CBL_MOUSE
ID CBL_MOUSE Reviewed; 913 AA.
AC P22682; Q3U527; Q8CEA1;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 212.
DE RecName: Full=E3 ubiquitin-protein ligase CBL;
DE EC=2.3.2.27 {ECO:0000269|PubMed:12649282, ECO:0000269|PubMed:20100865};
DE AltName: Full=Casitas B-lineage lymphoma proto-oncogene;
DE AltName: Full=Proto-oncogene c-Cbl;
DE AltName: Full=RING-type E3 ubiquitin transferase CBL {ECO:0000305};
DE AltName: Full=Signal transduction protein CBL;
GN Name=Cbl;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND MUTANT 70Z/3.
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 MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Skin, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 LYN, AND PHOSPHORYLATION.
RX PubMed=7782294; DOI=10.1074/jbc.270.24.14347;
RA Tanaka S., Neff L., Baron R., Levy J.B.;
RT "Tyrosine phosphorylation and translocation of the c-cbl protein after
RT activation of tyrosine kinase signaling pathways.";
RL J. Biol. Chem. 270:14347-14351(1995).
RN [5]
RP PHOSPHORYLATION BY SYK.
RX PubMed=8798454; DOI=10.1074/jbc.271.37.22782;
RA Latour S., Chow L.M., Veillette A.;
RT "Differential intrinsic enzymatic activity of Syk and Zap-70 protein-
RT tyrosine kinases.";
RL J. Biol. Chem. 271:22782-22790(1996).
RN [6]
RP PHOSPHORYLATION BY ZAP70.
RX PubMed=8551236; DOI=10.1084/jem.183.1.301;
RA Fournel M., Davidson D., Weil R., Veillette A.;
RT "Association of tyrosine protein kinase Zap-70 with the protooncogene
RT product p120c-cbl in T lymphocytes.";
RL J. Exp. Med. 183:301-306(1996).
RN [7]
RP INTERACTION WITH FLT1.
RX PubMed=9722576; DOI=10.1074/jbc.273.36.23410;
RA Ito N., Wernstedt C., Engstrom U., Claesson-Welsh L.;
RT "Identification of vascular endothelial growth factor receptor-1 tyrosine
RT phosphorylation sites and binding of SH2 domain-containing molecules.";
RL J. Biol. Chem. 273:23410-23418(1998).
RN [8]
RP INTERACTION WITH SORBS1.
RX PubMed=9447983; DOI=10.1128/mcb.18.2.872;
RA Ribon V., Printen J.A., Hoffman N.G., Kay B.K., Saltiel A.R.;
RT "A novel, multifunctional c-Cbl binding protein in insulin receptor
RT signaling in 3T3-L1 adipocytes.";
RL Mol. Cell. Biol. 18:872-879(1998).
RN [9]
RP FUNCTION.
RX PubMed=9653117; DOI=10.1073/pnas.95.14.7927;
RA Miyake S., Lupher M.L. Jr., Druker B., Band H.;
RT "The tyrosine kinase regulator Cbl enhances the ubiquitination and
RT degradation of the platelet-derived growth factor receptor alpha.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:7927-7932(1998).
RN [10]
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 [11]
RP FUNCTION.
RX PubMed=10393178; DOI=10.1093/emboj/18.13.3616;
RA Lee P.S., Wang Y., Dominguez M.G., Yeung Y.G., Murphy M.A., Bowtell D.D.,
RA Stanley E.R.;
RT "The Cbl protooncoprotein stimulates CSF-1 receptor multiubiquitination and
RT endocytosis, and attenuates macrophage proliferation.";
RL EMBO J. 18:3616-3628(1999).
RN [12]
RP INTERACTION WITH SLA2 AND ZAP70, AND MUTAGENESIS OF GLY-304.
RX PubMed=12024036; DOI=10.1128/mcb.22.12.4241-4255.2002;
RA Loreto M.P., Berry D.M., McGlade C.J.;
RT "Functional cooperation between c-Cbl and Src-like adaptor protein 2 in the
RT negative regulation of T-cell receptor signaling.";
RL Mol. Cell. Biol. 22:4241-4255(2002).
