CBL_HUMAN
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-AUG-2022, entry version 245.
DE RecName: Full=E3 ubiquitin-protein ligase CBL;
DE EC=2.3.2.27 {ECO:0000269|PubMed:10514377, ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:17509076};
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=RING-type E3 ubiquitin transferase CBL {ECO:0000305};
DE AltName: Full=Signal transduction protein CBL;
GN Name=CBL; Synonyms=CBL2, RNF55;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC 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 was
RT generated by a large truncation encompassing a proline-rich domain and a
RT 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., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., 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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INTERACTION WITH BLK.
RX PubMed=8083187; DOI=10.1016/s0021-9258(17)31595-8;
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 tyrosine-
RT phosphorylated protein in Jurkat cells activated via the T cell antigen
RT receptor.";
RL J. Biol. Chem. 269:22921-22924(1994).
RN [5]
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 and
RT 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 binds
RT to the Tyr292 negative regulatory phosphorylation site of ZAP-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 and
RT Syk tyrosine kinases.";
RL J. Biol. Chem. 273:8867-8874(1998).
RN [8]
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 protein-
RT tyrosine kinase.";
RL Biochem. Biophys. Res. Commun. 257:129-138(1999).
RN [9]
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 collaboration
RT with c-Cbl.";
RL Leukemia 13:760-767(1999).
RN [10]
RP INTERACTION WITH SH2B2.
RX PubMed=9989826; DOI=10.1038/sj.onc.1202326;
RA Yokouchi M., Wakioka T., Sakamoto H., Yasukawa H., Ohtsuka S., Sasaki A.,
RA Ohtsubo M., Valius M., Inoue A., Komiya S., Yoshimura A.;
RT "APS, an adaptor protein containing PH and SH2 domains, is associated with
RT the PDGF receptor and c-Cbl and inhibits PDGF-induced mitogenesis.";
RL Oncogene 18:759-767(1999).
RN [11]
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 [12]
RP FUNCTION, AND CATALYTIC ACTIVITY.
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., Liu Y.-C.;
RT "The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent
RT ubiquitin-protein ligase.";
RL Science 286:309-312(1999).
RN [13]
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 protein c-
RT Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain
RT interaction.";
RL J. Biol. Chem. 276:4957-4963(2001).
RN [14]
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., Yu S.,
RA Chan E., Wu X., Li C., Woisetschlager M., Aversa G., Kolbinger F.,
RA Bennett M.K., Molineaux S., Luo Y., Payan D.G., 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 [15]
RP INTERACTION WITH LAT2.
RX PubMed=12486104; DOI=10.1084/jem.20021405;
RA Brdicka T., Imrich M., Angelisova P., Brdickova N., Horvath O., Spicka J.,
RA Hilgert I., Luskova P., Draber P., Novak P., Engels N., Wienands J.,
RA Simeoni L., Oesterreicher J., Aguado E., Malissen M., Schraven B.,
RA 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 [16]
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 translocation in
RT response to insulin in 3T3-L1 adipocytes.";
RL Mol. Cell. Biol. 22:3599-3609(2002).
RN [17]
RP FUNCTION, SUBCELLULAR LOCATION, UBIQUITINATION, MUTAGENESIS OF CYS-381, AND
RP 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 [18]
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 phosphorylation
RT site in the receptor's carboxy-terminus.";
RL Oncogene 21:1079-1089(2002).
RN [19]
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 SH2-
RT containing inositol polyphosphate 5-phosphatase SHIP2.";
RL Biochem. Biophys. Res. Commun. 300:494-500(2003).
RN [20]
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-induced c-
RT Cbl-mediated ubiquitination in adherent human neutrophils.";
RL Biochem. J. 370:687-694(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., Ericson C.,
RA Sauer K., Brock A., Horn D.M., Schultz P.G., Peters E.C.;
RT "Profiling of tyrosine phosphorylation pathways in human cells using mass
RT 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 from
RT human T cells using immobilized metal affinity chromatography and tandem
RT mass spectrometry.";
RL Anal. Chem. 76:2763-2772(2004).
RN [23]
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 [24]
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 sites
RT within c-Cbl.";
RL FEBS Lett. 577:555-562(2004).
RN [25]
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 fibroblast
RT growth factor receptor-2 activation supports osteoblast differentiation.";
RL J. Biol. Chem. 279:36259-36267(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 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 outgrowth.";
RL J. Cell Sci. 117:3319-3329(2004).
RN [28]
RP FUNCTION, AND CATALYTIC ACTIVITY.
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-dependent
RT protein degradation.";
RL Oncogene 23:1645-1655(2004).
RN [29]
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 receptor.";
RL Biochem. Biophys. Res. Commun. 337:1-13(2005).
RN [30]
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 [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 cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [32]
RP FUNCTION, AND MUTAGENESIS OF GLY-306.
RX PubMed=17094949; DOI=10.1016/j.bbrc.2006.10.150;
RA Lock P., I S.T.T., Straffon A.F., Schieb H., Hovens C.M., Stylli S.S.;
RT "Spred-2 steady-state levels are regulated by phosphorylation and Cbl-
RT mediated ubiquitination.";
RL Biochem. Biophys. Res. Commun. 351:1018-1023(2006).
RN [33]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-900, AND IDENTIFICATION BY
RP 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 phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [34]
RP FUNCTION, CATALYTIC ACTIVITY, 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 type I
RT differentially affects phosphorylation, processing and ubiquitylation of
RT the receptor.";
RL FEBS J. 274:3078-3093(2007).
