ID CBL_HUMAN STANDARD; PRT; 906 AA. AC P22681; DT 01-AUG-1991 (Rel. 19, Created) DT 01-AUG-1991 (Rel. 19, Last sequence update) DT 13-SEP-2005 (Rel. 48, Last annotation update) DE CBL E3 ubiquitin protein ligase (EC 6.3.2.-) (Signal transduction DE protein CBL) (Proto-oncogene c-CBL) (Casitas B-lineage lymphoma proto- DE oncogene) (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; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE. 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 PHOSPHORYLATION SITES SER-669 AND TYR-674. RX 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 [7] RP INTERACTION WITH APS. 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 [8] RP INTERACTION WITH APS. 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 [9] RP INTERACTIONS 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 [10] 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 [11] 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 [12] RP INTERACTION WITH APS, MUTAGENESIS OF TYR-371; TYR-700; TYR-731 AND RP TYR-774, AND PHOSPHORYLATION SITES 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 [13] 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 [14] 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: Ubiquitin conjugation; third step. 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 APS. Interacts with EGFR, CC SYK and ZAP70 via the highly conserved Cbl-N region. Also CC interacts with SORBS1. CC -!- INTERACTION: CC Q07666:KHDRBS1; NbExp=1; IntAct=EBI-518228, EBI-1364; CC -!- SUBCELLULAR LOCATION: Cytoplasmic. 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 -!- DATABASE: NAME=Atlas Genet. Cytogenet. Oncol. Haematol.; CC WWW="http://www.infobiogen.fr/services/chromcancer/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 PDB; 1B47; X-ray; A/B/C=47-350. DR PDB; 1FBV; X-ray; A=47-434. DR PDB; 1YVH; X-ray; A=25-351. DR PDB; 2CBL; X-ray; A=47-351. DR IntAct; P22681; -. DR Ensembl; ENSG00000110395; Homo sapiens. DR HGNC; HGNC:1541; CBL. DR MIM; 165360; -. DR GO; GO:0005886; C:plasma membrane; IDA. DR GO; GO:0005515; F:protein binding; IPI. DR GO; GO:0003700; F:transcription factor activity; TAS. DR GO; GO:0004842; F:ubiquitin-protein ligase activity; TAS. DR GO; GO:0007166; P:cell surface receptor linked signal transdu...; TAS. DR GO; GO:0007173; P:epidermal growth factor receptor signaling ...; TAS. DR GO; GO:0048260; P:positive regulation of receptor mediated en...; TAS. DR GO; GO:0016567; P:protein ubiquitination; TAS. DR InterPro; IPR003153; Cbl_N. DR InterPro; IPR011992; EF-Hand_type. DR InterPro; IPR000980; SH2. DR InterPro; IPR000449; UBA. DR InterPro; IPR001841; Znf_RING. 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 PROSITE; PS50001; SH2; FALSE_NEG. DR PROSITE; PS50030; UBA; 1. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 1. KW 3D-structure; Calcium; Ligase; Metal-binding; Phosphorylation; KW Proto-oncogene; Repeat; SH2 domain; Ubl conjugation pathway; Zinc; KW Zinc-finger. 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 669 669 Phosphoserine. FT MOD_RES 674 674 Phosphotyrosine. FT MOD_RES 700 700 Phosphotyrosine. FT MOD_RES 774 774 Phosphotyrosine. 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 TURN 71 71 FT HELIX 73 75 FT TURN 78 79 FT TURN 81 82 FT HELIX 84 101 FT TURN 102 104 FT HELIX 106 110 FT TURN 111 111 FT HELIX 113 135 FT HELIX 138 140 FT HELIX 146 168 FT HELIX 170 172 FT HELIX 176 178 FT HELIX 184 194 FT TURN 195 196 FT STRAND 199 201 FT HELIX 202 212 FT HELIX 218 228 FT TURN 230 231 FT STRAND 235 237 FT HELIX 238 247 FT TURN 248 248 FT HELIX 251 253 FT HELIX 254 261 FT TURN 262 263 FT TURN 266 267 FT STRAND 268 268 FT HELIX 274 281 FT HELIX 282 284 FT TURN 285 286 FT TURN 288 289 FT STRAND 290 295 FT TURN 300 301 FT STRAND 303 308 FT TURN 310 311 FT STRAND 314 317 FT HELIX 324 333 FT TURN 334 335 FT STRAND 339 340 FT TURN 341 342 FT HELIX 365 372 FT TURN 373 374 FT TURN 378 379 FT STRAND 380 380 FT TURN 382 384 FT STRAND 388 388 FT STRAND 391 392 FT STRAND 399 400 FT HELIX 402 410 FT TURN 411 412 FT TURN 417 419 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 //