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 11-JUN-2014, entry version 175. 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 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 PHOSPHORYLATION BY HCK, AND INTERACTION WITH HCK. RX PubMed=10092522; DOI=10.1006/bbrc.1999.0427; RA Howlett C.J., Bisson S.A., Resek M.E., Tigley A.W., Robbins S.M.; RT "The proto-oncogene p120(Cbl) is a downstream substrate of the Hck RT protein-tyrosine kinase."; RL Biochem. Biophys. Res. Commun. 257:129-138(1999). RN [5] RP FUNCTION. RX 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 [6] RP INTERACTION WITH BLK. RX PubMed=8083187; RA Donovan J.A., Wange R.L., Langdon W.Y., Samelson L.E.; RT "The protein product of the c-cbl protooncogene is the 120-kDa RT tyrosine-phosphorylated protein in Jurkat cells activated via the T RT cell antigen receptor."; RL J. Biol. Chem. 269:22921-22924(1994). RN [7] RP PHOSPHORYLATION BY EGFR, AND INTERACTION WITH 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 [8] 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 [9] 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 [10] RP INTERACTION WITH LAT2. RX 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 [11] RP INTERACTION WITH CSF1R, AND PHOSPHORYLATION. RX PubMed=11850825; DOI=10.1038/sj.onc.1205166; RA Wilhelmsen K., Burkhalter S., van der Geer P.; RT "C-Cbl binds the CSF-1 receptor at tyrosine 973, a novel RT phosphorylation site in the receptor's carboxy-terminus."; RL Oncogene 21:1079-1089(2002). RN [12] RP FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION, MUTAGENESIS OF RP CYS-381, AND INTERACTION WITH HCK. RX PubMed=11896602; DOI=10.1038/sj.onc.1205228; RA Howlett C.J., Robbins S.M.; RT "Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated RT cellular transformation."; RL Oncogene 21:1707-1716(2002). RN [13] RP INTERACTION WITH FGR, AND PHOSPHORYLATION BY FGR. RX PubMed=12435267; DOI=10.1042/BJ20021201; RA Melander F., Andersson T., Dib K.; RT "Fgr but not Syk tyrosine kinase is a target for beta 2 integrin- RT induced c-Cbl-mediated ubiquitination in adherent human neutrophils."; RL Biochem. J. 370:687-694(2003). RN [14] RP INTERACTION WITH SH2B2. RX 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 [15] RP INTERACTION WITH SH2B2. RX 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 [16] RP INTERACTION WITH SLA AND ZAP70, AND MUTAGENESIS OF GLY-306. RX 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 [17] RP INTERACTION WITH SLA2. RX 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 [18] RP INTERACTION WITH CD2AP. RX 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 [19] 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 [20] 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 [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. 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 [22] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=15144186; DOI=10.1021/ac035352d; RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., RA Peters E.C.; RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites RT from human T cells using immobilized metal affinity chromatography and RT tandem mass spectrometry."; RL Anal. Chem. 76:2763-2772(2004). RN [23] RP FUNCTION. RX PubMed=14661060; DOI=10.1038/sj.onc.1207298; RA Kim M., Tezuka T., Tanaka K., Yamamoto T.; RT "Cbl-c suppresses v-Src-induced transformation through ubiquitin- RT dependent protein degradation."; RL Oncogene 23:1645-1655(2004). RN [24] RP REVIEW ON ROLE IN KIT SIGNALING AND KIT DEGRADATION. RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6; RA Ronnstrand L.; RT "Signal transduction via the stem cell factor receptor/c-Kit."; RL Cell. Mol. Life Sci. 61:2535-2548(2004). RN [25] RP PHOSPHORYLATION AT TYR-700. RX PubMed=15556646; DOI=10.1016/j.febslet.2004.10.054; RA Grossmann A.H., Kolibaba K.S., Willis S.G., Corbin A.S., Langdon W.S., RA Deininger M.W., Druker B.J.; RT "Catalytic domains of tyrosine kinases determine the phosphorylation RT sites within c-Cbl."; RL FEBS Lett. 577:555-562(2004). RN [26] 