RN [35]
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., Druker B.J.,
RA Naramura M., Band V., Band H.;
RT "Binding of Cbl to a phospholipase Cgamma1-docking site on platelet-derived
RT growth factor receptor beta provides a dual mechanism of negative
RT regulation.";
RL J. Biol. Chem. 282:29336-29347(2007).
RN [36]
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 protein
RT stability in imatinib-resistant chronic myelogenous leukemia cells.";
RL Blood 111:3821-3829(2008).
RN [37]
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 [38]
RP FUNCTION, AND INTERACTION WITH SPRY2.
RX PubMed=17974561; DOI=10.1074/jbc.m705457200;
RA Chandramouli S., Yu C.Y., Yusoff P., Lao D.H., Leong H.F., Mizuno K.,
RA Guy G.R.;
RT "Tesk1 interacts with Spry2 to abrogate its inhibition of ERK
RT phosphorylation downstream of receptor tyrosine kinase signaling.";
RL J. Biol. Chem. 283:1679-1691(2008).
RN [39]
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 [40]
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 through
RT the lysosomal pathway.";
RL Traffic 9:251-266(2008).
RN [41]
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 for
RT internalization and degradation.";
RL Biochem. J. 423:375-380(2009).
RN [42]
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 [43]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-452, AND IDENTIFICATION BY
RP 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 [44]
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 cell
RT proliferation but not migration.";
RL Cell. Signal. 22:1363-1368(2010).
RN [45]
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 [46]
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., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [47]
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., Buerckstuemmer T.,
RA 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 [48]
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 decreased
RT Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast
RT growth factor receptor 2 ubiquitination.";
RL J. Biol. Chem. 286:24443-24450(2011).
RN [49]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-439; SER-483 AND SER-669, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [50]
RP SUBUNIT, INTERACTION WITH IFT20 AND CBLB, UBIQUITINATION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=29237719; DOI=10.1083/jcb.201611050;
RA Schmid F.M., Schou K.B., Vilhelm M.J., Holm M.S., Breslin L., Farinelli P.,
RA Larsen L.A., Andersen J.S., Pedersen L.B., Christensen S.T.;
RT "IFT20 modulates ciliary PDGFRalpha signaling by regulating the stability
RT of Cbl E3 ubiquitin ligases.";
RL J. Cell Biol. 217:151-161(2018).
RN [51]
RP INTERACTION WITH MYCOBACTERIUM TUBERCULOSIS LPQN (MICROBIAL INFECTION).
RX PubMed=30118682; DOI=10.1016/j.molcel.2018.07.010;
RA Penn B.H., Netter Z., Johnson J.R., Von Dollen J., Jang G.M., Johnson T.,
RA Ohol Y.M., Maher C., Bell S.L., Geiger K., Golovkine G., Du X., Choi A.,
RA Parry T., Mohapatra B.C., Storck M.D., Band H., Chen C., Jaeger S.,
RA Shales M., Portnoy D.A., Hernandez R., Coscoy L., Cox J.S., Krogan N.J.;
RT "An Mtb-human protein-protein interaction map identifies a switch between
RT host antiviral and antibacterial responses.";
RL Mol. Cell 71:637-648(2018).
RN [52] {ECO:0007744|PDB:1B47, ECO:0007744|PDB:2CBL}
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 SER-80;
RP 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 binding
RT site on ZAP-70 kinase.";
RL Nature 398:84-90(1999).
RN [53]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 47-434 IN COMPLEX WITH ZAP70 AND
RP 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 ubiquitin-
RT protein ligases.";
RL Cell 102:533-539(2000).
RN [54]
RP VARIANTS NSLL PRO-367; GLU-382; TYR-390 AND GLN-420, AND CHARACTERIZATION
RP OF VARIANTS NSLL TYR-390 AND 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., Lepri F.,
RA Caputo V., Silvano M., Buscherini F., Consoli F., Ferrara G., Digilio M.C.,
RA Cavaliere M.L., van Hagen J.M., Zampino G., van der Burgt I., Ferrero G.B.,
RA Mazzanti L., Screpanti I., Yntema H.G., Nillesen W.M., Savarirayan R.,
RA Zenker M., Dallapiccola B., Gelb B.D., Tartaglia M.;
RT "Heterozygous germline mutations in the CBL tumor-suppressor gene cause a
RT Noonan syndrome-like phenotype.";
RL Am. J. Hum. Genet. 87:250-257(2010).
RN [55]
RP VARIANTS ARG-287; SER-LYS-365 INS; HIS-371 AND LEU-499, CHARACTERIZATION OF
RP VARIANTS SER-LYS-365 INS AND HIS-371, AND PHOSPHORYLATION AT TYR-674;
RP TYR-700 AND TYR-774.
RX PubMed=20622007; DOI=10.1074/jbc.m110.106161;
RA Fernandes M.S., Reddy M.M., Croteau N.J., Walz C., Weisbach H., Podar K.,
RA Band H., Carroll M., Reiter A., Larson R.A., Salgia R., Griffin J.D.,
RA Sattler M.;
RT "Novel oncogenic mutations of CBL in human acute myeloid leukemia that
RT activate growth and survival pathways depend on increased metabolism.";
RL J. Biol. Chem. 285:32596-32605(2010).
RN [56]
RP CHARACTERIZATION OF VARIANTS NSLL GLU-382; TYR-390 AND GLN-420.
