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E3 ubiquitin-protein ligase CBL (EC 2.3.2.27) (Casitas B-lineage lymphoma proto-oncogene) (Proto-oncogene c-Cbl) (RING finger protein 55) (RING-type E3 ubiquitin transferase CBL) (Signal transduction protein CBL)

 CBL_HUMAN               Reviewed;         906 AA.
P22681; A3KMP8;
01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
07-JUL-2009, sequence version 2.
25-APR-2018, entry version 219.
RecName: Full=E3 ubiquitin-protein ligase CBL;
EC=2.3.2.27 {ECO:0000269|PubMed:10514377, ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:17509076};
AltName: Full=Casitas B-lineage lymphoma proto-oncogene;
AltName: Full=Proto-oncogene c-Cbl;
AltName: Full=RING finger protein 55;
AltName: Full=RING-type E3 ubiquitin transferase CBL {ECO:0000305};
AltName: Full=Signal transduction protein CBL;
Name=CBL; Synonyms=CBL2, RNF55;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=2030914;
Blake T.J., Shapiro M., Morse H.C. III, Langdon W.Y.;
"The sequences of the human and mouse c-cbl proto-oncogenes show v-cbl
was generated by a large truncation encompassing a proline-rich domain
and a leucine zipper-like motif.";
Oncogene 6:653-657(1991).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=16554811; DOI=10.1038/nature04632;
Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F.,
Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E.,
FitzGerald M.G., Jaffe D.B., LaButti K., Nicol R., Park H.-S.,
Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W.,
Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S.,
Sakaki Y.;
"Human chromosome 11 DNA sequence and analysis including novel gene
identification.";
Nature 440:497-500(2006).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[4]
PHOSPHORYLATION BY HCK, AND INTERACTION WITH HCK.
PubMed=10092522; DOI=10.1006/bbrc.1999.0427;
Howlett C.J., Bisson S.A., Resek M.E., Tigley A.W., Robbins S.M.;
"The proto-oncogene p120(Cbl) is a downstream substrate of the Hck
protein-tyrosine kinase.";
Biochem. Biophys. Res. Commun. 257:129-138(1999).
[5]
FUNCTION, AND CATALYTIC ACTIVITY.
PubMed=10514377; DOI=10.1126/science.286.5438.309;
Joazeiro C.A., Wing S.S., Huang H.-K., Leverson J.D., Hunter T.,
Liu Y.-C.;
"The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-
dependent ubiquitin-protein ligase.";
Science 286:309-312(1999).
[6]
INTERACTION WITH BLK.
PubMed=8083187;
Donovan J.A., Wange R.L., Langdon W.Y., Samelson L.E.;
"The protein product of the c-cbl protooncogene is the 120-kDa
tyrosine-phosphorylated protein in Jurkat cells activated via the T
cell antigen receptor.";
J. Biol. Chem. 269:22921-22924(1994).
[7]
PHOSPHORYLATION BY EGFR, AND INTERACTION WITH EGFR.
PubMed=7657591; DOI=10.1074/jbc.270.35.20242;
Galisteo M.L., Dikic I., Batzer A.G., Langdon W.Y., Schlessinger J.;
"Tyrosine phosphorylation of the c-cbl proto-oncogene protein product
and association with epidermal growth factor (EGF) receptor upon EGF
stimulation.";
J. Biol. Chem. 270:20242-20245(1995).
[8]
INTERACTION WITH ZAP70.
PubMed=9407100; DOI=10.1074/jbc.272.52.33140;
Lupher M.L. Jr., Songyang Z., Shoelson S.E., Cantley L.C., Band H.;
"The Cbl phosphotyrosine-binding domain selects a D(N/D)XpY motif and
binds to the Tyr292 negative regulatory phosphorylation site of ZAP-
70.";
J. Biol. Chem. 272:33140-33144(1997).
[9]
PHOSPHORYLATION BY SYK AND FYN.
PubMed=9535867; DOI=10.1074/jbc.273.15.8867;
Deckert M., Elly C., Altman A., Liu Y.C.;
"Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn
and Syk tyrosine kinases.";
J. Biol. Chem. 273:8867-8874(1998).
[10]
INTERACTION WITH LAT2.
PubMed=12486104; DOI=10.1084/jem.20021405;
Brdicka T., Imrich M., Angelisova P., Brdickova N., Horvath O.,
Spicka J., Hilgert I., Luskova P., Draber P., Novak P., Engels N.,
Wienands J., Simeoni L., Oesterreicher J., Aguado E., Malissen M.,
Schraven B., Horejsi V.;
"Non-T cell activation linker (NTAL): a transmembrane adaptor protein
involved in immunoreceptor signaling.";
J. Exp. Med. 196:1617-1626(2002).
[11]
INTERACTION WITH CSF1R, AND PHOSPHORYLATION.
PubMed=11850825; DOI=10.1038/sj.onc.1205166;
Wilhelmsen K., Burkhalter S., van der Geer P.;
"C-Cbl binds the CSF-1 receptor at tyrosine 973, a novel
phosphorylation site in the receptor's carboxy-terminus.";
Oncogene 21:1079-1089(2002).
[12]
FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION, MUTAGENESIS OF
CYS-381, AND INTERACTION WITH HCK.
PubMed=11896602; DOI=10.1038/sj.onc.1205228;
Howlett C.J., Robbins S.M.;
"Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated
cellular transformation.";
Oncogene 21:1707-1716(2002).
[13]
INTERACTION WITH FGR, AND PHOSPHORYLATION BY FGR.
PubMed=12435267; DOI=10.1042/BJ20021201;
Melander F., Andersson T., Dib K.;
"Fgr but not Syk tyrosine kinase is a target for beta 2 integrin-
induced c-Cbl-mediated ubiquitination in adherent human neutrophils.";
Biochem. J. 370:687-694(2003).
[14]
INTERACTION WITH SH2B2.
PubMed=10374881; DOI=10.1038/sj/leu/2401397;
Wakioka T., Sasaki A., Mitsui K., Yokouchi M., Inoue A., Komiya S.,
Yoshimura A.;
"APS, an adaptor protein containing pleckstrin homology (PH) and Src
homology-2 (SH2) domains inhibits the JAK-STAT pathway in
collaboration with c-Cbl.";
Leukemia 13:760-767(1999).
[15]
INTERACTION WITH SH2B2.
PubMed=9989826; DOI=10.1038/sj.onc.1202326;
Yokouchi M., Wakioka T., Sakamoto H., Yasukawa H., Ohtsuka S.,
Sasaki A., Ohtsubo M., Valius M., Inoue A., Komiya S., Yoshimura A.;
"APS, an adaptor protein containing PH and SH2 domains, is associated
with the PDGF receptor and c-Cbl and inhibits PDGF-induced
mitogenesis.";
Oncogene 18:759-767(1999).
[16]
INTERACTION WITH SLA AND ZAP70, AND MUTAGENESIS OF GLY-306.
