ID CBLB_HUMAN Reviewed; 982 AA. AC Q13191; A8K9S7; B7WNM4; Q13192; Q13193; Q3LIC0; Q63Z43; Q8IVC5; DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot. DT 07-FEB-2006, sequence version 2. DT 27-MAR-2024, entry version 234. DE RecName: Full=E3 ubiquitin-protein ligase CBL-B; DE EC=2.3.2.27 {ECO:0000269|PubMed:14661060, ECO:0000269|PubMed:20525694}; DE AltName: Full=Casitas B-lineage lymphoma proto-oncogene b; DE AltName: Full=RING finger protein 56; DE AltName: Full=RING-type E3 ubiquitin transferase CBL-B {ECO:0000305}; DE AltName: Full=SH3-binding protein CBL-B; DE AltName: Full=Signal transduction protein CBL-B; GN Name=CBLB; Synonyms=RNF56; ORFNames=Nbla00127; 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] (ISOFORMS LONG; TRUNCATED 1 AND TRUNCATED 2). RX PubMed=7784085; RA Keane M.M., Rivero-Lezcano O.M., Mitchell J.A., Robbins K.C., Lipkowitz S.; RT "Cloning and characterization of cbl-b: a SH3 binding protein with homology RT to the c-cbl proto-oncogene."; RL Oncogene 10:2367-2377(1995). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG), TISSUE SPECIFICITY, AND RP INTERACTION WITH VAV1. RX PubMed=9399639; DOI=10.1038/sj.onc.1201430; RA Bustelo X.R., Crespo P., Lopez-Barahona M., Gutkind J.S., Barbacid M.; RT "Cbl-b, a member of the Sli-1/c-Cbl protein family, inhibits Vav-mediated RT c-Jun N-terminal kinase activation."; RL Oncogene 15:2511-2520(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG). RA Shen C.-R., Chen Y.-J., Pai L.-M., Liu C.-L.; RT "Cbl-b in Taiwan population."; RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG). RC TISSUE=Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16641997; DOI=10.1038/nature04728; RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.; RT "The DNA sequence, annotation and analysis of human chromosome 3."; RL Nature 440:1194-1198(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG), AND VARIANT LYS-584. RC TISSUE=Testis; 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 543-982 (ISOFORM LONG). RC TISSUE=Neuroblastoma; RX PubMed=12880961; DOI=10.1016/s0304-3835(03)00085-5; RA Ohira M., Morohashi A., Nakamura Y., Isogai E., Furuya K., Hamano S., RA Machida T., Aoyama M., Fukumura M., Miyazaki K., Suzuki Y., Sugano S., RA Hirato J., Nakagawara A.; RT "Neuroblastoma oligo-capping cDNA project: toward the understanding of the RT genesis and biology of neuroblastoma."; RL Cancer Lett. 197:63-68(2003). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 857-982 (ISOFORM LONG). RC TISSUE=Small intestine; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [10] RP TISSUE SPECIFICITY, MUTAGENESIS OF GLY-298; TYR-665 AND TYR-709, RP INTERACTION WITH GRB2 AND CRKL, PHOSPHORYLATION AT TYR-665 AND TYR-709, AND RP FUNCTION. RX PubMed=10022120; DOI=10.1038/sj.onc.1202411; RA Elly C., Witte S., Zhang Z., Rosnet O., Lipkowitz S., Altman A., Liu Y.-C.; RT "Tyrosine phosphorylation and complex formation of Cbl-b upon T cell RT receptor stimulation."; RL Oncogene 18:1147-1156(1999). RN [11] RP FUNCTION, PHOSPHORYLATION, AND INTERACTION WITH GRB2 AND PIK3R1. RX PubMed=10086340; DOI=10.1038/sj.onc.1202499; RA Ettenberg S.A., Keane M.M., Nau M.M., Frankel M., Wang L.-M., Pierce J.H., RA Lipkowitz S.; RT "cbl-b inhibits epidermal growth factor receptor signaling."; RL Oncogene 18:1855-1866(1999). RN [12] RP FUNCTION, INTERACTION WITH PIK3R1, AND MUTAGENESIS OF GLY-298 AND CYS-373. RX PubMed=11087752; DOI=10.1074/jbc.m008901200; RA Fang D., Wang H.-Y., Fang N., Altman Y., Elly C., Liu Y.-C.; RT "Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3- RT kinase for ubiquitination in T cells."; RL J. Biol. Chem. 276:4872-4878(2001). RN [13] RP UBIQUITINATION, AND MUTAGENESIS OF CYS-373. RX PubMed=11375397; DOI=10.1074/jbc.m102641200; RA Ettenberg S.A., Magnifico A., Cuello M., Nau M.M., Rubinstein Y.R., RA Yarden Y., Weissman A.M., Lipkowitz S.; RT "Cbl-b-dependent coordinated degradation of the epidermal growth factor RT receptor signaling complex."; RL J. Biol. Chem. 276:27677-27684(2001). RN [14] RP FUNCTION. RX PubMed=11526404; DOI=10.1038/ni0901-870; RA Fang D., Liu Y.