RX PubMed=25178484; DOI=10.1002/humu.22682;
RA Brand K., Kentsch H., Glashoff C., Rosenberger G.;
RT "RASopathy-associated CBL germline mutations cause aberrant ubiquitylation
RT and trafficking of EGFR.";
RL Hum. Mutat. 35:1372-1381(2014).
CC -!- FUNCTION: Adapter protein that functions as a negative regulator of
CC many signaling pathways that are triggered by activation of cell
CC surface receptors. Acts as an E3 ubiquitin-protein ligase, which
CC accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and
CC then transfers it to substrates promoting their degradation by the
CC proteasome (PubMed:17094949). Ubiquitinates SPRY2 (PubMed:17094949,
CC PubMed:17974561). Ubiquitinates EGFR (PubMed:17974561). Recognizes
CC activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2,
CC PDGFRA, PDGFRB, CSF1R, EPHA8 and KDR and terminates signaling.
CC Recognizes membrane-bound HCK, SRC and other kinases of the SRC family
CC and mediates their ubiquitination and degradation. Participates in
CC signal transduction in hematopoietic cells. Plays an important role in
CC the regulation of osteoblast differentiation and apoptosis. Essential
CC for osteoclastic bone resorption. The 'Tyr-731' phosphorylated form
CC induces the activation and recruitment of phosphatidylinositol 3-kinase
CC to the cell membrane in a signaling pathway that is critical for
CC osteoclast function. May be functionally coupled with the E2 ubiquitin-
CC protein ligase UB2D3. In association with CBLB, required for proper
CC feedback inhibition of ciliary platelet-derived growth factor receptor-
CC alpha (PDGFRA) signaling pathway via ubiquitination and internalization
CC of PDGFRA (By similarity). {ECO:0000250|UniProtKB:P22682,
CC ECO:0000269|PubMed:10514377, ECO:0000269|PubMed:11896602,
CC ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:14739300,
CC ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:17094949,
CC ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:17974561,
CC ECO:0000269|PubMed:18374639, ECO:0000269|PubMed:19689429,
CC ECO:0000269|PubMed:21596750}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27; Evidence={ECO:0000269|PubMed:10514377,
CC ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:17509076};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Forms homodimers; IFT20 promotes the formation of stable
CC homodimers (PubMed:29237719). Interacts (phosphorylated at Tyr-731)
CC with PIK3R1. Associates with NCK via its SH3 domain. The phosphorylated
CC C-terminus interacts with CD2AP via its second SH3 domain. Binds to
CC UBE2L3. Interacts with adapters SLA, SLA2 and with the phosphorylated
CC C-terminus of SH2B2. Interacts with EGFR, SYK and ZAP70 via the highly
CC conserved Cbl-N region. Also interacts with SORBS1 and INPPL1/SHIP2.
CC Interacts with phosphorylated LAT2 (By similarity). Interacts with CBLB
CC (PubMed:29237719). Interacts with ALK, AXL, BLK, FGR and FGFR2.
CC Interacts with CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates
CC receptor degradation through ubiquitination. Interacts with HCK and
CC LYN. Interacts with ATX2 (By similarity). Interacts with TEK/TIE2
CC (tyrosine phosphorylated). Interacts with SH3KBP1 and this interaction
CC is inhibited in the presence of SHKBP1 (By similarity). Interacts with
CC SIGLEC10 (By similarity). Interacts with IFT20 (PubMed:29237719).
CC Interacts with SPRY2; the interaction inhibits CBL-mediated
CC ubiquitination of EGFR (PubMed:17974561).
CC {ECO:0000250|UniProtKB:P22682, ECO:0000269|PubMed:10078535,
CC ECO:0000269|PubMed:10092522, ECO:0000269|PubMed:10374881,
CC ECO:0000269|PubMed:10449770, ECO:0000269|PubMed:10966114,
CC ECO:0000269|PubMed:11067845, ECO:0000269|PubMed:11696592,
CC ECO:0000269|PubMed:11850825, ECO:0000269|PubMed:11896602,
CC ECO:0000269|PubMed:11997497, ECO:0000269|PubMed:12435267,
CC ECO:0000269|PubMed:12486104, ECO:0000269|PubMed:12504111,
CC ECO:0000269|PubMed:15190072, ECO:0000269|PubMed:15226403,
CC ECO:0000269|PubMed:15958209, ECO:0000269|PubMed:17620338,
CC ECO:0000269|PubMed:17974561, ECO:0000269|PubMed:18034775,
CC ECO:0000269|PubMed:18235045, ECO:0000269|PubMed:18374639,
CC ECO:0000269|PubMed:19689429, ECO:0000269|PubMed:19836242,
CC ECO:0000269|PubMed:20494825, ECO:0000269|PubMed:21596750,
CC ECO:0000269|PubMed:29237719, ECO:0000269|PubMed:7657591,
CC ECO:0000269|PubMed:8083187, ECO:0000269|PubMed:9407100,
CC ECO:0000269|PubMed:9989826}.
CC -!- SUBUNIT: (Microbial infection) Interacts with M.tuberculosis LpqN,
CC which influences the balance between intrinsic antibacterial and
CC antiviral defense. {ECO:0000269|PubMed:30118682}.
