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 15-SEP-2003 (Rel. 42, Last annotation update) DE CBL E3 ubiquitin protein ligase (EC 6.3.2.-) (Signal transduction DE protein CBL) (Proto-oncogene c-CBL). GN CBL OR CBL2. OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Primates; Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP SEQUENCE FROM N.A. 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 RT v-cbl was generated by a large truncation encompassing a proline-rich RT domain and a leucine zipper-like motif."; RL Oncogene 6:653-657(1991). RN [2] RP FUNCTION. RX MEDLINE=99445925; PubMed=10514377; 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, RT E2-dependent ubiquitin-protein ligase."; RL Science 286:309-312(1999). RN [3] RP INTERACTION WITH APS. RX PubMed=10374881; 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 [4] RP INTERACTION WITH APS. RX PubMed=9989826; 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 [5] RP INTERACTION WITH SLA AND ZAP70, AND MUTAGENESIS OF GLY-306. RX MEDLINE=99380595; PubMed=10449770; 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 [6] RP INTERACTION WITH SLA2. RX MEDLINE=21553259; PubMed=11696592; 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 [7] RP INTERACTION WITH CD2AP. RX MEDLINE=21265017; PubMed=11067845; 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 [8] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 47-350. RX MEDLINE=99176421; PubMed=10078535; 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 [9] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 47-434 IN COMPLEX WITH ZAP70 RP AND UBE2L3. RX MEDLINE=20419298; PubMed=10966114; 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 -!- SUBUNIT: Associates with NCK via its SH3 domain. The CC phosphorylated C-terminus interacts with CD2AP via its second SH3 CC domain. Binds to ZAP70 and UBE2L3. Interacts with adapters SLA, CC SLA2 and with the phosphorylated C-terminus of APS. CC -!- SUBCELLULAR LOCATION: Cytoplasmic. CC -!- DOMAIN: The RING-type zinc finger domain mediates binding to an E2 CC ubiquitin-conjugating enzyme. CC -!- PTM: Phosphorylated on tyrosine residues. CC -!- SIMILARITY: Contains 1 RING-type zinc finger. 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; -. DR PIR; A43817; A43817. DR PDB; 1B47; 27-APR-99. DR PDB; 1FBV; 17-JUL-00. DR PDB; 2CBL; 18-MAY-99. DR Genew; HGNC:1541; CBL. DR MIM; 165360; -. DR GO; GO:0003700; F:transcription factor activity; TAS. DR GO; GO:0007048; P:oncogenesis; TAS. DR InterPro; IPR003153; Cbl_N. DR InterPro; IPR000449; UBA_domain. DR InterPro; IPR001841; Znf_ring. DR Pfam; PF02761; Cbl_N2; 1. DR Pfam; PF02762; Cbl_N3; 1. DR Pfam; PF02262; Cbl_N; 1. DR Pfam; PF00627; UBA; 1. DR Pfam; PF00097; zf-C3HC4; 1. DR SMART; SM00184; RING; 1. DR SMART; SM00165; UBA; 1. DR PROSITE; PS50030; UBA; 1. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 1. KW Ligase; Ubl conjugation pathway; Proto-oncogene; Zinc-finger; KW Phosphorylation; 3D-structure. FT ZN_FING 381 420 RING-TYPE. FT DOMAIN 357 476 ASP/GLU-RICH (ACIDIC). FT DOMAIN 477 688 PRO-RICH. FT DOMAIN 648 906 INTERACTS WITH CD2AP. FT DOMAIN 689 834 ASP/GLU-RICH (ACIDIC). FT DOMAIN 856 895 UBA. FT MOD_RES 700 700 PHOSPHORYLATION. FT MOD_RES 774 774 PHOSPHORYLATION. FT MUTAGEN 306 306 G->E: ABOLISHES INTERACTION WITH ZAP70, FT BUT DOES NOT AFFECT INTERACTION WITH SLA. FT HELIX 53 70 FT TURN 71 71 FT HELIX 73 75 FT HELIX 84 101 FT TURN 102 102 FT HELIX 106 110 FT TURN 111 111 FT HELIX 113 136 FT HELIX 137 141 FT TURN 143 144 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 238 248 FT HELIX 251 253 FT HELIX 254 262 FT TURN 263 263 FT TURN 266 267 FT STRAND 268 271 FT HELIX 274 281 FT HELIX 282 284 FT TURN 285 286 FT TURN 288 289 FT STRAND 290 295 FT TURN 297 298 FT TURN 300 301 FT STRAND 303 308 FT TURN 310 311 FT STRAND 314 317 FT TURN 320 321 FT HELIX 324 333 FT TURN 334 335 FT STRAND 339 340 FT TURN 341 342 SQ SEQUENCE 906 AA; 99646 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 //