ID CBL_HUMAN Reviewed; 906 AA. AC P22681; A3KMP8; DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot. DT 07-JUL-2009, sequence version 2. DT 03-MAY-2011, entry version 142. DE RecName: Full=E3 ubiquitin-protein ligase CBL; DE EC=6.3.2.-; DE AltName: Full=Casitas B-lineage lymphoma proto-oncogene; DE AltName: Full=Proto-oncogene c-Cbl; DE AltName: Full=RING finger protein 55; DE AltName: Full=Signal transduction protein CBL; 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 NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., RA Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., RA FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S., RA Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., RA Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., RA Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [4] 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 [5] 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 [6] 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 [7] 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 [8] 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 [9] 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 [10] 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 [11] 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 [12] 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 [13] 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 [14] 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 [15] 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 [16] 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 [17] RP FUNCTION, PHOSPHORYLATION AT TYR-731, AND MUTAGENESIS OF TYR-731. RX PubMed=14739300; DOI=10.1074/jbc.M311032200; RA Miyazaki T., Sanjay A., Neff L., Tanaka S., Horne W.C., Baron R.; RT "Src kinase activity is essential for osteoclast function."; RL J. Biol. Chem. 279:17660-17666(2004). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-371 AND TYR-552, AND RP MASS SPECTROMETRY. RC TISSUE=Mammary 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 [19] 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 [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-667 AND SER-675, AND RP MASS SPECTROMETRY. RC TISSUE=Leukemic 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 [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-900, AND MASS RP SPECTROMETRY. RC TISSUE=Cervix carcinoma; 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 [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-455; TYR-552 AND RP TYR-700, AND MASS SPECTROMETRY. RC TISSUE=Mammary epithelium; RX PubMed=17389395; DOI=10.1073/pnas.0608638104; RA Wolf-Yadlin A., Hautaniemi S., Lauffenburger D.A., White F.M.; RT "Multiple reaction monitoring for robust quantitative proteomic RT analysis of cellular signaling networks."; RL Proc. Natl. Acad. Sci. U.S.A. 104:5860-5865(2007). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-141; TYR-674 AND RP TYR-774, AND MASS SPECTROMETRY. RC TISSUE=Mammary epithelium; RX PubMed=19534553; DOI=10.1021/pr900044c; RA Heibeck T.H., Ding S.-J., Opresko L.K., Zhao R., Schepmoes A.A., RA Yang F., Tolmachev A.V., Monroe M.E., Camp D.G. II, Smith R.D., RA Wiley H.S., Qian W.-J.; RT "An extensive survey of tyrosine phosphorylation revealing new sites RT in human mammary epithelial cells."; RL J. Proteome Res. 8:3852-3861(2009). RN [24] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-452, AND MASS RP SPECTROMETRY. 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 [25] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-197, AND MASS SPECTROMETRY. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., RA 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 [26] 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 [27] 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 [28] 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). RN [29] RP VARIANTS NSL PRO-367; GLU-382; TYR-390 AND GLN-420, AND RP CHARACTERIZATION OF VARIANTS NSL PRO-367; GLU-382; TYR-390 AND RP GLN-420. RX PubMed=20619386; DOI=10.1016/j.ajhg.2010.06.015; RA Martinelli S., De Luca A., Stellacci E., Rossi C., Checquolo S., RA Lepri F., Caputo V., Silvano M., Buscherini F., Consoli F., RA Ferrara G., Digilio M.C., Cavaliere M.L., van Hagen J.M., Zampino G., RA van der Burgt I., Ferrero G.B., Mazzanti L., Screpanti I., RA Yntema H.G., Nillesen W.M., Savarirayan R., Zenker M., RA Dallapiccola B., Gelb B.D., Tartaglia M.; RT "Heterozygous germline mutations in the CBL tumor-suppressor gene RT cause a Noonan syndrome-like phenotype."; RL Am. J. Hum. Genet. 