-C.; RT "Proteolysis-independent regulation of PI3K by Cbl-b-mediated RT ubiquitination in T cells."; RL Nat. Immunol. 2:870-875(2001). RN [15] RP INTERACTION WITH SH3KBP1, AND SUBCELLULAR LOCATION. RX PubMed=12177062; DOI=10.1074/jbc.m205535200; RA Szymkiewicz I., Kowanetz K., Soubeyran P., Dinarina A., Lipkowitz S., RA Dikic I.; RT "CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine RT kinases."; RL J. Biol. Chem. 277:39666-39672(2002). RN [16] 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 [17] RP INTERACTION WITH UBIQUITINATED PROTEINS, AND MUTAGENESIS OF 943-GLY-TYR-944 RP AND LEU-967. RX PubMed=15273720; DOI=10.1038/sj.onc.1207952; RA Davies G.C., Ettenberg S.A., Coats A.O., Mussante M., Ravichandran S., RA Collins J., Nau M.M., Lipkowitz S.; RT "Cbl-b interacts with ubiquitinated proteins; differential functions of the RT UBA domains of c-Cbl and Cbl-b."; RL Oncogene 23:7104-7115(2004). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-521; SER-525 AND SER-529, AND 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 [20] RP PHOSPHORYLATION AT SER-282. RX PubMed=19549985; DOI=10.1126/scisignal.2000046; RA Gruber T., Hermann-Kleiter N., Hinterleitner R., Fresser F., Schneider R., RA Gastl G., Penninger J.M., Baier G.; RT "PKC-theta modulates the strength of T cell responses by targeting Cbl-b RT for ubiquitination and degradation."; RL Sci. Signal. 2:RA30-RA30(2009). RN [21] RP FUNCTION AS E3 UBIQUITIN-PROTEIN LIGASE, CATALYTIC ACTIVITY, RP PHOSPHORYLATION AT TYR-363, AND MUTAGENESIS OF TYR-363. RX PubMed=20525694; DOI=10.1074/jbc.m109.091157; RA Ryan P.E., Sivadasan-Nair N., Nau M.M., Nicholas S., Lipkowitz S.; RT "The N terminus of Cbl-c regulates ubiquitin ligase activity by modulating RT affinity for the ubiquitin-conjugating enzyme."; RL J. Biol. Chem. 285:23687-23698(2010). RN [22] RP INDUCTION, AND INTERACTION WITH IFT20 AND CBL. 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 [23] RP INVOLVEMENT IN ADMIO3, AND VARIANTS ADMIO3 LEU-257; TRP-436 AND RP 468-VAL--LEU-982 DEL. RX PubMed=36006710; DOI=10.1172/jci154487; RA Janssen E., Peters Z., Alosaimi M.F., Smith E., Milin E., Stafstrom K., RA Wallace J.G., Platt C.D., Chou J., El Ansari Y.S., Al Farsi T., RA Ameziane N., Al-Ali R., Calvo M., Rocha M.E., Bauer P., Al-Sannaa N.A., RA Al Sukaiti N.F., Alangari A.A., Bertoli-Avella A.M., Geha R.S.; RT "Immune dysregulation caused by homozygous mutations in CBLB."; RL J. Clin. Invest. 132:0-0(2022). RN [24] RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 899-914 IN COMPLEXES WITH SH3KBP1 RP AND ARHGEF7, MUTAGENESIS OF ARG-904 AND ARG-911, AND SUBUNIT. RX PubMed=16228008; DOI=10.1038/nsmb1000; RA Jozic D., Cardenes N., Deribe Y.L., Moncalian G., Hoeller D., Groemping Y., RA Dikic I., Rittinger K., Bravo J.; RT "Cbl promotes clustering of endocytic adaptor proteins."; RL Nat. Struct. Mol. Biol. 12:972-979(2005). RN [25] RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 902-912 IN COMPLEX WITH CD2AP, RP MUTAGENESIS OF ARG-904; LYS-907 AND ARG-911, AND SUBUNIT. RX PubMed=17020880; DOI=10.1074/jbc.m606411200; RA Moncalian G., Cardenes N., Deribe Y.L., Spinola-Amilibia M., Dikic I., RA Bravo J.; RT "Atypical polyproline recognition by the CMS N-terminal Src homology 3 RT domain."; RL J. Biol. Chem. 281:38845-38853(2006). RN [26] RP X-RAY CRYSTALLOGRAPHY (1.56 ANGSTROMS) OF 924-973 IN COMPLEX WITH RP UBIQUITIN, STRUCTURE BY NMR OF 924-973, TYROSINE PHOSPHORYLATION, AND RP MUTAGENESIS OF ALA-937; MET-940; PHE-946 AND ILE-966. RX PubMed=17679095; DOI=10.1016/j.molcel.2007.06.023; RA Peschard P., Kozlov G., Lin T., Mirza I.A., Berghuis A.M., Lipkowitz S., RA Park M., Gehring K.; RT "Structural basis for ubiquitin-mediated dimerization and activation of the RT ubiquitin protein ligase Cbl-b."; RL Mol. Cell 27:474-485(2007). RN [27] RP STRUCTURE BY NMR OF 931-970. RG RIKEN structural genomics initiative (RSGI); RT "Solution structure of RSGI RUH-065, a UBA domain from human cDNA."; RL Submitted (MAY-2007) to the PDB data bank. RN [28] RP X-RAY CRYSTALLOGRAPHY (2.27 ANGSTROMS) OF 38-344 IN COMPLEX WITH RP PHOSPHO-EGFR PEPTIDE, INTERACTION WITH EGFR, AND HETERODIMER. RG Structural genomics consortium (SGC); RT "Crystal structure of Cbl-b TKB domain in complex with EGFR pY1069 RT peptide."; RL Submitted (OCT-2010) to the PDB data bank. CC -!- FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from CC specific E2 ubiquitin-conjugating enzymes, and transfers it to CC substrates, generally promoting their degradation by the proteasome. CC Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and CC FCER1 (high affinity immunoglobulin epsilon receptor) signal CC transduction pathways. In naive T-cells, inhibits VAV1 activation upon CC TCR engagement and imposes a requirement for CD28 costimulation for CC proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 CC ubiquitination, which impairs its recruitment to the TCR and subsequent CC activation. In activated T-cells, inhibits PLCG1 activation and calcium CC mobilization upon restimulation and promotes anergy. In B-cells, acts CC by ubiquitinating SYK and promoting its proteasomal degradation. CC Slightly promotes SRC ubiquitination. May be involved in EGFR CC ubiquitination and internalization. May be functionally coupled with CC the E2 ubiquitin-protein ligase UB2D3. In association with CBL, CC required for proper feedback inhibition of ciliary platelet-derived CC growth factor receptor-alpha (PDGFRA) signaling pathway via CC ubiquitination and internalization of PDGFRA (By similarity). CC {ECO:0000250|UniProtKB:Q3TTA7, ECO:0000269|PubMed:10022120, CC ECO:0000269|PubMed:10086340, ECO:0000269|PubMed:11087752, CC ECO:0000269|PubMed:11526404, ECO:0000269|PubMed:14661060, CC ECO:0000269|PubMed:20525694}. 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:14661060, CC ECO:0000269|PubMed:20525694}; CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Interacts with SH3 domain-containing proteins LCK, CRK and CC SORBS1. Interacts with LCP2 and ZAP70. Interacts with CBL CC (PubMed:29237719). Interacts with SH3 domain-containing proteins VAV1, CC FYN, FGR, PLCG1, GRB2, CRKL, PIK3R1 and SH3KBP1/CIN85. Identified in CC heterotrimeric complexes with SH3KBP1/CIN85, CD2AP and ARHGEF7, where CC one CBLB peptide binds two copies of the other protein. Interacts with CC poly-ubiquitinated proteins. Dimerization is required for the binding CC of poly-ubiquitin, but not for the binding of mono-ubiquitin. Interacts CC with EGFR (phosphorylated). Interacts with IFT20 (PubMed:29237719). CC {ECO:0000269|PubMed:10022120, ECO:0000269|PubMed:10086340, CC ECO:0000269|PubMed:11087752, ECO:0000269|PubMed:12177062, CC ECO:0000269|PubMed:15273720, ECO:0000269|PubMed:16228008, CC ECO:0000269|PubMed:17020880, ECO:0000269|PubMed:17679095, CC ECO:0000269|PubMed:29237719, ECO:0000269|PubMed:9399639, CC ECO:0000269|Ref.28}. CC -!- INTERACTION: CC Q13191; Q8IZP0: ABI1; NbExp=2; IntAct=EBI-744027, EBI-375446; CC Q13191; Q9ULH1: ASAP1; NbExp=2; IntAct=EBI-744027, EBI-346622; CC Q13191; Q9Y5K6: CD2AP; NbExp=11; IntAct=EBI-744027, EBI-298152; CC Q13191; P46108: CRK; NbExp=4; IntAct=EBI-744027, EBI-886; CC Q13191; P46109: CRKL; NbExp=4; IntAct=EBI-744027, EBI-910; CC Q13191; O75190: DNAJB6; NbExp=3; IntAct=EBI-744027, EBI-1053164; CC Q13191; Q01658: DR1; NbExp=3; IntAct=EBI-744027, EBI-750300; CC Q13191; P35637: FUS; NbExp=3; IntAct=EBI-744027, EBI-400434; CC Q13191; P06241-3: FYN; NbExp=4; IntAct=EBI-744027, EBI-10691738; CC Q13191; O76003: GLRX3; NbExp=3; IntAct=EBI-744027, EBI-374781; CC Q13191; Q9H8Y8: GORASP2; NbExp=8; IntAct=EBI-744027, EBI-739467; CC Q13191; P62993: GRB2; NbExp=26; IntAct=EBI-744027, EBI-401755; CC Q13191; Q00403: GTF2B; NbExp=3; IntAct=EBI-744027, EBI-389564; CC Q13191; Q9Y5Q9: GTF3C3; NbExp=3; IntAct=EBI-744027, EBI-1054873; CC Q13191; Q5S007: LRRK2; NbExp=4; IntAct=EBI-744027, EBI-5323863; CC Q13191; P16333: NCK1; NbExp=4; IntAct=EBI-744027, EBI-389883; CC Q13191; O43639: NCK2; NbExp=8; IntAct=EBI-744027, EBI-713635; CC Q13191; P35240-4: NF2; NbExp=3; IntAct=EBI-744027, EBI-1014514; CC Q13191; P55345: PRMT2; NbExp=3; IntAct=EBI-744027, EBI-78458; CC Q13191; Q13882: PTK6; NbExp=3; IntAct=EBI-744027, EBI-1383632; CC Q13191; Q96B97: SH3KBP1; NbExp=22; IntAct=EBI-744027, EBI-346595; CC Q13191; P00441: SOD1; NbExp=3; IntAct=EBI-744027, EBI-990792; CC Q13191; O94875-10: SORBS2; NbExp=3; IntAct=EBI-744027, EBI-12037893; CC Q13191; Q6NUL7: SPTLC1; NbExp=3; IntAct=EBI-744027, EBI-25912847; CC Q13191; Q13148: TARDBP; NbExp=6; IntAct=EBI-744027, EBI-372899; CC Q13191; P57075-2: UBASH3A; NbExp=3; IntAct=EBI-744027, EBI-7353612; CC Q13191; Q8TF42: UBASH3B; NbExp=6; IntAct=EBI-744027, EBI-1380492; CC Q13191; Q9UKW4: VAV3; NbExp=3; IntAct=EBI-744027, EBI-297568; CC Q13191; O14972: VPS26C; NbExp=3; IntAct=EBI-744027, EBI-7207091; CC Q13191; P07947: YES1; NbExp=3; IntAct=EBI-744027, EBI-515331; CC Q13191-1; Q9BXL7: CARD11; NbExp=4; IntAct=EBI-15555129, EBI-7006141; CC Q13191-1; Q96B97-1: SH3KBP1; NbExp=3; IntAct=EBI-15555129, EBI-7585212; CC Q13191-1; P62837: UBE2D2; NbExp=2; IntAct=EBI-15555129, EBI-347677; CC Q13191-1; O55043: Arhgef7; Xeno; NbExp=2; IntAct=EBI-15555129, EBI-3649585; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12177062}. CC Note=Upon EGF stimulation, associates with endocytic vesicles. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=Long; CC IsoId=Q13191-1; Sequence=Displayed; CC Name=Truncated 1; CC IsoId=Q13191-2; Sequence=VSP_005729; CC Name=Truncated 2; CC IsoId=Q13191-3; Sequence=VSP_005730, VSP_005731; CC -!- TISSUE SPECIFICITY: Expressed in placenta, heart, lung, kidney, spleen, CC ovary and testis, as well as fetal brain and liver and hematopoietic CC cell lines, but not in adult brain, liver, pancreas, salivary gland, or CC skeletal muscle. Present in lymphocytes (at protein level). CC {ECO:0000269|PubMed:10022120, ECO:0000269|PubMed:9399639}. CC -!- INDUCTION: By serum starvation. {ECO:0000269|PubMed:29237719}. 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 -!- DOMAIN: The RING-type zinc finger domain mediates binding to an E2 CC ubiquitin-conjugating enzyme. CC -!- DOMAIN: The UBA domain interacts with poly-ubiquitinated proteins. CC -!- PTM: Phosphorylated on tyrosine and serine residues upon TCR or BCR CC activation, and upon various types of cell stimulation. CC {ECO:0000269|PubMed:10022120, ECO:0000269|PubMed:10086340, CC ECO:0000269|PubMed:19549985, ECO:0000269|PubMed:20525694}. CC -!- PTM: Auto-ubiquitinated upon EGF-mediated cell activation or upon T- CC cell costimulation by CD28; which promotes proteasomal degradation. CC {ECO:0000269|PubMed:11375397}. CC -!- DISEASE: Autoimmune disease, multisystem, infantile-onset, 3 (ADMIO3) CC [MIM:620430]: An autosomal recessive disorder characterized by CC autoimmune manifestations apparent in the first months or years of CC life. Clinical features may include hypothyroidism, type 1 diabetes CC mellitus, systemic inflammatory manifestations such as fever and CC hepatomegaly, and autoimmune cytopenias. {ECO:0000269|PubMed:36006710}. 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 {ECO:0000250}. CC -!- SEQUENCE CAUTION: CC Sequence=BAE45748.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305}; CC Sequence=CAH56175.1; Type=Miscellaneous discrepancy; Note=Probable cloning artifact.