PubMed=10449770; DOI=10.1073/pnas.96.17.9775;
Tang J., Sawasdikosol S., Chang J.-H., Burakoff S.J.;
"SLAP, a dimeric adapter protein, plays a functional role in T cell
receptor signaling.";
Proc. Natl. Acad. Sci. U.S.A. 96:9775-9780(1999).
[17]
INTERACTION WITH SLA2.
PubMed=11696592; DOI=10.1084/jem.194.9.1263;
Holland S.J., Liao X.C., Mendenhall M.K., Zhou X., Pardo J., Chu P.,
Spencer C., Fu A.C., Sheng N., Yu P., Pali E., Nagin A., Shen M.,
Yu S., Chan E., Wu X., Li C., Woisetschlager M., Aversa G.,
Kolbinger F., Bennett M.K., Molineaux S., Luo Y., Payan D.G.,
Mancebo H.S.Y., Wu J.;
"Functional cloning of Src-like adapter protein-2 (SLAP-2), a novel
inhibitor of antigen receptor signaling.";
J. Exp. Med. 194:1263-1276(2001).
[18]
INTERACTION WITH CD2AP.
PubMed=11067845; DOI=10.1074/jbc.M005784200;
Kirsch K.H., Georgescu M.M., Shishido T., Langdon W.Y., Birge R.B.,
Hanafusa H.;
"The adapter type protein CMS/CD2AP binds to the proto-oncogenic
protein c-Cbl through a tyrosine phosphorylation-regulated Src
homology 3 domain interaction.";
J. Biol. Chem. 276:4957-4963(2001).
[19]
INTERACTION WITH SH2B2, MUTAGENESIS OF TYR-371; TYR-700; TYR-731 AND
TYR-774, AND PHOSPHORYLATION AT TYR-371; TYR-700 AND TYR-774.
PubMed=11997497; DOI=10.1128/MCB.22.11.3599-3609.2002;
Liu J., Kimura A., Baumann C.A., Saltiel A.R.;
"APS facilitates c-Cbl tyrosine phosphorylation and GLUT4
translocation in response to insulin in 3T3-L1 adipocytes.";
Mol. Cell. Biol. 22:3599-3609(2002).
[20]
INTERACTION WITH INPPL1.
PubMed=12504111; DOI=10.1016/S0006-291X(02)02894-2;
Vandenbroere I., Paternotte N., Dumont J.E., Erneux C., Pirson I.;
"The c-Cbl-associated protein and c-Cbl are two new partners of the
SH2-containing inositol polyphosphate 5-phosphatase SHIP2.";
Biochem. Biophys. Res. Commun. 300:494-500(2003).
[21]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=12522270; DOI=10.1073/pnas.2436191100;
Salomon A.R., Ficarro S.B., Brill L.M., Brinker A., Phung Q.T.,
Ericson C., Sauer K., Brock A., Horn D.M., Schultz P.G., Peters E.C.;
"Profiling of tyrosine phosphorylation pathways in human cells using
mass spectrometry.";
Proc. Natl. Acad. Sci. U.S.A. 100:443-448(2003).
[22]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=15144186; DOI=10.1021/ac035352d;
Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M.,
Peters E.C.;
"Robust phosphoproteomic profiling of tyrosine phosphorylation sites
from human T cells using immobilized metal affinity chromatography and
tandem mass spectrometry.";
Anal. Chem. 76:2763-2772(2004).
[23]
FUNCTION, AND CATALYTIC ACTIVITY.
PubMed=14661060; DOI=10.1038/sj.onc.1207298;
Kim M., Tezuka T., Tanaka K., Yamamoto T.;
"Cbl-c suppresses v-Src-induced transformation through ubiquitin-
dependent protein degradation.";
Oncogene 23:1645-1655(2004).
[24]
REVIEW ON ROLE IN KIT SIGNALING AND KIT DEGRADATION.
PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
Ronnstrand L.;
"Signal transduction via the stem cell factor receptor/c-Kit.";
Cell. Mol. Life Sci. 61:2535-2548(2004).
[25]
PHOSPHORYLATION AT TYR-700.
PubMed=15556646; DOI=10.1016/j.febslet.2004.10.054;
Grossmann A.H., Kolibaba K.S., Willis S.G., Corbin A.S., Langdon W.S.,
Deininger M.W., Druker B.J.;
"Catalytic domains of tyrosine kinases determine the phosphorylation
sites within c-Cbl.";
FEBS Lett. 577:555-562(2004).
[26]
FUNCTION, PHOSPHORYLATION AT TYR-731, AND MUTAGENESIS OF TYR-731.
PubMed=14739300; DOI=10.1074/jbc.M311032200;
Miyazaki T., Sanjay A., Neff L., Tanaka S., Horne W.C., Baron R.;
"Src kinase activity is essential for osteoclast function.";
J. Biol. Chem. 279:17660-17666(2004).
[27]
FUNCTION, PHOSPHORYLATION, AND INTERACTION WITH FGFR2; LYN AND FYN.
PubMed=15190072; DOI=10.1074/jbc.M402469200;
Kaabeche K., Lemonnier J., Le Mee S., Caverzasio J., Marie P.J.;
"Cbl-mediated degradation of Lyn and Fyn induced by constitutive
fibroblast growth factor receptor-2 activation supports osteoblast
differentiation.";
J. Biol. Chem. 279:36259-36267(2004).
[28]
INTERACTION WITH ALK, AND PHOSPHORYLATION BY ALK.
PubMed=15226403; DOI=10.1242/jcs.01183;
Motegi A., Fujimoto J., Kotani M., Sakuraba H., Yamamoto T.;
"ALK receptor tyrosine kinase promotes cell growth and neurite
outgrowth.";
J. Cell Sci. 117:3319-3329(2004).
[29]
INTERACTION WITH AXL.
PubMed=15958209; DOI=10.1016/j.bbrc.2005.05.086;
Valverde P.;
"Effects of Gas6 and hydrogen peroxide in Axl ubiquitination and
downregulation.";
Biochem. Biophys. Res. Commun. 333:180-185(2005).
[30]
REVIEW ON ROLE IN KIT SIGNALING AND KIT DEGRADATION.
PubMed=16129412; DOI=10.1016/j.bbrc.2005.08.055;
Roskoski R. Jr.;
"Signaling by Kit protein-tyrosine kinase--the stem cell factor
receptor.";
Biochem. Biophys. Res. Commun. 337:1-13(2005).
[31]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=15592455; DOI=10.1038/nbt1046;
Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
Zha X.-M., Polakiewicz R.D., Comb M.J.;
"Immunoaffinity profiling of tyrosine phosphorylation in cancer
cells.";
Nat. Biotechnol. 23:94-101(2005).
[32]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-900, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=16964243; DOI=10.1038/nbt1240;
Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
"A probability-based approach for high-throughput protein
phosphorylation analysis and site localization.";
Nat. Biotechnol. 24:1285-1292(2006).