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 [27] RP FUNCTION, PHOSPHORYLATION, AND INTERACTION WITH FGFR2; LYN AND FYN. RX PubMed=15190072; DOI=10.1074/jbc.M402469200; RA Kaabeche K., Lemonnier J., Le Mee S., Caverzasio J., Marie P.J.; RT "Cbl-mediated degradation of Lyn and Fyn induced by constitutive RT fibroblast growth factor receptor-2 activation supports osteoblast RT differentiation."; RL J. Biol. Chem. 279:36259-36267(2004). RN [28] RP INTERACTION WITH ALK, AND PHOSPHORYLATION BY ALK. RX PubMed=15226403; DOI=10.1242/jcs.01183; RA Motegi A., Fujimoto J., Kotani M., Sakuraba H., Yamamoto T.; RT "ALK receptor tyrosine kinase promotes cell growth and neurite RT outgrowth."; RL J. Cell Sci. 117:3319-3329(2004). RN [29] RP INTERACTION WITH AXL. RX PubMed=15958209; DOI=10.1016/j.bbrc.2005.05.086; RA Valverde P.; RT "Effects of Gas6 and hydrogen peroxide in Axl ubiquitination and RT downregulation."; RL Biochem. Biophys. Res. Commun. 333:180-185(2005). RN [30] RP REVIEW ON ROLE IN KIT SIGNALING AND KIT DEGRADATION. RX PubMed=16129412; DOI=10.1016/j.bbrc.2005.08.055; RA Roskoski R. Jr.; RT "Signaling by Kit protein-tyrosine kinase--the stem cell factor RT receptor."; RL Biochem. Biophys. Res. Commun. 337:1-13(2005). RN [31] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. 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 [32] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-900, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. 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 [33] RP FUNCTION, AND PHOSPHORYLATION. RX PubMed=17509076; DOI=10.1111/j.1742-4658.2007.05835.x; RA Bonaventure J., Horne W.C., Baron R.; RT "The localization of FGFR3 mutations causing thanatophoric dysplasia RT type I differentially affects phosphorylation, processing and RT ubiquitylation of the receptor."; RL FEBS J. 274:3078-3093(2007). RN [34] RP INTERACTION WITH PDGFRB. RX PubMed=17620338; DOI=10.1074/jbc.M701797200; RA Reddi A.L., Ying G., Duan L., Chen G., Dimri M., Douillard P., RA Druker B.J., Naramura M., Band V., Band H.; RT "Binding of Cbl to a phospholipase Cgamma1-docking site on platelet- RT derived growth factor receptor beta provides a dual mechanism of RT negative regulation."; RL J. Biol. Chem. 282:29336-29347(2007). RN [35] RP INTERACTION WITH LYN. RX PubMed=18235045; DOI=10.1182/blood-2007-08-109330; RA Wu J., Meng F., Lu H., Kong L., Bornmann W., Peng Z., Talpaz M., RA Donato N.J.; RT "Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl RT protein stability in imatinib-resistant chronic myelogenous leukemia RT cells."; RL Blood 111:3821-3829(2008). RN [36] RP FUNCTION, INTERACTION WITH FGFR2, AND SUBCELLULAR LOCATION. RX PubMed=18374639; DOI=10.1016/j.bone.2008.02.009; RA Dufour C., Guenou H., Kaabeche K., Bouvard D., Sanjay A., Marie P.J.; RT "FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt RT signaling and osteoblast survival."; RL Bone 42:1032-1039(2008). RN [37] RP IDENTIFICATION BY 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 [38] RP INTERACTION WITH EPHB1, AND PHOSPHORYLATION. RX PubMed=18034775; DOI=10.1111/j.1600-0854.2007.00679.x; RA Fasen K., Cerretti D.P., Huynh-Do U.; RT "Ligand binding induces Cbl-dependent EphB1 receptor degradation RT through the lysosomal pathway."; RL Traffic 9:251-266(2008). RN [39] RP INTERACTION WITH TEK/TIE2, AND FUNCTION. RX PubMed=19689429; DOI=10.1042/BJ20091010; RA Wehrle C., Van Slyke P., Dumont D.J.; RT "Angiopoietin-1-induced ubiquitylation of Tie2 by c-Cbl is required RT for internalization and degradation."; RL Biochem. J. 423:375-380(2009). RN [40] RP INTERACTION WITH EGFR. RX PubMed=19836242; DOI=10.1016/j.cub.2009.09.048; RA Tarcic G., Boguslavsky S.K., Wakim J., Kiuchi T., Liu A., Reinitz F., RA Nathanson D., Takahashi T., Mischel P.S., Ng T., Yarden Y.; RT "An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase RT controlling EGFR endocytosis."; RL Curr. Biol. 19:1788-1798(2009). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-452, AND IDENTIFICATION RP BY 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 [42] RP INTERACTION WITH PDGFRB, AND PHOSPHORYLATION. RX PubMed=20494825; DOI=10.1016/j.cellsig.2010.05.004; RA Wardega P., Heldin C.H., Lennartsson J.; RT "Mutation of tyrosine residue 857 in the PDGF beta-receptor affects RT cell proliferation but not migration."; RL Cell. Signal. 22:1363-1368(2010). RN [43] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., RA Mann M.; RT "Quantitative phosphoproteomics reveals widespread full RT phosphorylation site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [44] 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 [45] RP FUNCTION, AND INTERACTION WITH FGFR2. RX PubMed=21596750; DOI=10.1074/jbc.M110.197525; RA Severe N., Miraoui H., Marie P.J.; RT "The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic RT differentiation in human mesenchymal stromal cells in part by RT decreased Cbl-mediated platelet-derived growth factor receptor alpha RT and fibroblast growth factor receptor 2 ubiquitination."; RL J. Biol. Chem. 286:24443-24450(2011). RN [46] RP REVIEW ON FUNCTION IN FGF SIGNALING, AND UBIQUITINATION OF FGFR1. RX PubMed=20094046; DOI=10.1038/nrc2780; RA Turner N., Grose R.; RT "Fibroblast growth factor signalling: from development to cancer."; RL Nat. Rev. Cancer 10:116-129(2010). RN [47] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 47-350 IN COMPLEX WITH ZAP70 RP PEPTIDE AND CALCIUM IONS, CALCIUM-BINDING SITE, AND MUTAGENESIS OF RP SER-80; PRO-82; ASP-229; GLU-240; ARG-294 AND GLY-306. RX 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 [48] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 47-434 IN COMPLEX WITH ZAP70 RP AND UBE2L3. RX 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 [49] RP VARIANTS NSLL PRO-367; GLU-382; TYR-390 AND GLN-420, AND RP CHARACTERIZATION OF VARIANTS NSLL 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: Adapter protein that functions as a negative regulator CC of many signaling pathways that are triggered by activation of CC cell surface receptors. Acts as an E3 ubiquitin-protein ligase, CC which accepts ubiquitin from specific E2 ubiquitin-conjugating CC enzymes, and then transfers it to substrates promoting their CC degradation by the proteasome. Recognizes activated receptor CC tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, CC PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. CC Recognizes membrane-bound HCK, SRC and other kinases of the SRC CC family and mediates their ubiquitination and degradation. CC Participates in signal transduction in hematopoietic cells. Plays CC an important role in the regulation of osteoblast differentiation CC and apoptosis. Essential for osteoclastic bone resorption. The CC 'Tyr-731' phosphorylated form induces the activation and CC recruitment of phosphatidylinositol 3-kinase to the cell membrane CC in a signaling pathway that is critical for osteoclast function. CC May be functionally coupled with the E2 ubiquitin-protein ligase CC UB2D3. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Interacts (phosphorylated at Tyr-731) with PIK3R1. CC Associates with NCK via its SH3 domain. The phosphorylated C- CC terminus interacts with CD2AP via its second SH3 domain. Binds to CC UBE2L3. Interacts with adapters SLA, SLA2 and with the CC phosphorylated C-terminus of SH2B2. Interacts with EGFR, SYK and CC ZAP70 via the highly conserved Cbl-N region. Also interacts with CC SORBS1 and INPPL1/SHIP2. Interacts with phosphorylated LAT2. May CC interact with CBLB (By similarity). Interacts with ALK, AXL, BLK, CC FGR and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and CC PDGFRB; regulates receptor degradation through ubiquitination. CC Interacts with HCK and LYN. Interacts with TEK/TIE2 (tyrosine CC phosphorylated). CC -!