RN [13]
RP INTERACTION WITH KDR, FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=12649282; DOI=10.1074/jbc.m301410200;
RA Duval M., Bedard-Goulet S., Delisle C., Gratton J.P.;
RT "Vascular endothelial growth factor-dependent down-regulation of Flk-1/KDR
RT involves Cbl-mediated ubiquitination. Consequences on nitric oxide
RT production from endothelial cells.";
RL J. Biol. Chem. 278:20091-20097(2003).
RN [14]
RP INTERACTION WITH CBLB.
RX PubMed=12842890; DOI=10.1074/jbc.m300664200;
RA Liu J., DeYoung S.M., Hwang J.B., O'Leary E.E., Saltiel A.R.;
RT "The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport.";
RL J. Biol. Chem. 278:36754-36762(2003).
RN [15]
RP INTERACTION WITH FLT1 AND CD2AP, AND PHOSPHORYLATION IN RESPONSE TO VEGFA.
RX PubMed=15001553; DOI=10.1096/fj.03-0767fje;
RA Kobayashi S., Sawano A., Nojima Y., Shibuya M., Maru Y.;
RT "The c-Cbl/CD2AP complex regulates VEGF-induced endocytosis and degradation
RT of Flt-1 (VEGFR-1).";
RL FASEB J. 18:929-931(2004).
RN [16]
RP PHOSPHORYLATION, AND INTERACTION WITH SLA2 AND CSF1R.
RX PubMed=17353186; DOI=10.1074/jbc.m701182200;
RA Pakuts B., Debonneville C., Liontos L.M., Loreto M.P., McGlade C.J.;
RT "The Src-like adaptor protein 2 regulates colony-stimulating factor-1
RT receptor signaling and down-regulation.";
RL J. Biol. Chem. 282:17953-17963(2007).
RN [17]
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 [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-666; SER-667 AND TYR-672, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Mast cell;
RX PubMed=17947660; DOI=10.4049/jimmunol.179.9.5864;
RA Cao L., Yu K., Banh C., Nguyen V., Ritz A., Raphael B.J., Kawakami Y.,
RA Kawakami T., Salomon A.R.;
RT "Quantitative time-resolved phosphoproteomic analysis of mast cell
RT signaling.";
RL J. Immunol. 179:5864-5876(2007).
RN [19]
RP INTERACTION WITH ATX2.
RX PubMed=18602463; DOI=10.1016/j.cellsig.2008.05.018;
RA Nonis D., Schmidt M.H., van de Loo S., Eich F., Dikic I., Nowock J.,
RA Auburger G.;
RT "Ataxin-2 associates with the endocytosis complex and affects EGF receptor
RT trafficking.";
RL Cell. Signal. 20:1725-1739(2008).
RN [20]
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 [21]
RP FUNCTION IN UBIQUITINATION OF KIT, AND PHOSPHORYLATION.
RX PubMed=19265199; DOI=10.1074/jbc.m808058200;
RA Sun J., Pedersen M., Ronnstrand L.;
RT "The D816V mutation of c-Kit circumvents a requirement for Src family
RT kinases in c-Kit signal transduction.";
RL J. Biol. Chem. 284:11039-11047(2009).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-617; SER-640 AND SER-692, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Heart, Kidney, Lung, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [23]
RP FUNCTION IN UBIQUITINATION OF EPHA8, AND CATALYTIC ACTIVITY.
RX PubMed=20100865; DOI=10.1128/mcb.01605-09;
RA Kim J., Lee H., Kim Y., Yoo S., Park E., Park S.;
RT "The SAM domains of Anks family proteins are critically involved in
RT modulating the degradation of EphA receptors.";
RL Mol. Cell. Biol. 30:1582-1592(2010).
RN [24]
RP INTERACTION WITH SH3KBP1.
RX PubMed=21830225; DOI=10.1002/cbf.1792;
RA Feng L., Wang J.T., Jin H., Qian K., Geng J.G.;
RT "SH3KBP1-binding protein 1 prevents epidermal growth factor receptor
RT degradation by the interruption of c-Cbl-CIN85 complex.";
RL Cell Biochem. Funct. 29:589-596(2011).
RN [25]
RP INTERACTION WITH SIGLEC10.
RX PubMed=23374343; DOI=10.1016/j.cell.2013.01.011;
RA Chen W., Han C., Xie B., Hu X., Yu Q., Shi L., Wang Q., Li D., Wang J.,
RA Zheng P., Liu Y., Cao X.;
RT "Induction of Siglec-G by RNA viruses inhibits the innate immune response
RT by promoting RIG-I degradation.";
RL Cell 152:467-478(2013).