[33]
FUNCTION, CATALYTIC ACTIVITY, AND PHOSPHORYLATION.
PubMed=17509076; DOI=10.1111/j.1742-4658.2007.05835.x;
Bonaventure J., Horne W.C., Baron R.;
"The localization of FGFR3 mutations causing thanatophoric dysplasia
type I differentially affects phosphorylation, processing and
ubiquitylation of the receptor.";
FEBS J. 274:3078-3093(2007).
[34]
INTERACTION WITH PDGFRB.
PubMed=17620338; DOI=10.1074/jbc.M701797200;
Reddi A.L., Ying G., Duan L., Chen G., Dimri M., Douillard P.,
Druker B.J., Naramura M., Band V., Band H.;
"Binding of Cbl to a phospholipase Cgamma1-docking site on platelet-
derived growth factor receptor beta provides a dual mechanism of
negative regulation.";
J. Biol. Chem. 282:29336-29347(2007).
[35]
INTERACTION WITH LYN.
PubMed=18235045; DOI=10.1182/blood-2007-08-109330;
Wu J., Meng F., Lu H., Kong L., Bornmann W., Peng Z., Talpaz M.,
Donato N.J.;
"Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl
protein stability in imatinib-resistant chronic myelogenous leukemia
cells.";
Blood 111:3821-3829(2008).
[36]
FUNCTION, INTERACTION WITH FGFR2, AND SUBCELLULAR LOCATION.
PubMed=18374639; DOI=10.1016/j.bone.2008.02.009;
Dufour C., Guenou H., Kaabeche K., Bouvard D., Sanjay A., Marie P.J.;
"FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt
signaling and osteoblast survival.";
Bone 42:1032-1039(2008).
[37]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18669648; DOI=10.1073/pnas.0805139105;
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
Elledge S.J., Gygi S.P.;
"A quantitative atlas of mitotic phosphorylation.";
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
[38]
INTERACTION WITH EPHB1, AND PHOSPHORYLATION.
PubMed=18034775; DOI=10.1111/j.1600-0854.2007.00679.x;
Fasen K., Cerretti D.P., Huynh-Do U.;
"Ligand binding induces Cbl-dependent EphB1 receptor degradation
through the lysosomal pathway.";
Traffic 9:251-266(2008).
[39]
INTERACTION WITH TEK/TIE2, AND FUNCTION.
PubMed=19689429; DOI=10.1042/BJ20091010;
Wehrle C., Van Slyke P., Dumont D.J.;
"Angiopoietin-1-induced ubiquitylation of Tie2 by c-Cbl is required
for internalization and degradation.";
Biochem. J. 423:375-380(2009).
[40]
INTERACTION WITH EGFR.
PubMed=19836242; DOI=10.1016/j.cub.2009.09.048;
Tarcic G., Boguslavsky S.K., Wakim J., Kiuchi T., Liu A., Reinitz F.,
Nathanson D., Takahashi T., Mischel P.S., Ng T., Yarden Y.;
"An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase
controlling EGFR endocytosis.";
Curr. Biol. 19:1788-1798(2009).
[41]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-452, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=19690332; DOI=10.1126/scisignal.2000007;
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
Rodionov V., Han D.K.;
"Quantitative phosphoproteomic analysis of T cell receptor signaling
reveals system-wide modulation of protein-protein interactions.";
Sci. Signal. 2:RA46-RA46(2009).
[42]
INTERACTION WITH PDGFRB, AND PHOSPHORYLATION.
PubMed=20494825; DOI=10.1016/j.cellsig.2010.05.004;
Wardega P., Heldin C.H., Lennartsson J.;
"Mutation of tyrosine residue 857 in the PDGF beta-receptor affects
cell proliferation but not migration.";
Cell. Signal. 22:1363-1368(2010).
[43]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=20068231; DOI=10.1126/scisignal.2000475;
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
Mann M.;
"Quantitative phosphoproteomics reveals widespread full
phosphorylation site occupancy during mitosis.";
Sci. Signal. 3:RA3-RA3(2010).
[44]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[45]
FUNCTION, AND INTERACTION WITH FGFR2.
PubMed=21596750; DOI=10.1074/jbc.M110.197525;
Severe N., Miraoui H., Marie P.J.;
"The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic
differentiation in human mesenchymal stromal cells in part by
decreased Cbl-mediated platelet-derived growth factor receptor alpha
and fibroblast growth factor receptor 2 ubiquitination.";
J. Biol. Chem. 286:24443-24450(2011).
[46]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439; SER-483 AND
SER-669, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
ANALYSIS].
TISSUE=Erythroleukemia;
PubMed=23186163; DOI=10.1021/pr300630k;
Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
Mohammed S.;
"Toward a comprehensive characterization of a human cancer cell
phosphoproteome.";
J. Proteome Res. 12:260-271(2013).
[47]
CHARACTERIZATION OF VARIANTS NSLL GLU-382; TYR-390 AND GLN-420.
PubMed=25178484; DOI=10.1002/humu.22682;
Brand K., Kentsch H., Glashoff C., Rosenberger G.;
"RASopathy-associated CBL germline mutations cause aberrant
ubiquitylation and trafficking of EGFR.";
Hum. Mutat. 35:1372-1381(2014).
[48]
REVIEW ON FUNCTION IN FGF SIGNALING, AND UBIQUITINATION OF FGFR1.
PubMed=20094046; DOI=10.1038/nrc2780;
Turner N., Grose R.;
"Fibroblast growth factor signalling: from development to cancer.";
Nat. Rev. Cancer 10:116-129(2010).
[49]
X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 47-350 IN COMPLEX WITH ZAP70
PEPTIDE AND CALCIUM IONS, CALCIUM-BINDING SITE, AND MUTAGENESIS OF
SER-80; PRO-82; ASP-229; GLU-240; ARG-294 AND GLY-306.
PubMed=10078535; DOI=10.1038/18050;
Meng W., Sawasdikosol S., Burakoff S.J., Eck M.J.;
"Structure of the amino-terminal domain of Cbl complexed to its
binding site on ZAP-70 kinase.";
Nature 398:84-90(1999).
[50]
X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 47-434 IN COMPLEX WITH ZAP70
AND UBE2L3.
PubMed=10966114; DOI=10.1016/S0092-8674(00)00057-X;
Zheng N., Wang P., Jeffrey P.D., Pavletich N.P.;
"Structure of a c-Cbl-UbcH7 complex: RING domain function in
ubiquitin-protein ligases.";
Cell 102:533-539(2000).
[51]
VARIANTS NSLL PRO-367; GLU-382; TYR-390 AND GLN-420, AND
CHARACTERIZATION OF VARIANTS NSLL TYR-390 AND GLN-420.
