cbl as a RING-type, E2- RT dependent ubiquitin-protein ligase."; RL Science 286:309-312(1999). RN [3] RP PHOSPHORYLATION BY EGFR. RX PubMed=7657591; DOI=10.1074/jbc.270.35.20242; RA Galisteo M.L., Dikic I., Batzer A.G., Langdon W.Y., Schlessinger J.; RT "Tyrosine phosphorylation of the c-cbl proto-oncogene protein product RT and association with epidermal growth factor (EGF) receptor upon EGF RT stimulation."; RL J. Biol. Chem. 270:20242-20245(1995). RN [4] RP INTERACTION WITH ZAP70. RX PubMed=9407100; DOI=10.1074/jbc.272.52.33140; RA Lupher M.L. Jr., Songyang Z., Shoelson S.E., Cantley L.C., Band H.; RT "The Cbl phosphotyrosine-binding domain selects a D(N/D)XpY motif and RT binds to the Tyr292 negative regulatory phosphorylation site of ZAP- RT 70."; RL J. Biol. Chem. 272:33140-33144(1997). RN [5] RP PHOSPHORYLATION BY SYK AND FYN. RX PubMed=9535867; DOI=10.1074/jbc.273.15.8867; RA Deckert M., Elly C., Altman A., Liu Y.C.; RT "Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn RT and Syk tyrosine kinases."; RL J. Biol. Chem. 273:8867-8874(1998). RN [6] RP INTERACTION WITH LAT2. RX MEDLINE=22373766; PubMed=12486104; DOI=10.1084/jem.20021405; RA Brdicka T., Imrich M., Angelisova P., Brdickova N., Horvath O., RA Spicka J., Hilgert I., Luskova P., Draber P., Novak P., Engels N., RA Wienands J., Simeoni L., Oesterreicher J., Aguado E., Malissen M., RA Schraven B., Horejsi V.; RT "Non-T cell activation linker (NTAL): a transmembrane adaptor protein RT involved in immunoreceptor signaling."; RL J. Exp. Med. 196:1617-1626(2002). RN [7] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-669 AND TYR-674, AND RP MASS SPECTROMETRY. RX MEDLINE=22426906; PubMed=12522270; DOI=10.1073/pnas.2436191100; RA Salomon A.R., Ficarro S.B., Brill L.M., Brinker A., Phung Q.T., RA Ericson C., Sauer K., Brock A., Horn D.M., Schultz P.G., Peters E.C.; RT "Profiling of tyrosine phosphorylation pathways in human cells using RT mass spectrometry."; RL Proc. Natl. Acad. Sci. U.S.A. 100:443-448(2003). RN [8] RP INTERACTION WITH SH2B2. RX MEDLINE=99301417; PubMed=10374881; DOI=10.1038/sj/leu/2401397; RA Wakioka T., Sasaki A., Mitsui K., Yokouchi M., Inoue A., Komiya S., RA Yoshimura A.; RT "APS, an adaptor protein containing pleckstrin homology (PH) and Src RT homology-2 (SH2) domains inhibits the JAK-STAT pathway in RT collaboration with c-Cbl."; RL Leukemia 13:760-767(1999). RN [9] RP INTERACTION WITH SH2B2. RX MEDLINE=99142932; PubMed=9989826; DOI=10.1038/sj.onc.1202326; RA Yokouchi M., Wakioka T., Sakamoto H., Yasukawa H., Ohtsuka S., RA Sasaki A., Ohtsubo M., Valius M., Inoue A., Komiya S., Yoshimura A.; RT "APS, an adaptor protein containing PH and SH2 domains, is associated RT with the PDGF receptor and c-Cbl and inhibits PDGF-induced RT mitogenesis."; RL Oncogene 18:759-767(1999). RN [10] RP INTERACTION WITH SLA AND ZAP70, AND MUTAGENESIS OF GLY-306. RX MEDLINE=99380595; PubMed=10449770; DOI=10.1073/pnas.96.17.9775; RA Tang J., Sawasdikosol S., Chang J.