RN [26]
RP FUNCTION, AND SUBCELLULAR 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).
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. Ubiquitinates SPRY2 (By similarity). Ubiquitinates EGFR (By
CC similarity). Recognizes activated receptor tyrosine kinases, including
CC KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and
CC terminates signaling. Recognizes membrane-bound HCK, SRC and other
CC kinases of the SRC family and mediates their ubiquitination and
CC degradation. Participates in signal transduction in hematopoietic
CC cells. Plays an important role in the regulation of osteoblast
CC differentiation and apoptosis. Essential for osteoclastic bone
CC resorption. The 'Tyr-737' phosphorylated form induces the activation
CC and recruitment of phosphatidylinositol 3-kinase to the cell membrane
CC in a signaling pathway that is critical for osteoclast function. May be
CC functionally coupled with the E2 ubiquitin-protein ligase UB2D3
CC (PubMed:10393178, PubMed:12649282, PubMed:19265199, PubMed:20100865,
CC PubMed:9653117). In association with CBLB, required for proper feedback
CC inhibition of ciliary platelet-derived growth factor receptor-alpha
CC (PDGFRA) signaling pathway via ubiquitination and internalization of
CC PDGFRA (PubMed:29237719). {ECO:0000250|UniProtKB:P22681,
CC ECO:0000269|PubMed:10393178, ECO:0000269|PubMed:12649282,
CC ECO:0000269|PubMed:19265199, ECO:0000269|PubMed:20100865,
CC ECO:0000269|PubMed:29237719, ECO:0000269|PubMed:9653117}.
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:12649282,
CC ECO:0000269|PubMed:20100865};
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Forms homodimers; IFT20 promotes the formation of stable
CC homodimers (By similarity). Interacts (phosphorylated) with PIK3R1.
CC Interacts with phosphorylated LAT2 (By similarity). Associates with NCK
CC via its SH3 domain. The phosphorylated C-terminus interacts with CD2AP
CC via its second SH3 domain. Binds to UBE2L3. Interacts with adapters
CC SLA, SLA2 and with the phosphorylated C-terminus of SH2B2. Interacts
CC with EGFR, SYK and ZAP70 via the highly conserved Cbl-N region.
CC Interacts with FGR. Also interacts with BLK, SORBS1 and INPPL1/SHIP2.
CC Interacts with CBLB. Interacts with TEK/TIE2 (tyrosine phosphorylated)
CC (By similarity). Interacts with ALK, AXL and FGFR2. Interacts with
CC CSF1R, EPHB1, FLT1, KDR, PDGFRA and PDGFRB; regulates receptor
CC degradation through ubiquitination. Interacts with HCK and LYN.
CC Interacts with ATX2 (PubMed:18602463). Interacts with SH3KBP1 and this
CC interaction is inhibited in the presence of SHKBP1 (PubMed:21830225).
CC Interacts with SIGLEC10 (PubMed:23374343). Interacts with IFT20 (By
CC similarity). Interacts with SPRY2; the interaction inhibits CBL-
CC mediated ubiquitination of EGFR (By similarity).
CC {ECO:0000250|UniProtKB:P22681, ECO:0000269|PubMed:10092522,
CC ECO:0000269|PubMed:12024036, ECO:0000269|PubMed:12649282,
CC ECO:0000269|PubMed:12842890, ECO:0000269|PubMed:15001553,
CC ECO:0000269|PubMed:17353186, ECO:0000269|PubMed:17620338,
CC ECO:0000269|PubMed:18034775, ECO:0000269|PubMed:18602463,
CC ECO:0000269|PubMed:21830225, ECO:0000269|PubMed:23374343,
CC ECO:0000269|PubMed:7782294, ECO:0000269|PubMed:9447983,
CC ECO:0000269|PubMed:9722576}.