PubMed=20619386; DOI=10.1016/j.ajhg.2010.06.015;
Martinelli S., De Luca A., Stellacci E., Rossi C., Checquolo S.,
Lepri F., Caputo V., Silvano M., Buscherini F., Consoli F.,
Ferrara G., Digilio M.C., Cavaliere M.L., van Hagen J.M., Zampino G.,
van der Burgt I., Ferrero G.B., Mazzanti L., Screpanti I.,
Yntema H.G., Nillesen W.M., Savarirayan R., Zenker M.,
Dallapiccola B., Gelb B.D., Tartaglia M.;
"Heterozygous germline mutations in the CBL tumor-suppressor gene
cause a Noonan syndrome-like phenotype.";
Am. J. Hum. Genet. 87:250-257(2010).
[52]
VARIANTS ARG-287; SER-LYS-365 INS; HIS-371 AND LEU-499,
CHARACTERIZATION OF VARIANTS SER-LYS-365 INS AND HIS-371, AND
PHOSPHORYLATION AT TYR-674; TYR-700 AND TYR-774.
PubMed=20622007; DOI=10.1074/jbc.M110.106161;
Fernandes M.S., Reddy M.M., Croteau N.J., Walz C., Weisbach H.,
Podar K., Band H., Carroll M., Reiter A., Larson R.A., Salgia R.,
Griffin J.D., Sattler M.;
"Novel oncogenic mutations of CBL in human acute myeloid leukemia that
activate growth and survival pathways depend on increased
metabolism.";
J. Biol. Chem. 285:32596-32605(2010).
-!- FUNCTION: Adapter protein that functions as a negative regulator
of many signaling pathways that are triggered by activation of
cell surface receptors. Acts as an E3 ubiquitin-protein ligase,
which accepts ubiquitin from specific E2 ubiquitin-conjugating
enzymes, and then transfers it to substrates promoting their
degradation by the proteasome. Recognizes activated receptor
tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA,
PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling.
Recognizes membrane-bound HCK, SRC and other kinases of the SRC
family and mediates their ubiquitination and degradation.
Participates in signal transduction in hematopoietic cells. Plays
an important role in the regulation of osteoblast differentiation
and apoptosis. Essential for osteoclastic bone resorption. The
'Tyr-731' phosphorylated form induces the activation and
recruitment of phosphatidylinositol 3-kinase to the cell membrane
in a signaling pathway that is critical for osteoclast function.
May be functionally coupled with the E2 ubiquitin-protein ligase
UB2D3. {ECO:0000269|PubMed:10514377, ECO:0000269|PubMed:11896602,
ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:14739300,
ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:17509076,
ECO:0000269|PubMed:18374639, ECO:0000269|PubMed:19689429,
ECO:0000269|PubMed:21596750}.
-!- CATALYTIC ACTIVITY: S-ubiquitinyl-[E2 ubiquitin-conjugating
enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-
conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor
protein]-L-lysine. {ECO:0000269|PubMed:10514377,
ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:17509076}.
-!- PATHWAY: Protein modification; protein ubiquitination.
-!- SUBUNIT: Interacts (phosphorylated at Tyr-731) with PIK3R1.
Associates with NCK via its SH3 domain. The phosphorylated C-
terminus interacts with CD2AP via its second SH3 domain. Binds to
UBE2L3. Interacts with adapters SLA, SLA2 and with the
phosphorylated C-terminus of SH2B2. Interacts with EGFR, SYK and
ZAP70 via the highly conserved Cbl-N region. Also interacts with
SORBS1 and INPPL1/SHIP2. Interacts with phosphorylated LAT2. May
interact with CBLB (By similarity). Interacts with ALK, AXL, BLK,
FGR and FGFR2. Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and
PDGFRB; regulates receptor degradation through ubiquitination.
Interacts with HCK and LYN. Interacts with TEK/TIE2 (tyrosine
phosphorylated). Interacts with SH3KBP1 and this interaction is
inhibited in the presence of SHKBP1 (By similarity). Interacts
with SIGLEC10 (By similarity). {ECO:0000250|UniProtKB:P22682,
ECO:0000269|PubMed:10078535, ECO:0000269|PubMed:10092522,
ECO:0000269|PubMed:10374881, ECO:0000269|PubMed:10449770,
ECO:0000269|PubMed:10966114, ECO:0000269|PubMed:11067845,
ECO:0000269|PubMed:11696592, ECO:0000269|PubMed:11850825,
ECO:0000269|PubMed:11896602, ECO:0000269|PubMed:11997497,
ECO:0000269|PubMed:12435267, ECO:0000269|PubMed:12486104,
ECO:0000269|PubMed:12504111, ECO:0000269|PubMed:15190072,
ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:15958209,
ECO:0000269|PubMed:17620338, ECO:0000269|PubMed:18034775,
ECO:0000269|PubMed:18235045, ECO:0000269|PubMed:18374639,
ECO:0000269|PubMed:19689429, ECO:0000269|PubMed:19836242,
ECO:0000269|PubMed:20494825, ECO:0000269|PubMed:21596750,
ECO:0000269|PubMed:7657591, ECO:0000269|PubMed:8083187,
ECO:0000269|PubMed:9407100, ECO:0000269|PubMed:9989826}.
-!- INTERACTION:
Q8IZP0-2:ABI1; NbExp=3; IntAct=EBI-518228, EBI-7358775;
Q14155:ARHGEF7; NbExp=9; IntAct=EBI-518228, EBI-717515;
Q9Y5K6:CD2AP; NbExp=7; IntAct=EBI-518228, EBI-298152;
P46108:CRK; NbExp=10; IntAct=EBI-518228, EBI-886;
P46109:CRKL; NbExp=8; IntAct=EBI-518228, EBI-910;
P00533:EGFR; NbExp=26; IntAct=EBI-518228, EBI-297353;
P55085:F2RL1; NbExp=3; IntAct=EBI-518228, EBI-4303189;
P17948:FLT1; NbExp=2; IntAct=EBI-518228, EBI-1026718;
P06241:FYN; NbExp=6; IntAct=EBI-518228, EBI-515315;
P39688:Fyn (xeno); NbExp=3; IntAct=EBI-518228, EBI-524514;
P62993:GRB2; NbExp=15; IntAct=EBI-518228, EBI-401755;
P62994:Grb2 (xeno); NbExp=5; IntAct=EBI-518228, EBI-401775;
P08631-2:HCK; NbExp=2; IntAct=EBI-518228, EBI-9834454;
Q15811:ITSN1; NbExp=12; IntAct=EBI-518228, EBI-602041;
P06239:LCK; NbExp=4; IntAct=EBI-518228, EBI-1348;
P06240:Lck (xeno); NbExp=2; IntAct=EBI-518228, EBI-1401;
P45983:MAPK8; NbExp=2; IntAct=EBI-518228, EBI-286483;
P08581:MET; NbExp=17; IntAct=EBI-518228, EBI-1039152;
P16333:NCK1; NbExp=3; IntAct=EBI-518228, EBI-389883;
P04629:NTRK1; NbExp=2; IntAct=EBI-518228, EBI-1028226;
Q13196:p72syk; NbExp=2; IntAct=EBI-518228, EBI-8609796;
P27986:PIK3R1; NbExp=16; IntAct=EBI-518228, EBI-79464;
O00459:PIK3R2; NbExp=4; IntAct=EBI-518228, EBI-346930;
Q92569:PIK3R3; NbExp=4; IntAct=EBI-518228, EBI-79893;
F1SDV6:PLCG1 (xeno); NbExp=2; IntAct=EBI-518228, EBI-15628084;
P08487:PLCG1 (xeno); NbExp=3; IntAct=EBI-518228, EBI-8013886;
P07949:RET; NbExp=8; IntAct=EBI-518228, EBI-2480756;
O14492:SH2B2; NbExp=7; IntAct=EBI-518228, EBI-7507432;
Q99962:SH3GL2; NbExp=2; IntAct=EBI-518228, EBI-77938;
Q96B97:SH3KBP1; NbExp=25; IntAct=EBI-518228, EBI-346595;
P29353:SHC1; NbExp=5; IntAct=EBI-518228, EBI-78835;
O43597:SPRY2; NbExp=17; IntAct=EBI-518228, EBI-742487;
Q9C004:SPRY4; NbExp=9; IntAct=EBI-518228, EBI-354861;
P12931:SRC; NbExp=8; IntAct=EBI-518228, EBI-621482;
P43405:SYK; NbExp=7; IntAct=EBI-518228, EBI-78302;
P62837:UBE2D2; NbExp=4; IntAct=EBI-518228, EBI-347677;
P31946:YWHAB; NbExp=3; IntAct=EBI-518228, EBI-359815;
P27348:YWHAQ; NbExp=6; IntAct=EBI-518228, EBI-359854;
P43403:ZAP70; NbExp=3; IntAct=EBI-518228, EBI-1211276;
-!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Note=Colocalizes
with FGFR2 in lipid rafts at the cell membrane.