- INTERACTION: CC Q8IZP0-2:ABI1; NbExp=3; IntAct=EBI-518228, EBI-7358775; CC Q14155:ARHGEF7; NbExp=9; IntAct=EBI-518228, EBI-717515; CC Q9Y5K6:CD2AP; NbExp=3; IntAct=EBI-518228, EBI-298152; CC P46108:CRK; NbExp=6; IntAct=EBI-518228, EBI-886; CC P46109:CRKL; NbExp=2; IntAct=EBI-518228, EBI-910; CC P00533:EGFR; NbExp=17; IntAct=EBI-518228, EBI-297353; CC P55085:F2RL1; NbExp=3; IntAct=EBI-518228, EBI-4303189; CC P17948:FLT1; NbExp=2; IntAct=EBI-518228, EBI-1026718; CC P39688:Fyn (xeno); NbExp=3; IntAct=EBI-518228, EBI-524514; CC P62993:GRB2; NbExp=7; IntAct=EBI-518228, EBI-401755; CC Q15811:ITSN1; NbExp=12; IntAct=EBI-518228, EBI-602041; CC P45983:MAPK8; NbExp=2; IntAct=EBI-518228, EBI-286483; CC P08581:MET; NbExp=14; IntAct=EBI-518228, EBI-1039152; CC P04629:NTRK1; NbExp=2; IntAct=EBI-518228, EBI-1028226; CC P27986:PIK3R1; NbExp=5; IntAct=EBI-518228, EBI-79464; CC P08487:PLCG1 (xeno); NbExp=3; IntAct=EBI-518228, EBI-8013886; CC O14492:SH2B2; NbExp=7; IntAct=EBI-518228, EBI-7507432; CC Q96B97:SH3KBP1; NbExp=17; IntAct=EBI-518228, EBI-346595; CC O43597:SPRY2; NbExp=17; IntAct=EBI-518228, EBI-742487; CC Q9C004:SPRY4; NbExp=9; IntAct=EBI-518228, EBI-354861; CC P12931:SRC; NbExp=8; IntAct=EBI-518228, EBI-621482; CC P43405:SYK; NbExp=2; IntAct=EBI-518228, EBI-78302; CC P31946:YWHAB; NbExp=3; IntAct=EBI-518228, EBI-359815; CC P27348:YWHAQ; NbExp=6; IntAct=EBI-518228, EBI-359854; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Note=Colocalizes CC with FGFR2 in lipid rafts at the cell membrane. 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 ALK, EGFR, SYK, FYN CC and ZAP70 (By similarity). Phosphorylated on tyrosine residues in CC response to FLT1 and KIT signaling. Phosphorylated on tyrosine CC residues by INSR and FGR. Phosphorylated on several tyrosine CC residues by constitutively activated FGFR3. Not phosphorylated at CC Tyr-731 by FGFR3. Phosphorylated on tyrosine residues by activated CC CSF1R, PDGFRA and PDGFRB. Phosphorylated on tyrosine residues by CC HCK. CC -!- PTM: Ubiquitinated, leading to its degradation via the proteasome. CC -!- DISEASE: Noonan syndrome-like disorder with or without juvenile CC myelomonocytic leukemia (NSLL) [MIM:613563]: A syndrome CC characterized by a phenotype reminiscent of Noonan syndrome. CC Clinical features are highly variable, including facial CC dysmorphism, short neck, developmental delay, hyperextensible CC joints and thorax abnormalities with widely spaced nipples. The CC facial features consist of triangular face with hypertelorism, CC large low-set ears, ptosis, and flat nasal bridge. Some patients CC manifest cardiac defects. Some have an increased risk for certain CC malignancies, particularly juvenile myelomonocytic leukemia. CC Note=The disease is caused by mutations affecting the gene CC represented in this entry. 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 PIR; A43817; A43817. DR RefSeq; NP_005179.2; NM_005188.3. 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; 2Y1M; X-ray; 2.67 A; A/B/C/D/E/F=47-435. DR PDB; 2Y1N; X-ray; 2.00 A; A/C=47-435. 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 PDB; 4A49; X-ray; 2.21 A; A=354-435. DR PDB; 4A4B; X-ray; 2.79 A; A=47-435. DR PDB; 4A4C; X-ray; 2.70 A; A=47-435. DR PDB; 4GPL; X-ray; 3.00 A; B=47-351. DR PDBsum; 1B47; -. DR PDBsum; 1FBV; -. DR PDBsum; 1YVH; -. DR PDBsum; 2CBL; -. DR PDBsum; 2JUJ; -. DR PDBsum; 2K4D; -. DR PDBsum; 2OO9; -. DR PDBsum; 2Y1M; -. DR PDBsum; 2Y1N; -. 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 PDBsum; 4A49; -. DR PDBsum; 4A4B; -. DR PDBsum; 4A4C; -. DR PDBsum; 4GPL; -. DR ProteinModelPortal; P22681; -. DR SMR; P22681; 48-435, 851-906. DR BioGrid; 107315; 214. DR DIP; DIP-189N; -. DR IntAct; P22681; 61. DR MINT; MINT-109040; -. DR STRING; 9606.ENSP00000264033; -. DR PhosphoSite; P22681; -. DR DMDM; 251757253; -. DR MaxQB; P22681; -. DR PaxDb; P22681; -. DR PRIDE; P22681; -. DR Ensembl; ENST00000264033; ENSP00000264033; ENSG00000110395. DR GeneID; 867; -. DR KEGG; hsa:867; -. DR UCSC; uc001pwe.4; human. DR CTD; 867; -. DR GeneCards; GC11P119110; -. DR HGNC; HGNC:1541; CBL. DR HPA; CAB004350; -. DR HPA; HPA027956; -. DR MIM; 165360; gene. DR MIM; 613563; phenotype. DR neXtProt; NX_P22681; -. DR Orphanet; 86834; Juvenile myelomonocytic leukemia. DR Orphanet; 363972; Noonan syndrome-like disorder with juvenile myelomonocytic leukemia. DR PharmGKB; PA26115; -. DR eggNOG; NOG242251; -. DR HOGENOM; HOG000294176; -. DR HOVERGEN; HBG005255; -. DR InParanoid; P22681; -. DR KO; K04707; -. DR OMA; MEPRADV; -. DR OrthoDB; EOG7M0NQX; -. DR PhylomeDB; P22681; -. DR TreeFam; TF314210; -. DR Reactome; REACT_111102; Signal Transduction. DR Reactome; REACT_116125; Disease. DR Reactome; REACT_6900; Immune System. DR SignaLink; P22681; -. DR UniPathway; UPA00143; -. DR EvolutionaryTrace; P22681; -. DR GeneWiki; CBL_(gene); -. DR GenomeRNAi; 867; -. DR NextBio; 3618; -. DR PMAP-CutDB; P22681; -. DR PRO; PR:P22681; -. DR Bgee; P22681; -. DR CleanEx; HS_CBL; -. DR Genevestigator; P22681; -. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0016600; C:flotillin complex; IEA:Ensembl. DR GO; GO:0005634; C:nucleus; IEA:InterPro. DR GO; GO:0005886; C:plasma membrane; IDA:HGNC. DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro. DR GO; GO:0046875; F:ephrin receptor binding; IPI:UniProtKB. DR GO; GO:0005515; F:protein binding; IPI:UniProtKB. 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:0007166; P:cell surface receptor signaling pathway; TAS:HGNC. DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:HGNC. DR GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome. DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IMP:BHF-UCL. DR GO; GO:0048260; P:positive regulation of receptor-mediated endocytosis; TAS:HGNC. DR GO; GO:0016567; P:protein ubiquitination; TAS:HGNC. DR GO; GO:0006355; P:regulation of transcription, DNA-templated; TAS:GOC. DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome. DR Gene3D; 1.10.238.10; -; 1. DR Gene3D; 1.20.930.20; -; 1. DR Gene3D; 3.30.40.10; -; 1. DR Gene3D; 3.30.505.10; -; 1. DR InterPro; IPR024162; Adaptor_Cbl. DR InterPro; IPR014741; Adaptor_Cbl_EF_hand-like. DR InterPro; IPR003153; Adaptor_Cbl_N_hlx. DR InterPro; IPR014742; Adaptor_Cbl_SH2-like. DR InterPro; IPR024159; Cbl_PTB. DR InterPro; IPR011992; EF-hand-dom_pair. DR InterPro; IPR000980; SH2. DR InterPro; IPR009060; UBA-like. DR InterPro; IPR015940; UBA/transl_elong_EF1B_N_euk. DR InterPro; IPR000449; UBA/Ts_N. 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 PANTHER; PTHR23007; PTHR23007; 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; SSF46934; SSF46934; 1. DR SUPFAM; SSF47668; SSF47668; 1. DR SUPFAM; SSF55550; SSF55550; 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; Calcium; Cell membrane; Complete proteome; Cytoplasm; KW Disease mutation; Ligase; Membrane; Metal-binding; Phosphoprotein; KW Polymorphism; Proto-oncogene; Reference proteome; Repeat; KW Ubl conjugation; 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 227 240 FT ZN_FING 381 420 RING-type. FT REGION 1 357 Sufficient for interaction with EPHB1. 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 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; by ABL1. 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 NSLL; 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 NSLL; 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 NSLL; 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 NSLL; 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 and EPHB1, but does not affect FT 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 381 381 C->A: Loss of ubiquitin ligase activity. 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. Abolishes interaction FT with PIK3R1. 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 STRAND 79 82 FT HELIX 84 101 FT TURN 102 104 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 202 212 FT HELIX 218 228 FT STRAND 233 237 FT HELIX 238 247 FT HELIX 251 253 FT HELIX 254 261 FT TURN 262 264 FT STRAND 268 271 FT HELIX 274 281 FT HELIX 282 284 FT STRAND 290 295 FT STRAND 297 299 FT STRAND 302 308 FT TURN 310 312 FT STRAND 314 317 FT STRAND 320 322 FT HELIX 324 333 FT TURN 350 353 FT STRAND 354 356 FT STRAND 360 362 FT HELIX 365 373 FT TURN 374 376 FT STRAND 377 380 FT TURN 382 384 FT STRAND 385 388 FT STRAND 391 394 FT STRAND 398 400 FT HELIX 402 411 FT TURN 417 419 FT STRAND 425 428 FT STRAND 430 432 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 //