-H., Burakoff S.J.; RT "SLAP, a dimeric adapter protein, plays a functional role in T cell RT receptor signaling."; RL Proc. Natl. Acad. Sci. U.S.A. 96:9775-9780(1999). RN [11] RP INTERACTION WITH SLA2. RX MEDLINE=21553259; PubMed=11696592; DOI=10.1084/jem.194.9.1263; RA Holland S.J., Liao X.C., Mendenhall M.K., Zhou X., Pardo J., Chu P., RA Spencer C., Fu A.C., Sheng N., Yu P., Pali E., Nagin A., Shen M., RA Yu S., Chan E., Wu X., Li C., Woisetschlager M., Aversa G., RA Kolbinger F., Bennett M.K., Molineaux S., Luo Y., Payan D.G., RA Mancebo H.S.Y., Wu J.; RT "Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel RT inhibitor of antigen receptor signaling."; RL J. Exp. Med. 194:1263-1276(2001). RN [12] RP INTERACTION WITH CD2AP. RX MEDLINE=21265017; PubMed=11067845; DOI=10.1074/jbc.M005784200; RA Kirsch K.H., Georgescu M.M., Shishido T., Langdon W.Y., Birge R.B., RA Hanafusa H.; RT "The adapter type protein CMS/CD2AP binds to the proto-oncogenic RT protein c-Cbl through a tyrosine phosphorylation-regulated Src RT homology 3 domain interaction."; RL J. Biol. Chem. 276:4957-4963(2001). RN [13] RP INTERACTION WITH SH2B2, MUTAGENESIS OF TYR-371; TYR-700; TYR-731 AND RP TYR-774, AND PHOSPHORYLATION AT TYR-371; TYR-700 AND TYR-774. RX PubMed=11997497; DOI=10.1128/MCB.22.11.3599-3609.2002; RA Liu J., Kimura A., Baumann C.A., Saltiel A.R.; RT "APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 RT translocation in response to insulin in 3T3-L1 adipocytes."; RL Mol. Cell. Biol. 22:3599-3609(2002). RN [14] RP INTERACTION WITH INPPL1. RX PubMed=12504111; DOI=10.1016/S0006-291X(02)02894-2; RA Vandenbroere I., Paternotte N., Dumont J.E., Erneux C., Pirson I.; RT "The c-Cbl-associated protein and c-Cbl are two new partners of the RT SH2-containing inositol polyphosphate 5-phosphatase SHIP2."; RL Biochem. Biophys. Res. Commun. 300:494-500(2003). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-371 AND TYR-552, AND RP MASS SPECTROMETRY. RC TISSUE=Epithelium; RX PubMed=15951569; DOI=10.1074/mcp.M500089-MCP200; RA Zhang Y., Wolf-Yadlin A., Ross P.L., Pappin D.J., Rush J., RA Lauffenburger D.A., White F.M.; RT "Time-resolved mass spectrometry of tyrosine phosphorylation sites in RT the epidermal growth factor receptor signaling network reveals dynamic RT modules."; RL Mol. Cell. Proteomics 4:1240-1250(2005). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-674, AND MASS RP SPECTROMETRY. RX PubMed=15592455; DOI=10.1038/nbt1046; RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., RA Zha X.-M., Polakiewicz R.D., Comb M.J.; RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer RT cells."; RL Nat. Biotechnol. 23:94-101(2005). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-667 AND SER-675, AND RP MASS SPECTROMETRY. RC TISSUE=T-cell; RX PubMed=16094384; DOI=10.1038/nmeth776; RA Tao W.A., Wollscheid B., O'Brien R., Eng J.K., Li X.-J., RA Bodenmiller B., Watts J.D., Hood L., Aebersold R.; RT "Quantitative phosphoproteome analysis using a dendrimer conjugation RT chemistry and tandem mass spectrometry."; RL Nat. Methods 2:591-598(2005). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-900, AND MASS RP SPECTROMETRY. RC TISSUE=Epithelium; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein RT phosphorylation analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [19] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 47-350, CALCIUM-BINDING SITE, RP AND MUTAGENESIS OF SER-80; PRO-82; ASP-229; GLU-240; ARG-294 AND RP GLY-306. RX MEDLINE=99176421; PubMed=10078535; DOI=10.1038/18050; RA Meng W., Sawasdikosol S., Burakoff S.J., Eck M.J.; RT "Structure of the amino-terminal domain of Cbl complexed to its RT binding site on ZAP-70 kinase."; RL Nature 398:84-90(1999). RN [20] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 47-434 IN COMPLEX WITH ZAP70 RP AND UBE2L3. RX MEDLINE=20419298; PubMed=10966114; DOI=10.1016/S0092-8674(00)00057-X; RA Zheng N., Wang P., Jeffrey P.D., Pavletich N.P.; RT "Structure of a c-Cbl-UbcH7 complex: RING domain function in RT ubiquitin-protein ligases."; RL Cell 102:533-539(2000). CC -!- FUNCTION: Participates in signal transduction in hematopoietic CC cells. Adapter protein that functions as a negative regulator of CC many signaling pathways that start from receptors at the cell CC surface. Acts as an E3 ubiquitin-protein ligase, which accepts CC ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then CC transfers it to substrates promoting their degradation by the CC proteasome. Recognizes activated receptor tyrosine kinases, CC including PDGFA, EGF and CSF1, and terminates signaling. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Associates with NCK via its SH3 domain. The CC phosphorylated C-terminus interacts with CD2AP via its second SH3 CC domain. Binds to UBE2L3. Interacts with adapters SLA, SLA2 and CC with the phosphorylated C-terminus of SH2B2. Interacts with EGFR, CC SYK and ZAP70 via the highly conserved Cbl-N region. Also CC interacts with SORBS1 and INPPL1/SHIP2. Interacts with CC phosphorylated LAT2. May interact with CBLB (By similarity). CC -!- INTERACTION: CC P00533:EGFR; NbExp=1; IntAct=EBI-518228, EBI-297353; CC Q07666:KHDRBS1; NbExp=1; IntAct=EBI-518228, EBI-1364; CC -!- SUBCELLULAR LOCATION: Cytoplasm. CC -!- DOMAIN: The RING-type zinc finger domain mediates binding to an E2 CC ubiquitin-conjugating enzyme. CC -!- DOMAIN: The N-terminus is composed of the phosphotyrosine binding CC (PTB) domain, a short linker region and the RING-type zinc finger. CC The PTB domain, which is also called TKB (tyrosine kinase binding) CC domain, is composed of three different subdomains: a four-helix CC bundle (4H), a calcium-binding EF hand and a divergent SH2 domain. CC -!- PTM: Phosphorylated on tyrosine residues by EGFR, SYK, FYN and CC ZAP70 (By similarity). Phosphorylated on tyrosine residues by CC INSR. CC -!- DISEASE: Can be converted to an oncogenic protein by deletions or CC mutations that disturb its ability to down-regulate RTKs. CC -!- MISCELLANEOUS: This protein has one functional calcium-binding CC site. CC -!- SIMILARITY: Contains 1 CBL N-terminal domain. CC -!- SIMILARITY: Contains 2 EF-hand-like domains. CC -!- SIMILARITY: Contains 1 RING-type zinc finger. CC -!- SIMILARITY: Contains 1 SH2 domain. CC -!- SIMILARITY: Contains 1 UBA domain. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology CC and Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/CBLID171.html"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X57110; CAA40393.1; -; mRNA. DR PIR; A43817; A43817. DR RefSeq; NP_005179.2; -. DR UniGene; Hs.504096; -. DR PDB; 1B47; X-ray; 2.20 A; A/B/C=47-350. DR PDB; 1FBV; X-ray; 2.90 A; A=47-434. DR PDB; 1YVH; X-ray; 2.05 A; A=23-351. DR PDB; 2CBL; X-ray; 2.10 A; A=47-351. DR PDB; 2JUJ; NMR; -; A=851-906. DR PDB; 2OO9; X-ray; 2.10 A; A/B/C=856-899. DR PDB; 3BUM; X-ray; 2.00 A; B=23-351. DR PDB; 3BUN; X-ray; 2.00 A; B=23-351. DR PDB; 3BUO; X-ray; 2.60 A; B/D=23-351. DR PDB; 3BUW; X-ray; 1.45 A; B/D=23-351. DR PDB; 3BUX; X-ray; 1.35 A; B/D=23-351. DR PDBsum; 1B47; -. DR PDBsum; 1FBV; -. DR PDBsum; 1YVH; -. DR PDBsum; 2CBL; -. DR PDBsum; 2JUJ; -. DR PDBsum; 2OO9; -. DR PDBsum; 3BUM; -. DR PDBsum; 3BUN; -. DR PDBsum; 3BUO; -. DR PDBsum; 3BUW; -. DR PDBsum; 3BUX; -. DR DIP; DIP:189N; -. DR IntAct; P22681; -. DR PhosphoSite; P22681; -. DR Ensembl; ENSG00000110395; Homo sapiens. DR GeneID; 867; -. DR KEGG; hsa:867; -. DR H-InvDB; HIX0010191; -. DR HGNC; HGNC:1541; CBL. DR HPA; CAB004350; -. DR MIM; 165360; gene. DR PharmGKB; PA26115; -. DR HOGENOM; P22681; -. DR HOVERGEN; P22681; -. DR LinkHub; P22681; -. DR NextBio; 3618; -. DR ArrayExpress; P22681; -. DR CleanEx; HS_CBL; -. DR GermOnline; ENSG00000110395; Homo sapiens. DR GO; GO:0005829; C:cytosol; EXP:Reactome. DR GO; GO:0005886; C:plasma membrane; IDA:HGNC. DR GO; GO:0005515; F:protein binding; IPI:UniProtKB. DR GO; GO:0003700; F:transcription factor activity; TAS:ProtInc. DR GO; GO:0004842; F:ubiquitin-protein ligase activity; TAS:HGNC. DR GO; GO:0007173; P:epidermal growth factor receptor signaling ...; TAS:HGNC. DR GO; GO:0048260; P:positive regulation of receptor-mediated en...; TAS:HGNC. DR GO; GO:0016567; P:protein ubiquitination; TAS:HGNC. DR InterPro; IPR014741; Adaptor_Cbl_EF_Hand-like. DR InterPro; IPR003153; Adaptor_Cbl_N. DR InterPro; IPR014742; Adaptor_Cbl_SH2-like. DR InterPro; IPR011992; EF-Hand_type. DR InterPro; IPR000980; SH2. DR InterPro; IPR000449; UBA/transl_elong_EF1B_N. DR InterPro; IPR015940; UBA/transl_elong_EF1B_N_euk. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR Gene3D; G3DSA:1.20.930.20; Adaptor_Cbl_N; 1. DR Gene3D; G3DSA:1.10.238.10; EF-Hand_type; 1. DR Gene3D; G3DSA:3.30.40.10; Znf_RING/FYVE/PHD; 1. DR Pfam; PF02262; Cbl_N; 1. DR Pfam; PF02761; Cbl_N2; 1. DR Pfam; PF02762; Cbl_N3; 1. DR Pfam; PF00627; UBA; 1. DR Pfam; PF00097; zf-C3HC4; 1. DR SMART; SM00184; RING; 1. DR SMART; SM00165; UBA; 1. DR PROSITE; PS50001; SH2; FALSE_NEG. DR PROSITE; PS50030; UBA; 1. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Calcium; Cytoplasm; Ligase; Metal-binding; KW Phosphoprotein; Proto-oncogene; Repeat; SH2 domain; KW Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1 906 E3 ubiquitin-protein ligase CBL. FT /FTId=PRO_0000055858. FT DOMAIN 46 357 CBL N-terminal. FT DOMAIN 212 220 EF-hand-like 1. FT DOMAIN 229 240 EF-hand-like 2. FT DOMAIN 267 341 SH2; atypical. FT DOMAIN 856 895 UBA. FT ZN_FING 381 420 RING-type. FT REGION 46 177 