-!- DOMAIN: The RING-type zinc finger domain mediates binding to an E2
ubiquitin-conjugating enzyme.
-!- DOMAIN: The N-terminus is composed of the phosphotyrosine binding
(PTB) domain, a short linker region and the RING-type zinc finger.
The PTB domain, which is also called TKB (tyrosine kinase binding)
domain, is composed of three different subdomains: a four-helix
bundle (4H), a calcium-binding EF hand and a divergent SH2 domain.
-!- PTM: Phosphorylated on tyrosine residues by ALK, EGFR, SYK, FYN
and ZAP70 (By similarity). Phosphorylated on tyrosine residues in
response to FLT1 and KIT signaling. Phosphorylated on tyrosine
residues by INSR and FGR. Phosphorylated on several tyrosine
residues by constitutively activated FGFR3. Not phosphorylated at
Tyr-731 by FGFR3. Phosphorylated on tyrosine residues by activated
CSF1R, PDGFRA and PDGFRB. Phosphorylated on tyrosine residues by
HCK. {ECO:0000250, ECO:0000269|PubMed:10092522,
ECO:0000269|PubMed:11850825, ECO:0000269|PubMed:11997497,
ECO:0000269|PubMed:12435267, ECO:0000269|PubMed:14739300,
ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:15226403,
ECO:0000269|PubMed:15556646, ECO:0000269|PubMed:17509076,
ECO:0000269|PubMed:18034775, ECO:0000269|PubMed:20494825,
ECO:0000269|PubMed:20622007, ECO:0000269|PubMed:7657591,
ECO:0000269|PubMed:9535867}.
-!- PTM: Ubiquitinated, leading to its degradation via the proteasome.
{ECO:0000269|PubMed:11896602, ECO:0000269|PubMed:20094046}.
-!- DISEASE: Noonan syndrome-like disorder with or without juvenile
myelomonocytic leukemia (NSLL) [MIM:613563]: A syndrome
characterized by a phenotype reminiscent of Noonan syndrome.
Clinical features are highly variable, including facial
dysmorphism, short neck, developmental delay, hyperextensible
joints and thorax abnormalities with widely spaced nipples. The
facial features consist of triangular face with hypertelorism,
large low-set ears, ptosis, and flat nasal bridge. Some patients
manifest cardiac defects. Some have an increased risk for certain
malignancies, particularly juvenile myelomonocytic leukemia.
{ECO:0000269|PubMed:20619386, ECO:0000269|PubMed:25178484}.
Note=The disease is caused by mutations affecting the gene
represented in this entry.
-!- MISCELLANEOUS: This protein has one functional calcium-binding
site.
-!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
and Haematology;
URL="http://atlasgeneticsoncology.org/Genes/CBLID171.html";
-----------------------------------------------------------------------
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EMBL; X57110; CAA40393.1; -; mRNA.
EMBL; AP002956; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; BC132733; AAI32734.1; -; mRNA.
EMBL; BC136463; AAI36464.1; -; mRNA.
CCDS; CCDS8418.1; -.
PIR; A43817; A43817.
RefSeq; NP_005179.2; NM_005188.3.
UniGene; Hs.504096; -.
PDB; 1B47; X-ray; 2.20 A; A/B/C=47-350.
PDB; 1FBV; X-ray; 2.90 A; A=47-434.
PDB; 1YVH; X-ray; 2.05 A; A=25-351.
PDB; 2CBL; X-ray; 2.10 A; A=47-351.
PDB; 2JUJ; NMR; -; A=851-906.
PDB; 2K4D; NMR; -; A=358-437.
PDB; 2OO9; X-ray; 2.10 A; A/B/C=856-895.
PDB; 2Y1M; X-ray; 2.67 A; A/B/C/D/E/F=47-435.
PDB; 2Y1N; X-ray; 2.00 A; A/C=47-435.
PDB; 3BUM; X-ray; 2.00 A; B=25-351.
PDB; 3BUN; X-ray; 2.00 A; B=25-351.
PDB; 3BUO; X-ray; 2.60 A; B/D=25-351.
PDB; 3BUW; X-ray; 1.45 A; B/D=25-351.
PDB; 3BUX; X-ray; 1.35 A; B/D=25-351.
PDB; 3OB1; X-ray; 2.20 A; B=25-351.
PDB; 3OB2; X-ray; 2.10 A; B=25-351.
PDB; 3PLF; X-ray; 1.92 A; B/D=25-351.
PDB; 4A49; X-ray; 2.21 A; A=354-435.
PDB; 4A4B; X-ray; 2.79 A; A=47-435.
PDB; 4A4C; X-ray; 2.70 A; A=47-435.
PDB; 4GPL; X-ray; 3.00 A; B=47-351.
PDB; 5HKW; X-ray; 2.25 A; A/B/C=47-351.
PDB; 5HKX; X-ray; 1.85 A; A=47-435.
PDB; 5HKY; X-ray; 1.80 A; A=47-351.
PDB; 5HKZ; X-ray; 1.80 A; A=47-351.
PDB; 5HL0; X-ray; 2.20 A; A=47-351.
PDB; 5J3X; X-ray; 2.82 A; A/B/C/D/E/F=47-435.