CC -!- INTERACTION:
CC P22681; Q8IZP0-2: ABI1; NbExp=3; IntAct=EBI-518228, EBI-7358775;
CC P22681; Q14155: ARHGEF7; NbExp=9; IntAct=EBI-518228, EBI-717515;
CC P22681; P54253: ATXN1; NbExp=3; IntAct=EBI-518228, EBI-930964;
CC P22681; Q9Y5K6: CD2AP; NbExp=4; IntAct=EBI-518228, EBI-298152;
CC P22681; P46108: CRK; NbExp=10; IntAct=EBI-518228, EBI-886;
CC P22681; P46109: CRKL; NbExp=3; IntAct=EBI-518228, EBI-910;
CC P22681; P00533: EGFR; NbExp=22; IntAct=EBI-518228, EBI-297353;
CC P22681; P55085: F2RL1; NbExp=3; IntAct=EBI-518228, EBI-4303189;
CC P22681; P17948: FLT1; NbExp=2; IntAct=EBI-518228, EBI-1026718;
CC P22681; P62993: GRB2; NbExp=13; IntAct=EBI-518228, EBI-401755;
CC P22681; P08631-2: HCK; NbExp=2; IntAct=EBI-518228, EBI-9834454;
CC P22681; P42858: HTT; NbExp=18; IntAct=EBI-518228, EBI-466029;
CC P22681; Q15811: ITSN1; NbExp=12; IntAct=EBI-518228, EBI-602041;
CC P22681; Q96JA1: LRIG1; NbExp=2; IntAct=EBI-518228, EBI-2865191;
CC P22681; P45983: MAPK8; NbExp=2; IntAct=EBI-518228, EBI-286483;
CC P22681; P08581: MET; NbExp=15; IntAct=EBI-518228, EBI-1039152;
CC P22681; P04629: NTRK1; NbExp=2; IntAct=EBI-518228, EBI-1028226;
CC P22681; P27986: PIK3R1; NbExp=5; IntAct=EBI-518228, EBI-79464;
CC P22681; O00459: PIK3R2; NbExp=4; IntAct=EBI-518228, EBI-346930;
CC P22681; Q92569: PIK3R3; NbExp=4; IntAct=EBI-518228, EBI-79893;
CC P22681; O14492: SH2B2; NbExp=7; IntAct=EBI-518228, EBI-7507432;
CC P22681; Q96B97: SH3KBP1; NbExp=20; IntAct=EBI-518228, EBI-346595;
CC P22681; O43597: SPRY2; NbExp=17; IntAct=EBI-518228, EBI-742487;
CC P22681; Q9C004: SPRY4; NbExp=9; IntAct=EBI-518228, EBI-354861;
CC P22681; P12931: SRC; NbExp=8; IntAct=EBI-518228, EBI-621482;
CC P22681; P43405: SYK; NbExp=2; IntAct=EBI-518228, EBI-78302;
CC P22681; P62837: UBE2D2; NbExp=4; IntAct=EBI-518228, EBI-347677;
CC P22681; P31946: YWHAB; NbExp=3; IntAct=EBI-518228, EBI-359815;
CC P22681; Q04917: YWHAH; NbExp=3; IntAct=EBI-518228, EBI-306940;
CC P22681; P27348: YWHAQ; NbExp=6; IntAct=EBI-518228, EBI-359854;
CC P22681; P43403: ZAP70; NbExp=3; IntAct=EBI-518228, EBI-1211276;
CC P22681; P39688: Fyn; Xeno; NbExp=3; IntAct=EBI-518228, EBI-524514;
CC P22681; A0A0H3L6J6: lpqN; Xeno; NbExp=3; IntAct=EBI-518228, EBI-25401182;
CC P22681; F1SDV6: PLCG1; Xeno; NbExp=2; IntAct=EBI-518228, EBI-15628084;
CC P22681; P08487: PLCG1; Xeno; NbExp=3; IntAct=EBI-518228, EBI-8013886;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Cell projection, cilium
CC {ECO:0000269|PubMed:29237719}. Golgi apparatus
CC {ECO:0000269|PubMed:29237719}. Note=Colocalizes with FGFR2 in lipid
CC 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 (PTB)
CC domain, a short linker region and the RING-type zinc finger. The PTB
CC domain, which is also called TKB (tyrosine kinase binding) domain, is
CC composed of three different subdomains: a four-helix bundle (4H), a
CC calcium-binding EF hand and a divergent SH2 domain.
CC -!- PTM: Phosphorylated on tyrosine residues by ALK, EGFR, SYK, FYN and
CC ZAP70 (By similarity). Phosphorylated on tyrosine residues in response
CC to FLT1 and KIT signaling. Phosphorylated on tyrosine residues by INSR
CC and FGR. Phosphorylated on several tyrosine residues by constitutively
CC activated FGFR3. Not phosphorylated at Tyr-731 by FGFR3. Phosphorylated
CC on tyrosine residues by activated CSF1R, PDGFRA and PDGFRB.
CC Phosphorylated on tyrosine residues by HCK. {ECO:0000250,
CC ECO:0000269|PubMed:10092522, ECO:0000269|PubMed:11850825,
CC ECO:0000269|PubMed:11997497, ECO:0000269|PubMed:12435267,
CC ECO:0000269|PubMed:14739300, ECO:0000269|PubMed:15190072,
CC ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:15556646,
CC ECO:0000269|PubMed:17509076, ECO:0000269|PubMed:18034775,
CC ECO:0000269|PubMed:20494825, ECO:0000269|PubMed:20622007,
CC ECO:0000269|PubMed:7657591, ECO:0000269|PubMed:9535867}.
CC -!- PTM: Ubiquitinated, leading to its degradation via the proteasome
CC (PubMed:11896602, PubMed:20094046). Ubiquitination is negatively
CC regulated by IFT20 (PubMed:29237719). {ECO:0000269|PubMed:11896602,
CC ECO:0000269|PubMed:20094046, ECO:0000269|PubMed:29237719}.