CC -!- INTERACTION:
CC P22682; Q9JLQ0: Cd2ap; NbExp=5; IntAct=EBI-640919, EBI-644807;
CC P22682; P13379: Cd5; NbExp=5; IntAct=EBI-640919, EBI-12600513;
CC P22682; Q6Q899: Ddx58; NbExp=3; IntAct=EBI-640919, EBI-6841237;
CC P22682; Q01279: Egfr; NbExp=2; IntAct=EBI-640919, EBI-6296235;
CC P22682; P39688: Fyn; NbExp=5; IntAct=EBI-640919, EBI-524514;
CC P22682; P16056: Met; NbExp=2; IntAct=EBI-640919, EBI-1798780;
CC P22682; P00533: EGFR; Xeno; NbExp=2; IntAct=EBI-640919, EBI-297353;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane {ECO:0000250}. Cell
CC projection, cilium {ECO:0000269|PubMed:29237719}. Golgi apparatus
CC {ECO:0000269|PubMed:29237719}. Note=Colocalizes with FGFR2 in lipid
CC rafts at the cell membrane. {ECO:0000250}.
CC -!- DOMAIN: The RING-type zinc finger domain mediates binding to an E2
CC ubiquitin-conjugating enzyme. {ECO:0000250}.
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, FGR, INSR, SYK,
CC FYN and ZAP70. Phosphorylated on several tyrosine residues by
CC constitutively activated FGFR3. Phosphorylated on tyrosine residues by
CC activated PDGFRA and PDGFRB (By similarity). Phosphorylated on tyrosine
CC residues in response to CSF1R, FLT1 and KIT signaling. Phosphorylated
CC on tyrosine residues by HCK. {ECO:0000250, ECO:0000269|PubMed:10092522,
CC ECO:0000269|PubMed:15001553, ECO:0000269|PubMed:17353186,
CC ECO:0000269|PubMed:18034775, ECO:0000269|PubMed:19265199,
CC ECO:0000269|PubMed:7782294, ECO:0000269|PubMed:8551236,
CC ECO:0000269|PubMed:8798454}.
CC -!- PTM: Ubiquitinated, leading to its degradation via the proteasome.
CC Ubiquitination is negatively regulated by IFT20.
CC {ECO:0000250|UniProtKB:P22681}.
CC -!- DISEASE: Note=Can be converted to an oncogenic protein by deletions or
CC mutations that disturb its ability to down-regulate RTKs.
CC -!- MISCELLANEOUS: This protein has one functional calcium-binding site.
CC {ECO:0000250}.
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DR EMBL; X57111; CAA40394.1; -; mRNA.
DR EMBL; AK028730; BAC26087.1; -; mRNA.
DR EMBL; AK153915; BAE32253.1; -; mRNA.
DR EMBL; BC125285; AAI25286.1; -; mRNA.
DR CCDS; CCDS40598.1; -.
DR PIR; B43817; B43817.
DR RefSeq; NP_031645.2; NM_007619.2.
DR PDB; 2D9S; NMR; -; A/B=863-902.
DR PDBsum; 2D9S; -.
DR AlphaFoldDB; P22682; -.
DR BMRB; P22682; -.
DR SMR; P22682; -.
DR BioGRID; 198527; 74.
DR CORUM; P22682; -.
DR DIP; DIP-33472N; -.
DR IntAct; P22682; 111.
DR MINT; P22682; -.
DR STRING; 10090.ENSMUSP00000041902; -.
DR iPTMnet; P22682; -.
DR PhosphoSitePlus; P22682; -.
DR EPD; P22682; -.
DR jPOST; P22682; -.
DR MaxQB; P22682; -.
DR PaxDb; P22682; -.
DR PeptideAtlas; P22682; -.
DR PRIDE; P22682; -.
DR ProteomicsDB; 281225; -.
DR Antibodypedia; 3815; 1191 antibodies from 49 providers.
DR DNASU; 12402; -.
DR Ensembl; ENSMUST00000206720; ENSMUSP00000146244; ENSMUSG00000034342.
DR GeneID; 12402; -.
DR KEGG; mmu:12402; -.
DR UCSC; uc009pce.1; mouse.
DR CTD; 867; -.
DR MGI; MGI:88279; Cbl.
DR VEuPathDB; HostDB:ENSMUSG00000034342; -.
DR eggNOG; KOG1785; Eukaryota.
DR GeneTree; ENSGT00940000155772; -.
DR HOGENOM; CLU_013535_3_0_1; -.
DR InParanoid; P22682; -.
DR OMA; GCMYEAM; -.
DR OrthoDB; 540689at2759; -.
DR PhylomeDB; P22682; -.