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/193/CBLb"; 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; U26710; AAB09291.1; -; mRNA. DR EMBL; U26711; AAB09292.1; -; mRNA. DR EMBL; U26712; AAB09293.1; -; mRNA. DR EMBL; DQ349203; ABC86700.1; -; mRNA. DR EMBL; AK292792; BAF85481.1; -; mRNA. DR EMBL; AC016138; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471052; EAW79752.1; -; Genomic_DNA. DR EMBL; CH471052; EAW79753.1; -; Genomic_DNA. DR EMBL; CH471052; EAW79754.1; -; Genomic_DNA. DR EMBL; BC032851; AAH32851.1; -; mRNA. DR EMBL; AB075490; BAE45748.1; ALT_SEQ; mRNA. DR EMBL; BX537484; CAH56175.1; ALT_SEQ; mRNA. DR CCDS; CCDS2948.1; -. [Q13191-1] DR RefSeq; NP_001308717.1; NM_001321788.1. [Q13191-1] DR RefSeq; NP_733762.2; NM_170662.4. [Q13191-1] DR RefSeq; XP_011511559.1; XM_011513257.1. [Q13191-1] DR PDB; 2AK5; X-ray; 1.85 A; D=904-911. DR PDB; 2BZ8; X-ray; 2.00 A; C=902-912. DR PDB; 2DO6; NMR; -; A/B=931-970. DR PDB; 2J6F; X-ray; 1.70 A; C=902-912. DR PDB; 2JNH; NMR; -; A=926-971. DR PDB; 2LDR; NMR; -; A=351-426. DR PDB; 2OOA; X-ray; 1.56 A; A/B=924-973. DR PDB; 2OOB; X-ray; 1.90 A; A=924-973. DR PDB; 3PFV; X-ray; 2.27 A; A/B=38-344. DR PDB; 3VGO; X-ray; 3.10 A; A/B/C=39-426. DR PDB; 3ZNI; X-ray; 2.21 A; A/E/I/M=36-427. DR PDB; 8GCY; X-ray; 1.81 A; A=38-427. DR PDB; 8QNG; X-ray; 2.20 A; A=36-427. DR PDB; 8QNH; X-ray; 2.00 A; A=36-427. DR PDB; 8QNI; X-ray; 2.48 A; A=36-427. DR PDBsum; 2AK5; -. DR PDBsum; 2BZ8; -. DR PDBsum; 2DO6; -. DR PDBsum; 2J6F; -. DR PDBsum; 2JNH; -. DR PDBsum; 2LDR; -. DR PDBsum; 2OOA; -. DR PDBsum; 2OOB; -. DR PDBsum; 3PFV; -. DR PDBsum; 3VGO; -. DR PDBsum; 3ZNI; -. DR PDBsum; 8GCY; -. DR PDBsum; 8QNG; -. DR PDBsum; 8QNH; -. DR PDBsum; 8QNI; -. DR AlphaFoldDB; Q13191; -. DR BMRB; Q13191; -. DR SMR; Q13191; -. DR BioGRID; 107316; 95. DR CORUM; Q13191; -. DR DIP; DIP-33091N; -. DR IntAct; Q13191; 68. DR MINT; Q13191; -. DR STRING; 9606.ENSP00000499037; -. DR BindingDB; Q13191; -. DR ChEMBL; CHEMBL4879459; -. DR GuidetoPHARMACOLOGY; 3234; -. DR iPTMnet; Q13191; -. DR PhosphoSitePlus; Q13191; -. DR BioMuta; CBLB; -. DR DMDM; 88911265; -. DR EPD; Q13191; -. DR jPOST; Q13191; -. DR MassIVE; Q13191; -. DR MaxQB; Q13191; -. DR PaxDb; 9606-ENSP00000264122; -. DR PeptideAtlas; Q13191; -. DR ProteomicsDB; 59215; -. [Q13191-1] DR ProteomicsDB; 59216; -. [Q13191-2] DR ProteomicsDB; 59217; -. [Q13191-3] DR Pumba; Q13191; -. DR Antibodypedia; 16015; 296 antibodies from 33 providers. DR DNASU; 868; -. DR Ensembl; ENST00000394030.8; ENSP00000377598.4; ENSG00000114423.23. [Q13191-1] DR Ensembl; ENST00000403724.5; ENSP00000384816.1; ENSG00000114423.23. [Q13191-3] DR Ensembl; ENST00000405772.5; ENSP00000384938.1; ENSG00000114423.23. [Q13191-2] DR GeneID; 868; -. DR KEGG; hsa:868; -. DR MANE-Select; ENST00000394030.8; ENSP00000377598.4; NM_170662.5; NP_733762.2. DR UCSC; uc003dwc.4; human. [Q13191-1] DR AGR; HGNC:1542; -. DR CTD; 868; -. DR DisGeNET; 868; -. DR GeneCards; CBLB; -. DR HGNC; HGNC:1542; CBLB. DR HPA; ENSG00000114423; Low tissue specificity. DR MalaCards; CBLB; -. DR MIM; 604491; gene. DR MIM; 620430; phenotype. DR neXtProt; NX_Q13191; -. DR OpenTargets; ENSG00000114423; -. DR PharmGKB; PA26116; -. DR VEuPathDB; HostDB:ENSG00000114423; -. DR eggNOG; KOG1785; Eukaryota. DR GeneTree; ENSGT00940000156631; -. DR HOGENOM; CLU_013535_3_0_1; -. DR InParanoid; Q13191; -. DR OMA; FACFPPP; -. DR OrthoDB; 1123734at2759; -. DR PhylomeDB; Q13191; -. DR TreeFam; TF314210; -. DR PathwayCommons; Q13191; -. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR SignaLink; Q13191; -. DR SIGNOR; Q13191; -. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 868; 35 hits in 1209 CRISPR screens. DR ChiTaRS; CBLB; human. DR EvolutionaryTrace; Q13191; -. DR GeneWiki; CBLB_(gene); -. DR GenomeRNAi; 868; -. DR Pharos; Q13191; Tchem. DR PRO; PR:Q13191; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; Q13191; Protein. DR Bgee; ENSG00000114423; Expressed in pericardium and 191 other cell types or tissues. DR ExpressionAtlas; Q13191; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0045121; C:membrane raft; IBA:GO_Central. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro. 