PDB; 5O76; X-ray; 2.47 A; A/C=47-435.
PDBsum; 1B47; -.
PDBsum; 1FBV; -.
PDBsum; 1YVH; -.
PDBsum; 2CBL; -.
PDBsum; 2JUJ; -.
PDBsum; 2K4D; -.
PDBsum; 2OO9; -.
PDBsum; 2Y1M; -.
PDBsum; 2Y1N; -.
PDBsum; 3BUM; -.
PDBsum; 3BUN; -.
PDBsum; 3BUO; -.
PDBsum; 3BUW; -.
PDBsum; 3BUX; -.
PDBsum; 3OB1; -.
PDBsum; 3OB2; -.
PDBsum; 3PLF; -.
PDBsum; 4A49; -.
PDBsum; 4A4B; -.
PDBsum; 4A4C; -.
PDBsum; 4GPL; -.
PDBsum; 5HKW; -.
PDBsum; 5HKX; -.
PDBsum; 5HKY; -.
PDBsum; 5HKZ; -.
PDBsum; 5HL0; -.
PDBsum; 5J3X; -.
PDBsum; 5O76; -.
ProteinModelPortal; P22681; -.
SMR; P22681; -.
BioGrid; 107315; 252.
CORUM; P22681; -.
DIP; DIP-189N; -.
IntAct; P22681; 108.
MINT; P22681; -.
STRING; 9606.ENSP00000264033; -.
iPTMnet; P22681; -.
PhosphoSitePlus; P22681; -.
BioMuta; CBL; -.
DMDM; 251757253; -.
EPD; P22681; -.
MaxQB; P22681; -.
PaxDb; P22681; -.
PeptideAtlas; P22681; -.
PRIDE; P22681; -.
Ensembl; ENST00000264033; ENSP00000264033; ENSG00000110395.
GeneID; 867; -.
KEGG; hsa:867; -.
UCSC; uc001pwe.5; human.
CTD; 867; -.
DisGeNET; 867; -.
EuPathDB; HostDB:ENSG00000110395.5; -.
GeneCards; CBL; -.
HGNC; HGNC:1541; CBL.
HPA; CAB004350; -.
HPA; HPA027956; -.
MalaCards; CBL; -.
MIM; 165360; gene.
MIM; 613563; phenotype.
neXtProt; NX_P22681; -.
OpenTargets; ENSG00000110395; -.
Orphanet; 86834; Juvenile myelomonocytic leukemia.
Orphanet; 363972; Noonan syndrome-like disorder with juvenile myelomonocytic leukemia.
PharmGKB; PA26115; -.
eggNOG; KOG1785; Eukaryota.
eggNOG; ENOG410YDNH; LUCA.
GeneTree; ENSGT00390000011617; -.
HOGENOM; HOG000294176; -.
HOVERGEN; HBG005255; -.
InParanoid; P22681; -.
KO; K04707; -.
OMA; CEHPKIK; -.
OrthoDB; EOG091G0GPE; -.
PhylomeDB; P22681; -.
TreeFam; TF314210; -.
BRENDA; 2.3.2.B10; 2681.
Reactome; R-HSA-1059683; Interleukin-6 signaling.
Reactome; R-HSA-1236382; Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants.
Reactome; R-HSA-1295596; Spry regulation of FGF signaling.
Reactome; R-HSA-1433559; Regulation of KIT signaling.
Reactome; R-HSA-182971; EGFR downregulation.
Reactome; R-HSA-2173789; TGF-beta receptor signaling activates SMADs.
Reactome; R-HSA-5637810; Constitutive Signaling by EGFRvIII.
Reactome; R-HSA-5654726; Negative regulation of FGFR1 signaling.
Reactome; R-HSA-5654727; Negative regulation of FGFR2 signaling.
Reactome; R-HSA-5654732; Negative regulation of FGFR3 signaling.
Reactome; R-HSA-5654733; Negative regulation of FGFR4 signaling.
Reactome; R-HSA-6807004; Negative regulation of MET activity.
Reactome; R-HSA-8849469; PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1.
Reactome; R-HSA-8856825; Cargo recognition for clathrin-mediated endocytosis.
Reactome; R-HSA-8856828; Clathrin-mediated endocytosis.
Reactome; R-HSA-8875360; InlB-mediated entry of Listeria monocytogenes into host cell.
Reactome; R-HSA-912631; Regulation of signaling by CBL.
Reactome; R-HSA-983695; Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.
SignaLink; P22681; -.
SIGNOR; P22681; -.
UniPathway; UPA00143; -.
ChiTaRS; CBL; human.
EvolutionaryTrace; P22681; -.
GeneWiki; CBL_(gene); -.
GenomeRNAi; 867; -.
PMAP-CutDB; P22681; -.
PRO; PR:P22681; -.
Proteomes; UP000005640; Chromosome 11.
Bgee; ENSG00000110395; -.
CleanEx; HS_CBL; -.
ExpressionAtlas; P22681; baseline and differential.
Genevisible; P22681; HS.
GO; GO:0005829; C:cytosol; IDA:HPA.
GO; GO:0016600; C:flotillin complex; IEA:Ensembl.
GO; GO:0005925; C:focal adhesion; IEA:Ensembl.
GO; GO:0030426; C:growth cone; IEA:Ensembl.
GO; GO:0042629; C:mast cell granule; IEA:GOC.
GO; GO:0045121; C:membrane raft; IBA:GO_Central.
GO; GO:0005634; C:nucleus; IEA:InterPro.
GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
GO; GO:0005886; C:plasma membrane; IDA:HGNC.
GO; GO:0045296; F:cadherin binding; IDA:BHF-UCL.
GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
GO; GO:0003700; F:DNA binding transcription factor activity; TAS:ProtInc.
GO; GO:0046875; F:ephrin receptor binding; IPI:UniProtKB.
GO; GO:0005154; F:epidermal growth factor receptor binding; IEA:Ensembl.
GO; GO:0036312; F:phosphatidylinositol 3-kinase regulatory subunit binding; IEA:Ensembl.
GO; GO:0001784; F:phosphotyrosine residue binding; IEA:InterPro.
GO; GO:0030971; F:receptor tyrosine kinase binding; IBA:GO_Central.
GO; GO:0017124; F:SH3 domain binding; IPI:BHF-UCL.
GO; GO:0004871; F:signal transducer activity; IEA:InterPro.
GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
GO; GO:0004842; F:ubiquitin-protein transferase activity; TAS:HGNC.
GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:HGNC.
GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:Ensembl.
GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IEA:Ensembl.
GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEA:Ensembl.
GO; GO:0090650; P:cellular response to oxygen-glucose deprivation; IEA:Ensembl.
GO; GO:0036120; P:cellular response to platelet-derived growth factor stimulus; IEA:Ensembl.
GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
GO; GO:0035635; P:entry of bacterium into host cell; TAS:Reactome.
GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:HGNC.
GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
GO; GO:0070102; P:interleukin-6-mediated signaling pathway; TAS:Reactome.