DR TreeFam; TF314210; -.
DR Reactome; R-MMU-1059683; Interleukin-6 signaling.
DR Reactome; R-MMU-1295596; Spry regulation of FGF signaling.
DR Reactome; R-MMU-1433559; Regulation of KIT signaling.
DR Reactome; R-MMU-182971; EGFR downregulation.
DR Reactome; R-MMU-2173789; TGF-beta receptor signaling activates SMADs.
DR Reactome; R-MMU-5654726; Negative regulation of FGFR1 signaling.
DR Reactome; R-MMU-5654727; Negative regulation of FGFR2 signaling.
DR Reactome; R-MMU-5654732; Negative regulation of FGFR3 signaling.
DR Reactome; R-MMU-5654733; Negative regulation of FGFR4 signaling.
DR Reactome; R-MMU-6807004; Negative regulation of MET activity.
DR Reactome; R-MMU-8849469; PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1.
DR Reactome; R-MMU-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR Reactome; R-MMU-8856828; Clathrin-mediated endocytosis.
DR Reactome; R-MMU-912631; Regulation of signaling by CBL.
DR Reactome; R-MMU-9706369; Negative regulation of FLT3.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 12402; 2 hits in 74 CRISPR screens.
DR ChiTaRS; Cbl; mouse.
DR EvolutionaryTrace; P22682; -.
DR PRO; PR:P22682; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; P22682; protein.
DR Bgee; ENSMUSG00000034342; Expressed in thymus and 241 other tissues.
DR ExpressionAtlas; P22682; baseline and differential.
DR Genevisible; P22682; MM.
DR GO; GO:0030424; C:axon; ISO:MGI.
DR GO; GO:0005929; C:cilium; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0016600; C:flotillin complex; IDA:BHF-UCL.
DR GO; GO:0005925; C:focal adhesion; ISO:MGI.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0030426; C:growth cone; ISO:MGI.
DR GO; GO:0045121; C:membrane raft; ISO:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
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; ISO:MGI.
DR GO; GO:0001784; F:phosphotyrosine residue binding; IEA:InterPro.
DR GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:1990782; F:protein tyrosine kinase binding; ISO:MGI.
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; ISO:MGI.
DR GO; GO:0045453; P:bone resorption; ISS:UniProtKB.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IEA:InterPro.
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: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; ISO:MGI.
DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; ISS: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; ISO:MGI.
DR GO; GO:0070997; P:neuron death; IEA:Ensembl.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISO:MGI.
DR GO; GO:0048260; P:positive regulation of receptor-mediated endocytosis; ISS:UniProtKB.
DR GO; GO:0051865; P:protein autoubiquitination; ISO:MGI.
DR GO; GO:0006513; P:protein monoubiquitination; ISO:MGI.
DR GO; GO:0006468; P:protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0000209; P:protein polyubiquitination; ISO:MGI.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR GO; GO:2000583; P:regulation of platelet-derived growth factor receptor-alpha signaling pathway; IMP:UniProtKB.
DR GO; GO:0032487; P:regulation of Rap protein signal transduction; IMP:MGI.
DR GO; GO:0014823; P:response to activity; IEA:Ensembl.
DR GO; GO:0046677; P:response to antibiotic; ISO:MGI.
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; ISS: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 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 Golgi apparatus; Membrane; Metal-binding; Phosphoprotein; Proto-oncogene;
KW Reference proteome; Repeat; Transferase; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1..913
FT /note="E3 ubiquitin-protein ligase CBL"
FT /id="PRO_0000055859"
FT DOMAIN 45..349
FT /note="Cbl-PTB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00839"
FT DOMAIN 863..902
FT /note="UBA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212"
FT ZN_FING 379..418
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT REGION 1..355
FT /note="Sufficient for interaction with EPHB1"
FT /evidence="ECO:0000269|PubMed:18034775"
FT REGION 45..173
FT /note="4H"
FT REGION 174..246
FT /note="EF-hand-like"
FT REGION 247..349
FT /note="SH2-like"
FT REGION 350..378
FT /note="Linker"
FT REGION 356..913
FT /note="Required for ubiquitination of SPRED2"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT REGION 430..460
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 476..613
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 646..913
FT /note="Interaction with CD2AP"
FT /evidence="ECO:0000250"
FT REGION 647..727
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 750..787
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 814..863
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 505..519
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 534..551
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 750..769
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 839..863
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 227
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 229
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 231
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 233
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 238
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT BINDING 292
FT /ligand="4-O-phospho-L-tyrosine"
FT /ligand_id="ChEBI:CHEBI:62338"
FT /evidence="ECO:0000250"
FT MOD_RES 369
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT MOD_RES 437
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT MOD_RES 450
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT MOD_RES 481
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT MOD_RES 617
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 640
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 666
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17947660"
FT MOD_RES 667
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17947660"
FT MOD_RES 672
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:17947660"
FT MOD_RES 692
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 698
FT /note="Phosphotyrosine; by ABL1"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT MOD_RES 737
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT MOD_RES 780
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT MOD_RES 907
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P22681"
FT VARIANT 364..380
FT /note="Missing (in oncogenic variant 70Z/3)"
FT MUTAGEN 304
FT /note="G->E: Abolishes interaction with ZAP70, but does not
FT affect interaction with SLA."
