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 27-MAR-2024, entry version 221. 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). Interacts CC (phosphorylated at Tyr-780) with tensin TNS4 (via SH2 domain); the CC interaction is enhanced in the presence of EGF and reduces interaction CC of CBL with EGFR (By similarity). Interacts with EGFR; the interaction CC is reduced in the presence of TNS4 (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; 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; Q6Q899: Rigi; NbExp=3; IntAct=EBI-640919, EBI-6841237; 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}. 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; 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; 75. DR CORUM; P22682; -. DR DIP; DIP-33472N; -. DR IntAct; P22682; 111. DR MINT; P22682; -. DR STRING; 10090.ENSMUSP00000146244; -. DR GlyGen; P22682; 3 sites, 1 O-linked glycan (3 sites). DR iPTMnet; P22682; -. DR PhosphoSitePlus; P22682; -. DR SwissPalm; P22682; -. DR EPD; P22682; -. DR jPOST; P22682; -. DR MaxQB; P22682; -. DR PaxDb; 10090-ENSMUSP00000041902; -. DR PeptideAtlas; P22682; -. DR ProteomicsDB; 281225; -. DR Pumba; P22682; -. DR Antibodypedia; 3815; 1337 antibodies from 49 providers. DR DNASU; 12402; -. DR Ensembl; ENSMUST00000206720.2; ENSMUSP00000146244.2; ENSMUSG00000034342.10. DR GeneID; 12402; -. DR KEGG; mmu:12402; -. DR UCSC; uc009pce.1; mouse. DR AGR; MGI:88279; -. 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; 1123734at2759; -. 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 79 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 244 other cell types or tissues. DR ExpressionAtlas; P22682; baseline and differential. 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; IEA:Ensembl. 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; IBA:GO_Central. DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI. DR GO; GO:0005886; C:plasma membrane; IDA: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; IDA: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:0071456; P:cellular response to hypoxia; IEA:Ensembl. DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; IEA:Ensembl. DR GO; GO:0036120; P:cellular response to platelet-derived growth factor stimulus; IEA:Ensembl. DR GO; GO:0006974; P:DNA damage response; 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; IDA:MGI. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; 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; IDA:MGI. 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: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:0070086; P:ubiquitin-dependent endocytosis; IMP:MGI. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IMP:MGI. DR CDD; cd16708; RING-HC_Cbl; 1. DR CDD; cd09920; SH2_Cbl-b_TKB; 1. DR CDD; cd14393; UBA_c-Cbl; 1. DR Gene3D; 1.20.930.20; Adaptor protein Cbl, N-terminal domain; 1. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR Gene3D; 1.10.238.10; EF-hand; 1. DR Gene3D; 3.30.505.10; SH2 domain; 1. DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 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; 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; IPR018957; Znf_C3HC4_RING-type. DR InterPro; IPR001841; Znf_RING. DR InterPro; IPR013083; Znf_RING/FYVE/PHD. DR InterPro; IPR017907; Znf_RING_CS. DR PANTHER; PTHR23007; CBL; 1. DR PANTHER; PTHR23007:SF5; E3 UBIQUITIN-PROTEIN LIGASE CBL; 1. DR Pfam; PF02262; Cbl_N; 1. DR Pfam; PF02761; Cbl_N2; 1. DR Pfam; PF02762; Cbl_N3; 1. DR Pfam; PF00627; UBA; 1. DR Pfam; PF00097; zf-C3HC4; 1. DR SMART; SM00184; RING; 1. DR SMART; SM00165; UBA; 1. DR SUPFAM; SSF47473; EF-hand; 1. DR SUPFAM; SSF47668; N-terminal domain of cbl (N-cbl); 1. DR SUPFAM; SSF57850; RING/U-box; 1. DR SUPFAM; SSF55550; SH2 domain; 1. DR SUPFAM; SSF46934; UBA-like; 1. DR PROSITE; PS51506; CBL_PTB; 1. DR PROSITE; PS50030; UBA; 1. DR PROSITE; PS00518; ZF_RING_1; 1. DR PROSITE; PS50089; ZF_RING_2; 1. DR Genevisible; P22682; MM. 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 //