GO; GO:0008584; P:male gonad development; IEA:Ensembl.
GO; GO:0043303; P:mast cell degranulation; IEA:Ensembl.
GO; GO:0061024; P:membrane organization; TAS:Reactome.
GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; IMP:UniProtKB.
GO; GO:0007175; P:negative regulation of epidermal growth factor-activated receptor activity; IBA:GO_Central.
GO; GO:1901215; P:negative regulation of neuron death; IEA:Ensembl.
GO; GO:0070997; P:neuron death; IEA:Ensembl.
GO; GO:0045742; P:positive regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome.
GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IMP:BHF-UCL.
GO; GO:0048260; P:positive regulation of receptor-mediated endocytosis; IMP:UniProtKB.
GO; GO:0006513; P:protein monoubiquitination; IEA:Ensembl.
GO; GO:0000209; P:protein polyubiquitination; IEA:Ensembl.
GO; GO:0016567; P:protein ubiquitination; TAS:HGNC.
GO; GO:0014823; P:response to activity; IEA:Ensembl.
GO; GO:0046677; P:response to antibiotic; IEA:Ensembl.
GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
GO; GO:0010332; P:response to gamma radiation; IEA:Ensembl.
GO; GO:0042594; P:response to starvation; IEA:Ensembl.
GO; GO:0033574; P:response to testosterone; IEA:Ensembl.
GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome.
GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
CDD; cd09920; SH2_Cbl-b_TKB; 1.
Gene3D; 1.20.930.20; -; 1.
Gene3D; 3.30.40.10; -; 1.
Gene3D; 3.30.505.10; -; 1.
InterPro; IPR024162; Adaptor_Cbl.
InterPro; IPR014741; Adaptor_Cbl_EF_hand-like.
InterPro; IPR036537; Adaptor_Cbl_N_dom_sf.
InterPro; IPR003153; Adaptor_Cbl_N_hlx.
InterPro; IPR014742; Adaptor_Cbl_SH2-like.
InterPro; IPR024159; Cbl_PTB.
InterPro; IPR011992; EF-hand-dom_pair.
InterPro; IPR036860; SH2_dom_sf.
InterPro; IPR015940; UBA.
InterPro; IPR009060; UBA-like_sf.
InterPro; IPR001841; Znf_RING.
InterPro; IPR013083; Znf_RING/FYVE/PHD.
InterPro; IPR017907; Znf_RING_CS.
PANTHER; PTHR23007; PTHR23007; 1.
Pfam; PF02262; Cbl_N; 1.
Pfam; PF02761; Cbl_N2; 1.
Pfam; PF02762; Cbl_N3; 1.
Pfam; PF00627; UBA; 1.
SMART; SM00184; RING; 1.
SMART; SM00165; UBA; 1.
SUPFAM; SSF46934; SSF46934; 1.
SUPFAM; SSF47473; SSF47473; 1.
SUPFAM; SSF47668; SSF47668; 1.
SUPFAM; SSF55550; SSF55550; 1.
PROSITE; PS51506; CBL_PTB; 1.
PROSITE; PS50030; UBA; 1.
PROSITE; PS00518; ZF_RING_1; 1.
PROSITE; PS50089; ZF_RING_2; 1.
1: Evidence at protein level;
3D-structure; Calcium; Cell membrane; Complete proteome; Cytoplasm;
Disease mutation; Membrane; Metal-binding; Phosphoprotein;
Polymorphism; Proto-oncogene; Reference proteome; Repeat; Transferase;
Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger.
CHAIN 1 906 E3 ubiquitin-protein ligase CBL.
/FTId=PRO_0000055858.
DOMAIN 47 351 Cbl-PTB. {ECO:0000255|PROSITE-
ProRule:PRU00839}.
DOMAIN 856 895 UBA. {ECO:0000255|PROSITE-
ProRule:PRU00212}.
CA_BIND 227 240
ZN_FING 381 420 RING-type. {ECO:0000255|PROSITE-
ProRule:PRU00175}.
REGION 1 357 Sufficient for interaction with EPHB1.
{ECO:0000269|PubMed:18034775}.
REGION 47 175 4H.
REGION 176 248 EF-hand-like.
REGION 249 351 SH2-like.
REGION 352 380 Linker.
REGION 648 906 Interaction with CD2AP.
{ECO:0000269|PubMed:11067845}.
COMPBIAS 357 476 Asp/Glu-rich (acidic).
COMPBIAS 477 688 Pro-rich.
COMPBIAS 689 834 Asp/Glu-rich (acidic).
BINDING 294 294 Phosphotyrosine. {ECO:0000250}.
MOD_RES 371 371 Phosphotyrosine; by INSR.
{ECO:0000269|PubMed:11997497}.
MOD_RES 439 439 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
MOD_RES 452 452 Phosphoserine.
{ECO:0000244|PubMed:19690332}.
MOD_RES 483 483 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
MOD_RES 619 619 Phosphoserine.
{ECO:0000250|UniProtKB:P22682}.
MOD_RES 642 642 Phosphoserine.
{ECO:0000250|UniProtKB:P22682}.
MOD_RES 668 668 Phosphoserine.
{ECO:0000250|UniProtKB:P22682}.
MOD_RES 669 669 Phosphoserine.
{ECO:0000244|PubMed:23186163}.
MOD_RES 674 674 Phosphotyrosine.
{ECO:0000269|PubMed:20622007}.
MOD_RES 700 700 Phosphotyrosine; by ABL1.
{ECO:0000269|PubMed:11997497,
ECO:0000269|PubMed:15556646,
ECO:0000269|PubMed:20622007}.
MOD_RES 731 731 Phosphotyrosine; by SRC.
{ECO:0000269|PubMed:14739300}.
MOD_RES 774 774 Phosphotyrosine.
{ECO:0000269|PubMed:11997497,
ECO:0000269|PubMed:20622007}.
MOD_RES 900 900 Phosphoserine.
{ECO:0000244|PubMed:16964243}.
VARIANT 287 287 K -> R (found in patients with acute
myeloid leukemia; unknown pathological
significance).
{ECO:0000269|PubMed:20622007}.
/FTId=VAR_071040.
VARIANT 365 365 Q -> QSK (found in patients with acute
myeloid leukemia; unknown pathological
significance; loss of the ability to
negatively regulate signaling pathways;
promotes cell cycle progression;
decreases apoptosis).
/FTId=VAR_071041.
VARIANT 367 367 Q -> P (in NSLL; dbSNP:rs267606704).
{ECO:0000269|PubMed:20619386}.
/FTId=VAR_064332.
VARIANT 371 371 Y -> H (found in patients with acute
myeloid leukemia; unknown pathological
significance; loss of the ability to
negatively regulate signaling pathways;
promotes cell cycle progression;
decreases apoptosis; dbSNP:rs267606706).
{ECO:0000269|PubMed:20622007}.
/FTId=VAR_071042.