CC -!- DISEASE: Noonan syndrome-like disorder with or without juvenile
CC myelomonocytic leukemia (NSLL) [MIM:613563]: A syndrome characterized
CC by a phenotype reminiscent of Noonan syndrome. Clinical features are
CC highly variable, including facial dysmorphism, short neck,
CC developmental delay, hyperextensible joints and thorax abnormalities
CC with widely spaced nipples. The facial features consist of triangular
CC face with hypertelorism, large low-set ears, ptosis, and flat nasal
CC bridge. Some patients manifest cardiac defects. Some have an increased
CC risk for certain malignancies, particularly juvenile myelomonocytic
CC leukemia. {ECO:0000269|PubMed:20619386, ECO:0000269|PubMed:25178484}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- MISCELLANEOUS: This protein has one functional calcium-binding site.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC 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 CCDS; CCDS8418.1; -.
DR PIR; A43817; A43817.
DR RefSeq; NP_005179.2; NM_005188.3.
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 PDB; 5HKW; X-ray; 2.25 A; A/B/C=47-351.
DR PDB; 5HKX; X-ray; 1.85 A; A=47-435.
DR PDB; 5HKY; X-ray; 1.80 A; A=47-351.
DR PDB; 5HKZ; X-ray; 1.80 A; A=47-351.
DR PDB; 5HL0; X-ray; 2.20 A; A=47-351.
DR PDB; 5J3X; X-ray; 2.82 A; A/B/C/D/E/F=47-435.
DR PDB; 5O76; X-ray; 2.47 A; A/C=47-435.
DR PDB; 6O02; X-ray; 2.95 A; A=47-353.
DR PDB; 6O03; X-ray; 3.30 A; A/B=47-353.
DR PDB; 6XAR; X-ray; 2.50 A; A/B=25-357.
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 PDBsum; 5HKW; -.
DR PDBsum; 5HKX; -.
DR PDBsum; 5HKY; -.
DR PDBsum; 5HKZ; -.
DR PDBsum; 5HL0; -.
DR PDBsum; 5J3X; -.
DR PDBsum; 5O76; -.
DR PDBsum; 6O02; -.
DR PDBsum; 6O03; -.
DR PDBsum; 6XAR; -.
DR AlphaFoldDB; P22681; -.
DR BMRB; P22681; -.
DR SMR; P22681; -.
DR BioGRID; 107315; 330.
DR CORUM; P22681; -.
DR DIP; DIP-189N; -.
DR IntAct; P22681; 111.
DR MINT; P22681; -.
DR STRING; 9606.ENSP00000264033; -.
DR GlyGen; P22681; 7 sites, 2 O-linked glycans (7 sites).
DR iPTMnet; P22681; -.
DR MetOSite; P22681; -.
DR PhosphoSitePlus; P22681; -.
DR BioMuta; CBL; -.
DR DMDM; 251757253; -.
DR CPTAC; CPTAC-1567; -.
DR EPD; P22681; -.
DR jPOST; P22681; -.
DR MassIVE; P22681; -.
DR MaxQB; P22681; -.
DR PaxDb; P22681; -.
DR PeptideAtlas; P22681; -.
DR PRIDE; P22681; -.
DR ProteomicsDB; 54017; -.
DR Antibodypedia; 3815; 1191 antibodies from 49 providers.
DR DNASU; 867; -.
DR Ensembl; ENST00000264033.6; ENSP00000264033.3; ENSG00000110395.7.
DR GeneID; 867; -.
DR KEGG; hsa:867; -.
DR MANE-Select; ENST00000264033.6; ENSP00000264033.3; NM_005188.4; NP_005179.2.
DR UCSC; uc001pwe.5; human.
DR CTD; 867; -.
DR DisGeNET; 867; -.
DR GeneCards; CBL; -.
DR HGNC; HGNC:1541; CBL.
DR HPA; ENSG00000110395; Low tissue specificity.
DR MalaCards; CBL; -.
DR MIM; 165360; gene.
DR MIM; 613563; phenotype.
DR neXtProt; NX_P22681; -.
DR OpenTargets; ENSG00000110395; -.
DR Orphanet; 98850; Aggressive systemic mastocytosis.
DR Orphanet; 86834; Juvenile myelomonocytic leukemia.
DR Orphanet; 648; Noonan syndrome.
DR Orphanet; 363972; Noonan syndrome-like disorder with juvenile myelomonocytic leukemia.
DR PharmGKB; PA26115; -.
DR VEuPathDB; HostDB:ENSG00000110395; -.
DR eggNOG; KOG1785; Eukaryota.
DR GeneTree; ENSGT00940000155772; -.
DR HOGENOM; CLU_013535_3_0_1; -.
DR InParanoid; P22681; -.
DR OMA; GCMYEAM; -.
DR OrthoDB; 540689at2759; -.
DR PhylomeDB; P22681; -.
DR TreeFam; TF314210; -.
DR BRENDA; 2.3.2.27; 2681.
DR PathwayCommons; P22681; -.
DR Reactome; R-HSA-1059683; Interleukin-6 signaling.
DR Reactome; R-HSA-1236382; Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants.
DR Reactome; R-HSA-1295596; Spry regulation of FGF signaling.
DR Reactome; R-HSA-1433559; Regulation of KIT signaling.
DR Reactome; R-HSA-182971; EGFR downregulation.
DR Reactome; R-HSA-2173789; TGF-beta receptor signaling activates SMADs.