4H. FT REGION 342 380 Linker. FT REGION 648 906 Interaction with CD2AP. FT COMPBIAS 357 476 Asp/Glu-rich (acidic). FT COMPBIAS 477 688 Pro-rich. FT COMPBIAS 689 834 Asp/Glu-rich (acidic). FT BINDING 294 294 Phosphotyrosine (By similarity). FT MOD_RES 371 371 Phosphotyrosine; by INSR. FT MOD_RES 552 552 Phosphotyrosine. FT MOD_RES 667 667 Phosphoserine. FT MOD_RES 668 668 Phosphoserine (By similarity). FT MOD_RES 669 669 Phosphoserine. FT MOD_RES 674 674 Phosphotyrosine. FT MOD_RES 675 675 Phosphoserine. FT MOD_RES 700 700 Phosphotyrosine. FT MOD_RES 774 774 Phosphotyrosine. FT MOD_RES 900 900 Phosphoserine. FT MUTAGEN 80 80 S->D: Abolishes interaction with ZAP70. FT MUTAGEN 82 82 P->A: Abolishes interaction with ZAP70. FT MUTAGEN 229 229 D->Q: Abolishes interaction with ZAP70. FT MUTAGEN 240 240 E->S: Abolishes interaction with ZAP70. FT MUTAGEN 294 294 R->K: Abolishes interaction with ZAP70. FT MUTAGEN 306 306 G->E: Abolishes interaction with ZAP70, FT but does not affect interaction with SLA. FT MUTAGEN 371 371 Y->F: Strongly reduces tyrosine FT phosphorylation by INSR; when associated FT with F-700 and F-774. FT MUTAGEN 700 700 Y->F: Strongly reduces tyrosine FT phosphorylation by INSR; when associated FT with F-371 and F-774. FT MUTAGEN 731 731 Y->F: No effect on tyrosine FT phosphorylation by INSR. FT MUTAGEN 774 774 Y->F: Strongly reduces tyrosine FT phosphorylation by INSR; when associated FT with F-371 and F-700. FT HELIX 53 70 FT HELIX 73 75 FT HELIX 84 101 FT HELIX 106 111 FT HELIX 113 136 FT HELIX 137 141 FT HELIX 146 168 FT HELIX 170 172 FT HELIX 176 178 FT HELIX 184 194 FT STRAND 198 201 FT HELIX 202 210 FT HELIX 218 228 FT STRAND 233 237 FT HELIX 238 247 FT HELIX 251 253 FT HELIX 254 261 FT HELIX 274 281 FT HELIX 282 284 FT STRAND 290 295 FT STRAND 297 299 FT STRAND 302 308 FT STRAND 314 317 FT STRAND 320 322 FT HELIX 324 333 FT STRAND 354 356 FT HELIX 365 372 FT TURN 382 384 FT STRAND 385 388 FT STRAND 394 396 FT HELIX 402 410 FT TURN 417 419 FT HELIX 856 866 FT HELIX 871 880 FT TURN 881 883 FT HELIX 885 895 SQ SEQUENCE 906 AA; 99647 MW; 7D686B050204AD8F CRC64; MAGNVKKSSG AGGGTGSGGS GSGGLIGLMK DAFQPHHHHH HHLSPHPPGT VDKKMVEKCW KLMDKVVRLC QNPKLALKNS PPYILDLLPD TYQHLRTILS RYEGKMETLG ENEYFRVFME NLMKKTKQTI SLFKEGKERM YEENSQPRRN LTKLSLIFSH MLAELKGIFP SGLFQGDTFR ITKADAAEFW RKAFGEKTIV PWKSFRQALH EVHPISSGLE AMALKSTIDL TCNDYISVFE FDIFTRLFQP WSSLLRNWNS LAVTHPGYMA FLTYDEVKAR LQKFIHKPGS YIFRLSCTRL GQWAIGYVTA DGNILQTIPH NKPLFQALID GFREGFYLFP DGRNQNPDLT GLCEPTPQDH IKVTQEQYEL YCEMGSTFQL CKICAENDKD VKIEPCGHLM CTSCLTSWQE SEGQGCPFCR CEIKGTEPIV VDPFDPRGSG SLLRQGAEGA PSPNYDDDDD ERADDTLFMM KELAGAKVER PPSPFSMAPQ ASLPPVPPRL DLLPQRVCVP SSASALGTAS KAASGSLHKD KPLPVPPTLR DLPPPPPPDR PYSVGAESRP QRRPLPCTPG DCPSRDKLPP VPSSRLGDSW LPRPIPKVPV SAPSSSDPWT GRELTNRHSL PFSLPSQMEP RPDVPRLGST FSLDTSMSMN SSPLVGPECD HPKIKPSSSA NAIYSLAARP LPVPKLPPGE QCEGEEDTEY MTPSSRPLRP LDTSQSSRAC DCDQQIDSCT YEAMYNIQSQ APSITESSTF GEGNLAAAHA NTGPEESENE DDGYDVPKPP VPAVLARRTL SDISNASSSF GWLSLDGDPT TNVTEGSQVP ERPPKPFPRR INSERKAGSC QQGSGPAASA ATASPQLSSE IENLMSQGYS YQDIQKALVI AQNNIEMAKN ILREFVSISS PAHVAT //