FT /evidence="ECO:0000269|PubMed:12024036"
FT CONFLICT 72..73
FT /note="KL -> NV (in Ref. 1; CAA40394)"
FT /evidence="ECO:0000305"
FT CONFLICT 218
FT /note="E -> D (in Ref. 2; BAC26087)"
FT /evidence="ECO:0000305"
FT CONFLICT 592
FT /note="P -> T (in Ref. 1; CAA40394)"
FT /evidence="ECO:0000305"
FT CONFLICT 742
FT /note="N -> T (in Ref. 1; CAA40394)"
FT /evidence="ECO:0000305"
FT HELIX 865..874
FT /evidence="ECO:0007829|PDB:2D9S"
FT HELIX 878..887
FT /evidence="ECO:0007829|PDB:2D9S"
FT TURN 888..890
FT /evidence="ECO:0007829|PDB:2D9S"
FT HELIX 892..902
FT /evidence="ECO:0007829|PDB:2D9S"
SQ SEQUENCE 913 AA; 100564 MW; 22F8A5C29F0262B8 CRC64;
MAGNVKKSSG AGGGGSGGSG AGGLIGLMKD AFQPHHHHHH LSPHPPCTVD KKMVEKCWKL
MDKVVRLCQN PKLALKNSPP YILDLLPDTY QHLRTVLSRY EGKMETLGEN EYFRVFMENL
MKKTKQTISL FKEGKERMYE ENSQPRRNLT KLSLIFSHML AELKGIFPSG LFQGDTFRIT
KADAAEFWRK AFGEKTIVPW KSFRQALHEV HPISSGLEAM ALKSTIDLTC NDYISVFEFD
IFTRLFQPWS SLLRNWNSLA VTHPGYMAFL TYDEVKARLQ KFIHKPGSYI FRLSCTRLGQ
WAIGYVTADG NILQTIPHNK PLFQALIDGF REGFYLFPDG RNQNPDLTGL CEPTPQDHIK
VTQEQYELYC EMGSTFQLCK ICAENDKDVK IEPCGHLMCT SCLTSWQESE GQGCPFCRCE
IKGTEPIVVD PFDPRGSGSL LRQGAEGAPS PNYDDDDDER ADDSLFMMKE LAGAKVERPS
SPFSMAPQAS LPPVPPRLDL LQQRAPVPAS TSVLGTASKA ASGSLHKDKP LPIPPTLRDL
PPPPPPDRPY SVGAETRPQR RPLPCTPGDC PSRDKLPPVP SSRPGDSWLS RPIPKVPVAT
PNPGDPWNGR ELTNRHSLPF SLPSQMEPRA DVPRLGSTFS LDTSMTMNSS PVAGPESEHP
KIKPSSSANA IYSLAARPLP MPKLPPGEQG ESEEDTEYMT PTSRPVGVQK PEPKRPLEAT
QSSRACDCDQ QIDSCTYEAM YNIQSQALSV AENSASGEGN LATAHTSTGP EESENEDDGY
DVPKPPVPAV LARRTLSDIS NASSSFGWLS LDGDPTNFNE GSQVPERPPK PFPRRINSER
KASSYQQGGG ATANPVATAP SPQLSSEIER LMSQGYSYQD IQKALVIAHN NIEMAKNILR
EFVSISSPAH VAT