DR Reactome; R-HSA-5637810; Constitutive Signaling by EGFRvIII.
DR Reactome; R-HSA-5654726; Negative regulation of FGFR1 signaling.
DR Reactome; R-HSA-5654727; Negative regulation of FGFR2 signaling.
DR Reactome; R-HSA-5654732; Negative regulation of FGFR3 signaling.
DR Reactome; R-HSA-5654733; Negative regulation of FGFR4 signaling.
DR Reactome; R-HSA-6807004; Negative regulation of MET activity.
DR Reactome; R-HSA-8849469; PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1.
DR Reactome; R-HSA-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-HSA-8856828; Clathrin-mediated endocytosis.
DR Reactome; R-HSA-8875360; InlB-mediated entry of Listeria monocytogenes into host cell.
DR Reactome; R-HSA-912631; Regulation of signaling by CBL.
DR Reactome; R-HSA-9706369; Negative regulation of FLT3.
DR Reactome; R-HSA-9706377; FLT3 signaling by CBL mutants.
DR SignaLink; P22681; -.
DR SIGNOR; P22681; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 867; 28 hits in 1132 CRISPR screens.
DR ChiTaRS; CBL; human.
DR EvolutionaryTrace; P22681; -.
DR GeneWiki; CBL_(gene); -.
DR GenomeRNAi; 867; -.
DR Pharos; P22681; Tbio.
DR PRO; PR:P22681; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P22681; protein.
DR Bgee; ENSG00000110395; Expressed in trigeminal ganglion and 186 other tissues.
DR ExpressionAtlas; P22681; baseline and differential.
DR Genevisible; P22681; HS.
DR GO; GO:0005929; C:cilium; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0016600; C:flotillin complex; ISS:BHF-UCL.
DR GO; GO:0005925; C:focal adhesion; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0030426; C:growth cone; IEA:Ensembl.
DR GO; GO:0045121; C:membrane raft; IBA:GO_Central.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:HGNC-UCL.
DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0046875; F:ephrin receptor binding; IPI:UniProtKB.
DR GO; GO:0036312; F:phosphatidylinositol 3-kinase regulatory subunit binding; IEA:Ensembl.
DR GO; GO:0001784; F:phosphotyrosine residue binding; IEA:InterPro.
DR GO; GO:0030971; F:receptor tyrosine kinase binding; IBA:GO_Central.
DR GO; GO:0017124; F:SH3 domain binding; IPI:BHF-UCL.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; TAS:HGNC-UCL.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:HGNC-UCL.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:Ensembl.
DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEA:Ensembl.
DR GO; GO:0090650; P:cellular response to oxygen-glucose deprivation; IEA:Ensembl.
DR GO; GO:0036120; P:cellular response to platelet-derived growth factor stimulus; IEA:Ensembl.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome.
DR GO; GO:0035635; P:entry of bacterium into host cell; TAS:Reactome.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:HGNC-UCL.
DR GO; GO:0008584; P:male gonad development; IEA:Ensembl.
DR GO; GO:0043303; P:mast cell degranulation; IEA:Ensembl.
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; IMP:UniProtKB.
DR GO; GO:0007175; P:negative regulation of epidermal growth factor-activated receptor activity; IBA:GO_Central.
DR GO; GO:1901215; P:negative regulation of neuron death; IEA:Ensembl.
DR GO; GO:0070997; P:neuron death; IEA:Ensembl.
DR GO; GO:0045742; P:positive 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; IMP:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; IEA:Ensembl.
DR GO; GO:0006513; P:protein monoubiquitination; IEA:Ensembl.
DR GO; GO:0000209; P:protein polyubiquitination; IEA:Ensembl.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:2000583; P:regulation of platelet-derived growth factor receptor-alpha signaling pathway; ISS:UniProtKB.
DR GO; GO:0032487; P:regulation of Rap protein signal transduction; IEA:Ensembl.
DR GO; GO:0014823; P:response to activity; IEA:Ensembl.
DR GO; GO:0046677; P:response to antibiotic; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0010332; P:response to gamma radiation; IEA:Ensembl.
DR GO; GO:0042594; P:response to starvation; IEA:Ensembl.
DR GO; GO:0033574; P:response to testosterone; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR CDD; cd16709; RING-HC_Cbl-b; 1.
DR CDD; cd09920; SH2_Cbl-b_TKB; 1.
DR Gene3D; 1.20.930.20; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR IDEAL; IID00300; -.
DR InterPro; IPR024162; Adaptor_Cbl.
DR InterPro; IPR014741; Adaptor_Cbl_EF_hand-like.
DR InterPro; IPR036537; Adaptor_Cbl_N_dom_sf.
DR InterPro; IPR003153; Adaptor_Cbl_N_hlx.
DR InterPro; IPR014742; Adaptor_Cbl_SH2-like.
DR InterPro; IPR039520; CBL-B_RING-HC.
DR InterPro; IPR024159; Cbl_PTB.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR036860; SH2_dom_sf.
DR InterPro; IPR015940; UBA.
DR InterPro; IPR009060; UBA-like_sf.
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 SMART; SM00184; RING; 1.
DR SMART; SM00165; UBA; 1.
DR SUPFAM; SSF46934; SSF46934; 1.