87:250-257(2010). 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. Essential CC for osteoclastic bone resorption. The Tyr-731 phosphorylated form CC induces the activation and recruitment of phosphatidylinositol 3- CC kinase to the cell membrane in a signaling pathway that is CC critical for osteoclast function. 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 Q08012:drk (xeno); NbExp=1; IntAct=EBI-518228, EBI-161391; CC P00533:EGFR; NbExp=2; IntAct=EBI-518228, EBI-297353; CC Q07666:KHDRBS1; NbExp=1; IntAct=EBI-518228, EBI-1364; CC P23467:PTPRB; NbExp=1; IntAct=EBI-518228, EBI-1265766; CC P08575:PTPRC; NbExp=1; IntAct=EBI-518228, EBI-1341; CC P23470:PTPRG; NbExp=1; IntAct=EBI-518228, EBI-2258115; CC Q12913:PTPRJ; NbExp=1; IntAct=EBI-518228, EBI-2264500; CC Q15262:PTPRK; NbExp=1; IntAct=EBI-518228, EBI-474052; CC Q16827:PTPRO; NbExp=1; IntAct=EBI-518228, EBI-723739; 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: Defects in CBL are the cause of Noonan syndrome-like CC disorder (NSL) [MIM:613563]. NSL is a syndrome characterized by a CC phenotype reminiscent of Noonan syndrome. Clinical features are CC highly variable, including facial dysmorphism, short neck, CC developmental delay, hyperextensible joints and thorax CC abnormalities with widely spaced nipples. The facial features CC consist of triangular face with hypertelorism, large low-set ears, CC ptosis, and flat nasal bridge. Some patients manifest cardiac CC defects. CC -!- MISCELLANEOUS: This protein has one functional calcium-binding CC site. CC -!- SIMILARITY: Contains 1 Cbl-PTB (Cbl-type phosphotyrosine-binding) CC domain. CC -!- SIMILARITY: Contains 1 RING-type zinc finger. 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 EMBL; AP002956; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC132733; AAI32734.1; -; mRNA. DR EMBL; BC136463; AAI36464.1; -; mRNA. DR IPI; IPI00027269; -. DR PIR; A43817; A43817. DR RefSeq; NP_005179.2; NM_005188.2. 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=25-351. DR PDB; 2CBL; X-ray; 2.10 A; A=47-351. DR PDB; 2JUJ; NMR; -; A=851-906. DR PDB; 2K4D; NMR; -; A=358-437. DR PDB; 2OO9; X-ray; 2.10 A; A/B/C=856-895. DR PDB; 3BUM; X-ray; 2.00 A; B=25-351. DR PDB; 3BUN; X-ray; 2.00 A; B=25-351. DR PDB; 3BUO; X-ray; 2.60 A; B/D=25-351. DR PDB; 3BUW; X-ray; 1.45 A; B/D=25-351. DR PDB; 3BUX; X-ray; 1.35 A; B/D=25-351. DR PDB; 3OB1; X-ray; 2.20 A; B=25-351. DR PDB; 3OB2; X-ray; 2.10 A; B=25-351. DR PDB; 3PLF; X-ray; 1.92 A; B/D=25-351. DR PDBsum; 1B47; -. DR PDBsum; 1FBV; -. DR PDBsum; 1YVH; -. DR PDBsum; 2CBL; -. DR PDBsum; 2JUJ; -. DR PDBsum; 2K4D; -. DR PDBsum; 2OO9; -. DR PDBsum; 3BUM; -. DR PDBsum; 3BUN; -. DR PDBsum; 3BUO; -. DR PDBsum; 3BUW; -. DR PDBsum; 3BUX; -. DR PDBsum; 3OB1; -. DR PDBsum; 3OB2; -. DR PDBsum; 3PLF; -. DR ProteinModelPortal; P22681; -. DR SMR; P22681; 47-434, 851-906. DR DIP; DIP-189N; -. DR IntAct; P22681; 33. DR MINT; MINT-109040; -. DR STRING; P22681; -. DR PhosphoSite; P22681; -. DR PRIDE; P22681; -. DR Ensembl; ENST00000264033; ENSP00000264033; ENSG00000110395. DR GeneID; 867; -. DR KEGG; hsa:867; -. DR CTD; 867; -. DR GeneCards; GC11P115017; -. DR HGNC; HGNC:1541; CBL. DR HPA; CAB004350; -. DR HPA; HPA027956; -. DR MIM; 165360; gene. DR MIM; 613563; phenotype. DR neXtProt; NX_P22681; -. DR PharmGKB; PA26115; -. DR GeneTree; ENSGT00390000011617; -. DR HOGENOM; HBG714021; -. DR HOVERGEN; HBG005255; -. DR InParanoid; P22681; -. DR OMA; ASANAIY; -. DR OrthoDB; EOG444KJR; -. DR Pathway_Interaction_DB; epha_fwdpathway; EPHA forward signaling. DR Pathway_Interaction_DB; epha2_fwdpathway; EPHA2 forward signaling. DR Pathway_Interaction_DB; epopathway; EPO signaling pathway. DR Pathway_Interaction_DB; fcer1pathway; Fc-epsilon receptor I signaling in mast cells. DR Pathway_Interaction_DB; fgf_pathway; FGF signaling pathway. DR Pathway_Interaction_DB; ifngpathway; IFN-gamma pathway. DR Pathway_Interaction_DB; il4_2pathway; IL4-mediated signaling events. DR Pathway_Interaction_DB; insulin_pathway; Insulin Pathway. DR Pathway_Interaction_DB; avb3_integrin_pathway; Integrins in angiogenesis. DR Pathway_Interaction_DB; a4b1_paxdep_pathway; Paxillin-dependent events mediated by a4b1. DR