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; IBA:GO_Central. DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central. DR GO; GO:0008270; F:zinc ion binding; TAS:ProtInc. DR GO; GO:0035739; P:CD4-positive, alpha-beta T cell proliferation; IEA:Ensembl. DR GO; GO:0006955; P:immune response; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; IEA:Ensembl. DR GO; GO:2000562; P:negative regulation of CD4-positive, alpha-beta T cell proliferation; IEA:Ensembl. DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; IEA:Ensembl. DR GO; GO:0006607; P:NLS-bearing protein import into nucleus; TAS:ProtInc. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IEA:Ensembl. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IEA:Ensembl. DR GO; GO:0002669; P:positive regulation of T cell anergy; IEA:Ensembl. DR GO; GO:0030163; P:protein catabolic process; IEA:Ensembl. DR GO; GO:0016567; P:protein ubiquitination; IEA:UniProtKB-UniPathway. DR GO; GO:2000583; P:regulation of platelet-derived growth factor receptor-alpha signaling pathway; ISS:UniProtKB. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR GO; GO:0002870; P:T cell anergy; IEA:Ensembl. DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl. DR CDD; cd16709; RING-HC_Cbl-b; 1. DR CDD; cd09920; SH2_Cbl-b_TKB; 1. DR CDD; cd14392; UBA_Cbl-b; 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 IDEAL; IID00319; -. 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; 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:SF3; E3 UBIQUITIN-PROTEIN LIGASE CBL-B; 1. DR Pfam; PF02262; Cbl_N; 1. DR Pfam; PF02761; Cbl_N2; 1. DR Pfam; PF02762; Cbl_N3; 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 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; Q13191; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Calcium; Cytoplasm; Disease variant; KW Metal-binding; Phosphoprotein; Reference proteome; Repeat; Transferase; KW Ubl conjugation; Ubl conjugation pathway; Zinc; Zinc-finger. FT CHAIN 1..982 FT /note="E3 ubiquitin-protein ligase CBL-B" FT /id="PRO_0000055860" FT DOMAIN 35..343 FT /note="Cbl-PTB" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00839" FT DOMAIN 931..970 FT /note="UBA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00212" FT ZN_FING 373..412 FT /note="RING-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175" FT REGION 35..167 FT /note="4H" FT REGION 168..240 FT /note="EF-hand-like" FT REGION 241..343 FT /note="SH2-like" FT REGION 344..372 FT /note="Linker" FT REGION 466..571 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 543..568 FT /note="Interaction with VAV1" FT /evidence="ECO:0000269|PubMed:9399639" FT REGION 688..731 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 769..929 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 891..927 FT /note="Interaction with SH3KBP1" FT /evidence="ECO:0000269|PubMed:12177062" FT COMPBIAS 468..487 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 541..569 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 697..712 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 714..728 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 817..832 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 836..850 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 879..898 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 221 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000250|UniProtKB:P22681" FT BINDING 223 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000250|UniProtKB:P22681" FT BINDING 225 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000250|UniProtKB:P22681" FT BINDING 227 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000250|UniProtKB:P22681" FT BINDING 232 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /evidence="ECO:0000250|UniProtKB:P22681" FT BINDING 286 FT /ligand="4-O-phospho-L-tyrosine" FT /ligand_id="ChEBI:CHEBI:62338" FT /evidence="ECO:0000250" FT MOD_RES 282 FT /note="Phosphoserine; by PKC/PRKCQ" FT /evidence="ECO:0000269|PubMed:19549985" FT MOD_RES 363 FT /note="Phosphotyrosine" FT /evidence="ECO:0000305|PubMed:20525694" FT MOD_RES 476 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8K4S7" FT MOD_RES 480 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q3TTA7" FT MOD_RES 484 