DR SUPFAM; SSF47473; SSF47473; 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; Cell projection; Cytoplasm;
KW Disease variant; Golgi apparatus; Membrane; Metal-binding; Phosphoprotein;
KW Proto-oncogene; Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..906
FT /note="E3 ubiquitin-protein ligase CBL"
FT /id="PRO_0000055858"
FT DOMAIN 47..351
FT /note="Cbl-PTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00839"
FT DOMAIN 856..895
FT /note="UBA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212"
FT ZN_FING 381..420
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 1..357
FT /note="Sufficient for interaction with EPHB1"
FT /evidence="ECO:0000269|PubMed:18034775"
FT REGION 1..21
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 47..175
FT /note="4H"
FT REGION 176..248
FT /note="EF-hand-like"
FT REGION 249..351
FT /note="SH2-like"
FT REGION 352..380
FT /note="Linker"
FT REGION 358..906
FT /note="Required for ubiquitination of SPRED2"
FT /evidence="ECO:0000269|PubMed:17094949"
FT REGION 432..462
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 477..498
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 519..667
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 648..906
FT /note="Interaction with CD2AP"
FT /evidence="ECO:0000269|PubMed:11067845"
FT REGION 680..719
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 743..781
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 799..854
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 536..553
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 603..623
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 639..653
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 799..818
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 835..854
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 229
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0007744|PDB:1B47, ECO:0007744|PDB:2CBL"
FT BINDING 231
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0007744|PDB:1B47, ECO:0007744|PDB:2CBL"
FT BINDING 233
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0007744|PDB:1B47, ECO:0007744|PDB:2CBL"
FT BINDING 235
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0007744|PDB:1B47, ECO:0007744|PDB:2CBL"
FT BINDING 240
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0007744|PDB:1B47, ECO:0007744|PDB:2CBL"
FT BINDING 294
FT /ligand="4-O-phospho-L-tyrosine"
FT /ligand_id="ChEBI:CHEBI:62338"
FT /evidence="ECO:0000250"
FT MOD_RES 371
FT /note="Phosphotyrosine; by INSR"
FT /evidence="ECO:0000269|PubMed:11997497"
FT MOD_RES 439
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 452
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 483
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 619
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P22682"
FT MOD_RES 642
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P22682"
FT MOD_RES 668
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P22682"
FT MOD_RES 669
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 674
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:20622007"
FT MOD_RES 700
FT /note="Phosphotyrosine; by ABL1"
FT /evidence="ECO:0000269|PubMed:11997497,
FT ECO:0000269|PubMed:15556646, ECO:0000269|PubMed:20622007"
FT MOD_RES 731
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000269|PubMed:14739300"
FT MOD_RES 774
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:11997497,
FT ECO:0000269|PubMed:20622007"
FT MOD_RES 900
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16964243"
FT VARIANT 287
FT /note="K -> R (found in patients with acute myeloid
FT leukemia; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:20622007"
FT /id="VAR_071040"
FT VARIANT 365
FT /note="Q -> QSK (found in patients with acute myeloid
FT leukemia; unknown pathological significance; loss of the
FT ability to negatively regulate signaling pathways; promotes
FT cell cycle progression; decreases apoptosis)"
FT /id="VAR_071041"
FT VARIANT 367
FT /note="Q -> P (in NSLL; dbSNP:rs267606704)"
FT /evidence="ECO:0000269|PubMed:20619386"
FT /id="VAR_064332"
FT VARIANT 371
FT /note="Y -> H (found in patients with acute myeloid
FT leukemia; unknown pathological significance; loss of the
FT ability to negatively regulate signaling pathways; promotes
FT cell cycle progression; decreases apoptosis;
FT dbSNP:rs267606706)"
FT /evidence="ECO:0000269|PubMed:20622007"
FT /id="VAR_071042"
FT VARIANT 382
FT /note="K -> E (in NSLL; dominant-negative; impairs CBL-
FT mediated ubiquitination, internalization and degradation of
FT the EGF receptor/EGFR; decreases the ability to negatively
FT regulate EGFR signaling; dbSNP:rs267606705)"
FT /evidence="ECO:0000269|PubMed:25178484"
FT /id="VAR_064333"
FT VARIANT 390
FT /note="D -> Y (in NSLL; dominant-negative; impairs CBL-
FT mediated ubiquitination, internalization and degradation of
FT the EGF receptor/EGFR; decreases the ability to negatively
FT regulate EGFR signaling; dbSNP:rs267606707)"
FT /evidence="ECO:0000269|PubMed:20619386,
FT ECO:0000269|PubMed:25178484"
FT /id="VAR_064334"
FT VARIANT 420
FT /note="R -> Q (in NSLL; dominant-negative; impairs CBL-
FT mediated ubiquitination, internalization and degradation of
FT the EGF receptor/EGFR; decreases the ability to negatively
FT regulate EGFR signaling; dbSNP:rs267606708)"
FT /evidence="ECO:0000269|PubMed:20619386,
FT ECO:0000269|PubMed:25178484"
FT /id="VAR_064335"
FT VARIANT 499
FT /note="R -> L (found in patients with acute myeloid
FT leukemia; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:20622007"
FT /id="VAR_071043"
FT VARIANT 620
FT /note="L -> F (in dbSNP:rs2227988)"
FT /id="VAR_057211"
FT VARIANT 782
FT /note="P -> L (in dbSNP:rs2229073)"
FT /id="VAR_057212"
FT VARIANT 904
FT /note="V -> I (in dbSNP:rs17122769)"
FT /id="VAR_057213"
FT MUTAGEN 80
FT /note="S->D: Abolishes interaction with ZAP70."
FT /evidence="ECO:0000269|PubMed:10078535"
FT MUTAGEN 82
FT /note="P->A: Abolishes interaction with ZAP70."