Pathway_Interaction_DB; a4b1_paxindep_pathway; Paxillin-independent events mediated by a4b1 and a4b7. DR Pathway_Interaction_DB; pdgfrbpathway; PDGFR-beta signaling pathway. DR Pathway_Interaction_DB; reelinpathway; Reelin signaling pathway. DR Pathway_Interaction_DB; met_pathway; Signaling events activated by Hepatocyte Growth Factor Receptor (c-Met). DR Pathway_Interaction_DB; kitpathway; Signaling events mediated by Stem cell factor receptor (c-Kit). DR Pathway_Interaction_DB; tcrpathway; TCR signaling in naive CD4+ T cells. DR Pathway_Interaction_DB; cd8tcrpathway; TCR signaling in naive CD8+ T cells. DR Pathway_Interaction_DB; vegfr1_pathway; VEGFR1 specific signals. DR Reactome; REACT_6900; Signaling in Immune system. DR Reactome; REACT_9417; Signaling by EGFR. DR NextBio; 3618; -. DR PMAP-CutDB; P22681; -. DR ArrayExpress; P22681; -. DR Bgee; P22681; -. DR CleanEx; HS_CBL; -. DR Genevestigator; P22681; -. DR GermOnline; ENSG00000110395; Homo sapiens. DR GO; GO:0005829; C:cytosol; EXP:Reactome. DR GO; GO:0005634; C:nucleus; IEA:InterPro. DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro. DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; TAS:ProtInc. DR GO; GO:0017124; F:SH3 domain binding; IPI:BHF-UCL. DR GO; GO:0004871; F:signal transducer activity; IEA:InterPro. DR GO; GO:0004842; F:ubiquitin-protein ligase activity; TAS:HGNC. DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:HGNC. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0048260; P:positive regulation of receptor-mediated endocytosis; 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-like_dom. DR InterPro; IPR000980; SH2. DR InterPro; IPR009060; UBA-like. DR InterPro; IPR000449; UBA/transl_elong_EF1B_N. DR InterPro; IPR015940; UBA/transl_elong_EF1B_N_euk. DR InterPro; IPR018957; Znf_C3HC4_RING-type. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR InterPro; IPR017907; Znf_RING_CS. 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:3.30.505.10; SH2; 2. 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 SUPFAM; SSF47668; Adaptor_Cbl_N; 1. DR SUPFAM; SSF46934; UBA_like; 1. DR PROSITE; PS51506; CBL_PTB; 1. 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; Acetylation; Calcium; Complete proteome; Cytoplasm; KW Disease mutation; Ligase; Metal-binding; Phosphoprotein; Polymorphism; KW Proto-oncogene; Repeat; Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1 906 E3 ubiquitin-protein ligase CBL. FT /FTId=PRO_0000055858. FT DOMAIN 47 351 Cbl-PTB. FT DOMAIN 856 895 UBA. FT CA_BIND 227 238 Potential. FT ZN_FING 381 420 RING-type. FT REGION 47 175 4H. FT REGION 176 248 EF-hand-like. FT REGION 249 351 SH2-like. FT REGION 352 380 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 141 141 Phosphotyrosine. FT MOD_RES 197 197 N6-acetyllysine. FT MOD_RES 371 371 Phosphotyrosine; by INSR. FT MOD_RES 452 452 Phosphoserine. FT MOD_RES 455 455 Phosphotyrosine. 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 731 731 Phosphotyrosine; by SRC. FT MOD_RES 774 774 Phosphotyrosine. FT MOD_RES 900 900 Phosphoserine. FT VARIANT 367 367 Q -> P (in NSL; causes impaired CBL- FT mediated degradation of cell-surface FT receptors in a dominant-negative FT fashion). FT /FTId=VAR_064332. FT VARIANT 382 382 K -> E (in NSL; causes impaired CBL- FT mediated degradation of cell-surface FT receptors in a dominant-negative FT fashion). FT /FTId=VAR_064333. FT VARIANT 390 390 D -> Y (in NSL; causes impaired CBL- FT mediated degradation of cell-surface FT receptors in a dominant-negative FT fashion). FT /FTId=VAR_064334. FT VARIANT 420 420 R -> Q (in NSL; causes impaired CBL- FT mediated degradation of cell-surface FT receptors in a dominant-negative fashion FT as well as constitutive ERK FT phosphorylation). FT /FTId=VAR_064335. FT VARIANT 620 620 L -> F (in dbSNP:rs2227988). FT /FTId=VAR_057211. FT VARIANT 782 782 P -> L (in dbSNP:rs2229073). FT /FTId=VAR_057212. FT VARIANT 904 904 V -> I (in dbSNP:rs17122769). FT /FTId=VAR_057213. 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. Loss of FT phosphorylation by SRC. Inhibition of FT bone resorption. FT MUTAGEN 774 774 Y->F: Strongly reduces tyrosine FT phosphorylation by INSR; when associated FT with F-371 and F-700. FT CONFLICT 15 15 S -> T (in Ref. 1; CAA40393). 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; 99633 MW; 1AA6BF67377322CA CRC64; MAGNVKKSSG AGGGSGSGGS 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 //