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q3TTA7" FT MOD_RES 521 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 525 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 529 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 634 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8K4S7" FT MOD_RES 665 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:10022120" FT MOD_RES 709 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:10022120" FT MOD_RES 889 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q3TTA7" FT VAR_SEQ 767..770 FT /note="DVFD -> TYRI (in isoform Truncated 2)" FT /evidence="ECO:0000303|PubMed:7784085" FT /id="VSP_005730" FT VAR_SEQ 771..982 FT /note="Missing (in isoform Truncated 2)" FT /evidence="ECO:0000303|PubMed:7784085" FT /id="VSP_005731" FT VAR_SEQ 811..982 FT /note="Missing (in isoform Truncated 1)" FT /evidence="ECO:0000303|PubMed:7784085" FT /id="VSP_005729" FT VARIANT 257 FT /note="H -> L (in ADMIO3; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:36006710" FT /id="VAR_088738" FT VARIANT 436 FT /note="C -> W (in ADMIO3; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36006710" FT /id="VAR_088739" FT VARIANT 468..982 FT /note="Missing (in ADMIO3; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:36006710" FT /id="VAR_088740" FT VARIANT 584 FT /note="R -> K (in dbSNP:rs17853100)" FT /evidence="ECO:0000269|PubMed:15489334" FT /id="VAR_025303" FT VARIANT 883 FT /note="N -> D (in dbSNP:rs35835913)" FT /id="VAR_039241" FT MUTAGEN 298 FT /note="G->E: Inhibits interaction with SYK. No effect on E3 FT activity." FT /evidence="ECO:0000269|PubMed:10022120, FT ECO:0000269|PubMed:11087752" FT MUTAGEN 363 FT /note="Y->E: Decreases affinity for E2 FT ubiquitin-conjugating enzymes." FT /evidence="ECO:0000269|PubMed:20525694" FT MUTAGEN 373 FT /note="C->A: Abolishes E3 activity but does not affect FT binding to substrates." FT /evidence="ECO:0000269|PubMed:11087752, FT ECO:0000269|PubMed:11375397" FT MUTAGEN 665 FT /note="Y->F: Slightly inhibits interaction with CRKL. FT Abolishes interaction with CRKL; when associated with FT F-709." FT /evidence="ECO:0000269|PubMed:10022120" FT MUTAGEN 709 FT /note="Y->F: Inhibits interaction with CRKL. Abolishes FT interaction with CRKL; when associated with F-665." FT /evidence="ECO:0000269|PubMed:10022120" FT MUTAGEN 904 FT /note="R->A: No effect on interaction with CD2AP. Reduced FT interaction with SH3KBP1. Strongly reduced interaction with FT SH3KBP1; when associated with A-911." FT /evidence="ECO:0000269|PubMed:16228008, FT ECO:0000269|PubMed:17020880" FT MUTAGEN 907 FT /note="K->A: No effect on interaction with SH3KBP1. Reduced FT interaction with CD2AP. Strongly reduced interaction with FT CD2AP; when associated with A-911." FT /evidence="ECO:0000269|PubMed:17020880" FT MUTAGEN 911 FT /note="R->A: Reduced interaction with CD2AP and with FT SH3KBP1. Strongly reduced interaction with CD2AP; when FT associated with A-907. Strongly reduced interaction with FT SH3KBP1; when associated with A-904." FT /evidence="ECO:0000269|PubMed:16228008, FT ECO:0000269|PubMed:17020880" FT MUTAGEN 937 FT /note="A->E: Loss of ubiquitin binding. Reduced levels of FT tyrosine phosphorylation." FT /evidence="ECO:0000269|PubMed:17679095" FT MUTAGEN 940 FT /note="M->A: Loss of ubiquitin binding. Reduced levels of FT tyrosine phosphorylation." FT /evidence="ECO:0000269|PubMed:17679095" FT MUTAGEN 943..944 FT /note="GY->AQ: Abolishes interaction with ubiquitinated FT proteins." FT /evidence="ECO:0000269|PubMed:15273720" FT MUTAGEN 946 FT /note="F->A: Loss of ubiquitin binding. Reduced levels of FT tyrosine phosphorylation." FT /evidence="ECO:0000269|PubMed:17679095" FT MUTAGEN 966 FT /note="I->E: Interferes with dimerization. Reduced E3 FT ubiquitin-protein ligase activity. Reduced levels of FT tyrosine phosphorylation." FT /evidence="ECO:0000269|PubMed:17679095" FT MUTAGEN 967 FT /note="L->A: No effect on interaction with ubiquitinated FT proteins." FT /evidence="ECO:0000269|PubMed:15273720" FT CONFLICT 210 FT /note="G -> S (in Ref. 1; AAB09291/AAB09292/AAB09293)" FT /evidence="ECO:0000305" FT CONFLICT 911 FT /note="R -> C (in Ref. 9; CAH56175)" FT /evidence="ECO:0000305" FT HELIX 43..60 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 63..65 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 69..72 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 74..91 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 95..102 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 105..128 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 129..133 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 138..160 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 162..164 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 168..170 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 176..186 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 190..193 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 194..204 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 210..220 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 225..229 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 230..239 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 243..245 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 246..253 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 260..263 FT /evidence="ECO:0007829|PDB:3VGO" FT HELIX 266..273 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 274..276 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 282..287 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 289..291 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 295..300 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 306..309 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 312..314 FT /evidence="ECO:0007829|PDB:3PFV" FT HELIX 316..325 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 332..334 FT /evidence="ECO:0007829|PDB:3VGO" FT HELIX 342..344 FT /evidence="ECO:0007829|PDB:3PFV" FT STRAND 352..354 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 357..364 FT /evidence="ECO:0007829|PDB:3ZNI" FT TURN 365..367 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 370..372 FT /evidence="ECO:0007829|PDB:3ZNI" FT TURN 374..376 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 377..380 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 383..386 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 394..402 FT /evidence="ECO:0007829|PDB:3ZNI" FT TURN 409..411 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 417..420 FT /evidence="ECO:0007829|PDB:3ZNI" FT STRAND 422..424 FT /evidence="ECO:0007829|PDB:3ZNI" FT HELIX 933..941 FT /evidence="ECO:0007829|PDB:2OOA" FT HELIX 946..955 FT /evidence="ECO:0007829|PDB:2OOA" FT TURN 956..958 FT /evidence="ECO:0007829|PDB:2OOA" FT HELIX 960..970 FT /evidence="ECO:0007829|PDB:2OOA" SQ SEQUENCE 982 AA; 109450 MW; B4E307D31B9F0779 CRC64; MANSMNGRNP GGRGGNPRKG RILGIIDAIQ DAVGPPKQAA ADRRTVEKTW KLMDKVVRLC QNPKLQLKNS PPYILDILPD TYQHLRLILS KYDDNQKLAQ LSENEYFKIY IDSLMKKSKR AIRLFKEGKE RMYEEQSQDR RNLTKLSLIF SHMLAEIKAI FPNGQFQGDN FRITKADAAE FWRKFFGDKT IVPWKVFRQC LHEVHQISSG LEAMALKSTI DLTCNDYISV FEFDIFTRLF QPWGSILRNW NFLAVTHPGY MAFLTYDEVK ARLQKYSTKP GSYIFRLSCT RLGQWAIGYV TGDGNILQTI PHNKPLFQAL IDGSREGFYL YPDGRSYNPD LTGLCEPTPH DHIKVTQEQY ELYCEMGSTF QLCKICAEND KDVKIEPCGH LMCTSCLTAW QESDGQGCPF CRCEIKGTEP IIVDPFDPRD EGSRCCSIID PFGMPMLDLD DDDDREESLM MNRLANVRKC TDRQNSPVTS PGSSPLAQRR KPQPDPLQIP HLSLPPVPPR LDLIQKGIVR SPCGSPTGSP KSSPCMVRKQ DKPLPAPPPP LRDPPPPPPE RPPPIPPDNR LSRHIHHVES VPSRDPPMPL EAWCPRDVFG TNQLVGCRLL GEGSPKPGIT ASSNVNGRHS RVGSDPVLMR KHRRHDLPLE GAKVFSNGHL GSEEYDVPPR LSPPPPVTTL LPSIKCTGPL ANSLSEKTRD PVEEDDDEYK IPSSHPVSLN SQPSHCHNVK PPVRSCDNGH CMLNGTHGPS SEKKSNIPDL SIYLKGDVFD SASDPVPLPP ARPPTRDNPK HGSSLNRTPS DYDLLIPPLG EDAFDALPPS LPPPPPPARH SLIEHSKPPG SSSRPSSGQD LFLLPSDPFV DLASGQVPLP PARRLPGENV KTNRTSQDYD QLPSCSDGSQ APARPPKPRP RRTAPEIHHR KPHGPEAALE NVDAKIAKLM GEGYAFEEVK RALEIAQNNV EVARSILREF AFPPPVSPRL NL //