FT /evidence="ECO:0000269|PubMed:10078535"
FT MUTAGEN 229
FT /note="D->Q: Abolishes interaction with ZAP70."
FT /evidence="ECO:0000269|PubMed:10078535"
FT MUTAGEN 240
FT /note="E->S: Abolishes interaction with ZAP70."
FT /evidence="ECO:0000269|PubMed:10078535"
FT MUTAGEN 294
FT /note="R->K: Abolishes interaction with ZAP70."
FT /evidence="ECO:0000269|PubMed:10078535"
FT MUTAGEN 306
FT /note="G->E: Abolishes interaction with ZAP70 and EPHB1,
FT but does not affect interaction with SLA. Reduces
FT ubiquitination and therefore proteasomal degradation of
FT SPRED2."
FT /evidence="ECO:0000269|PubMed:10078535,
FT ECO:0000269|PubMed:10449770, ECO:0000269|PubMed:17094949"
FT MUTAGEN 371
FT /note="Y->F: Strongly reduces tyrosine phosphorylation by
FT INSR; when associated with F-700 and F-774."
FT /evidence="ECO:0000269|PubMed:11997497"
FT MUTAGEN 381
FT /note="C->A: Loss of ubiquitin ligase activity."
FT /evidence="ECO:0000269|PubMed:11896602"
FT MUTAGEN 700
FT /note="Y->F: Strongly reduces tyrosine phosphorylation by
FT INSR; when associated with F-371 and F-774."
FT /evidence="ECO:0000269|PubMed:11997497"
FT MUTAGEN 731
FT /note="Y->F: No effect on tyrosine phosphorylation by INSR.
FT Loss of phosphorylation by SRC. Inhibition of bone
FT resorption. Abolishes interaction with PIK3R1."
FT /evidence="ECO:0000269|PubMed:11997497,
FT ECO:0000269|PubMed:14739300"
FT MUTAGEN 774
FT /note="Y->F: Strongly reduces tyrosine phosphorylation by
FT INSR; when associated with F-371 and F-700."
FT /evidence="ECO:0000269|PubMed:11997497"
FT CONFLICT 15
FT /note="S -> T (in Ref. 1; CAA40393)"
FT /evidence="ECO:0000305"
FT HELIX 53..70
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 73..75
FT /evidence="ECO:0007829|PDB:3BUX"
FT STRAND 80..82
FT /evidence="ECO:0007829|PDB:5HKY"
FT HELIX 84..101
FT /evidence="ECO:0007829|PDB:3BUX"
FT TURN 102..104
FT /evidence="ECO:0007829|PDB:5HKY"
FT HELIX 106..111
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 113..136
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 137..141
FT /evidence="ECO:0007829|PDB:3BUX"
FT STRAND 142..144
FT /evidence="ECO:0007829|PDB:6XAR"
FT HELIX 146..168
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 170..172
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 176..178
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 184..194
FT /evidence="ECO:0007829|PDB:3BUX"
FT STRAND 198..201
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 202..212
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 218..228
FT /evidence="ECO:0007829|PDB:3BUX"
FT STRAND 233..237
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 238..247
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 251..253
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 254..261
FT /evidence="ECO:0007829|PDB:3BUX"
FT TURN 262..264
FT /evidence="ECO:0007829|PDB:2Y1M"
FT STRAND 268..271
FT /evidence="ECO:0007829|PDB:5HKX"
FT HELIX 274..281
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 282..284
FT /evidence="ECO:0007829|PDB:3BUX"
FT STRAND 290..295
FT /evidence="ECO:0007829|PDB:3BUX"
FT STRAND 297..299
FT /evidence="ECO:0007829|PDB:3BUX"
FT STRAND 302..308
FT /evidence="ECO:0007829|PDB:3BUX"
FT TURN 310..312
FT /evidence="ECO:0007829|PDB:3BUO"
FT STRAND 314..317
FT /evidence="ECO:0007829|PDB:3BUX"
FT STRAND 320..322
FT /evidence="ECO:0007829|PDB:3BUW"
FT HELIX 324..333
FT /evidence="ECO:0007829|PDB:3BUX"
FT HELIX 350..352
FT /evidence="ECO:0007829|PDB:5HKX"
FT STRAND 354..356
FT /evidence="ECO:0007829|PDB:1FBV"
FT STRAND 360..362
FT /evidence="ECO:0007829|PDB:4A49"
FT HELIX 365..378
FT /evidence="ECO:0007829|PDB:5HKX"
FT TURN 382..384
FT /evidence="ECO:0007829|PDB:5HKX"
FT STRAND 385..388
FT /evidence="ECO:0007829|PDB:5HKX"
FT STRAND 391..394
FT /evidence="ECO:0007829|PDB:5HKX"
FT STRAND 398..400
FT /evidence="ECO:0007829|PDB:2K4D"
FT HELIX 402..410
FT /evidence="ECO:0007829|PDB:5HKX"
FT TURN 417..419
FT /evidence="ECO:0007829|PDB:5HKX"
FT STRAND 425..428
FT /evidence="ECO:0007829|PDB:5HKX"
FT STRAND 430..432
FT /evidence="ECO:0007829|PDB:4A49"
FT HELIX 856..866
FT /evidence="ECO:0007829|PDB:2OO9"
FT HELIX 871..880
FT /evidence="ECO:0007829|PDB:2OO9"
FT TURN 881..883
FT /evidence="ECO:0007829|PDB:2OO9"
FT HELIX 885..895
FT /evidence="ECO:0007829|PDB:2OO9"
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