VARIANT 382 382 K -> E (in NSLL; dominant-negative;
impairs CBL-mediated ubiquitination,
internalization and degradation of the
EGF receptor/EGFR; decreases the ability
to negatively regulate EGFR signaling;
dbSNP:rs267606705).
{ECO:0000269|PubMed:25178484}.
/FTId=VAR_064333.
VARIANT 390 390 D -> Y (in NSLL; dominant-negative;
impairs CBL-mediated ubiquitination,
internalization and degradation of the
EGF receptor/EGFR; decreases the ability
to negatively regulate EGFR signaling;
dbSNP:rs267606707).
{ECO:0000269|PubMed:20619386,
ECO:0000269|PubMed:25178484}.
/FTId=VAR_064334.
VARIANT 420 420 R -> Q (in NSLL; dominant-negative;
impairs CBL-mediated ubiquitination,
internalization and degradation of the
EGF receptor/EGFR; decreases the ability
to negatively regulate EGFR signaling;
dbSNP:rs267606708).
{ECO:0000269|PubMed:20619386,
ECO:0000269|PubMed:25178484}.
/FTId=VAR_064335.
VARIANT 499 499 R -> L (found in patients with acute
myeloid leukemia; unknown pathological
significance).
{ECO:0000269|PubMed:20622007}.
/FTId=VAR_071043.
VARIANT 620 620 L -> F (in dbSNP:rs2227988).
/FTId=VAR_057211.
VARIANT 782 782 P -> L (in dbSNP:rs2229073).
/FTId=VAR_057212.
VARIANT 904 904 V -> I (in dbSNP:rs17122769).
/FTId=VAR_057213.
MUTAGEN 80 80 S->D: Abolishes interaction with ZAP70.
{ECO:0000269|PubMed:10078535}.
MUTAGEN 82 82 P->A: Abolishes interaction with ZAP70.
{ECO:0000269|PubMed:10078535}.
MUTAGEN 229 229 D->Q: Abolishes interaction with ZAP70.
{ECO:0000269|PubMed:10078535}.
MUTAGEN 240 240 E->S: Abolishes interaction with ZAP70.
{ECO:0000269|PubMed:10078535}.
MUTAGEN 294 294 R->K: Abolishes interaction with ZAP70.
{ECO:0000269|PubMed:10078535}.
MUTAGEN 306 306 G->E: Abolishes interaction with ZAP70
and EPHB1, but does not affect
interaction with SLA.
{ECO:0000269|PubMed:10078535,
ECO:0000269|PubMed:10449770}.
MUTAGEN 371 371 Y->F: Strongly reduces tyrosine
phosphorylation by INSR; when associated
with F-700 and F-774.
{ECO:0000269|PubMed:11997497}.
MUTAGEN 381 381 C->A: Loss of ubiquitin ligase activity.
{ECO:0000269|PubMed:11896602}.
MUTAGEN 700 700 Y->F: Strongly reduces tyrosine
phosphorylation by INSR; when associated
with F-371 and F-774.
{ECO:0000269|PubMed:11997497}.
MUTAGEN 731 731 Y->F: No effect on tyrosine
phosphorylation by INSR. Loss of
phosphorylation by SRC. Inhibition of
bone resorption. Abolishes interaction
with PIK3R1.
{ECO:0000269|PubMed:11997497,
ECO:0000269|PubMed:14739300}.
MUTAGEN 774 774 Y->F: Strongly reduces tyrosine
phosphorylation by INSR; when associated
with F-371 and F-700.
{ECO:0000269|PubMed:11997497}.
CONFLICT 15 15 S -> T (in Ref. 1; CAA40393).
{ECO:0000305}.
HELIX 53 70 {ECO:0000244|PDB:3BUX}.
HELIX 73 75 {ECO:0000244|PDB:3BUX}.
STRAND 80 82 {ECO:0000244|PDB:5HKY}.
HELIX 84 101 {ECO:0000244|PDB:3BUX}.
TURN 102 104 {ECO:0000244|PDB:5HKY}.
HELIX 106 111 {ECO:0000244|PDB:3BUX}.
HELIX 113 136 {ECO:0000244|PDB:3BUX}.
HELIX 137 141 {ECO:0000244|PDB:3BUX}.
HELIX 146 168 {ECO:0000244|PDB:3BUX}.
HELIX 170 172 {ECO:0000244|PDB:3BUX}.
HELIX 176 178 {ECO:0000244|PDB:3BUX}.
HELIX 184 194 {ECO:0000244|PDB:3BUX}.
STRAND 198 201 {ECO:0000244|PDB:3BUX}.
HELIX 202 212 {ECO:0000244|PDB:3BUX}.
HELIX 218 228 {ECO:0000244|PDB:3BUX}.
STRAND 233 237 {ECO:0000244|PDB:3BUX}.
HELIX 238 247 {ECO:0000244|PDB:3BUX}.
HELIX 251 253 {ECO:0000244|PDB:3BUX}.
HELIX 254 261 {ECO:0000244|PDB:3BUX}.
TURN 262 264 {ECO:0000244|PDB:2Y1M}.
STRAND 268 271 {ECO:0000244|PDB:5HKX}.
HELIX 274 281 {ECO:0000244|PDB:3BUX}.
HELIX 282 284 {ECO:0000244|PDB:3BUX}.
STRAND 290 295 {ECO:0000244|PDB:3BUX}.
STRAND 297 299 {ECO:0000244|PDB:3BUX}.
STRAND 302 308 {ECO:0000244|PDB:3BUX}.
TURN 310 312 {ECO:0000244|PDB:3BUO}.
STRAND 314 317 {ECO:0000244|PDB:3BUX}.
STRAND 320 322 {ECO:0000244|PDB:3BUW}.
HELIX 324 333 {ECO:0000244|PDB:3BUX}.
HELIX 350 352 {ECO:0000244|PDB:5HKX}.
STRAND 354 356 {ECO:0000244|PDB:1FBV}.
STRAND 360 362 {ECO:0000244|PDB:4A49}.
HELIX 365 378 {ECO:0000244|PDB:5HKX}.
TURN 382 384 {ECO:0000244|PDB:5HKX}.
STRAND 385 388 {ECO:0000244|PDB:5HKX}.
STRAND 391 394 {ECO:0000244|PDB:5HKX}.
STRAND 398 400 {ECO:0000244|PDB:2K4D}.
HELIX 402 410 {ECO:0000244|PDB:5HKX}.
TURN 417 419 {ECO:0000244|PDB:5HKX}.
STRAND 425 428 {ECO:0000244|PDB:5HKX}.
STRAND 430 432 {ECO:0000244|PDB:4A49}.
HELIX 856 866 {ECO:0000244|PDB:2OO9}.
HELIX 871 880 {ECO:0000244|PDB:2OO9}.
TURN 881 883 {ECO:0000244|PDB:2OO9}.
HELIX 885 895 {ECO:0000244|PDB:2OO9}.
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


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