Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

E3 Ubiquitin Ligase CBL-B

  • Juan Tang
  • Jian Zhang
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101569

Synonyms

Historical Background

The E3 ubiquitin ligase CBL-B (Casitas Blymphoma-b) is a member of the highly conserved mammalian Cbl family consisting of c-Cbl, Cbl-b, and Cbl-3. c-Cbl is the founding member, which was first discovered in 1989 (Langdon et al. 1989), whereas Cbl-b was first cloned in 1995 (Keane et al. 1995). Both Cbl-b and c-Cbl contain an N-terminal protein tyrosine kinase binding (TKB) domain, a RING finger, a C-terminal proline-rich region (PRR) with potential tyrosine phosphorylation sites, and a ubiquitin-associated domain (UBA) (Fig. 1). With these multiple domains, c-Cbl and Cbl-b can act as adaptor proteins and forms multiple complexes with many signaling molecules to modulate intracellular signaling events.
This is a preview of subscription content, log in to check access.

References

  1. Bachmaier K, Krawczyk C, Kozieradzki I, Kong YY, Sasaki T, Oliveira-dos-Santos A, Mariathasan S, Bouchard D, Wakeham A, Itie A, Le J, Ohashi PS, Sarosi I, Nishina H, Lipkowitz S, Penninger JM. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature. 2000;403:211–6.CrossRefPubMedGoogle Scholar
  2. Bachmaier K, Toya S, Gao X, Triantafillou T, Garrean S, Park GY, Frey RS, Vogel S, Minshall R, Christman JW, Tiruppathi C, Malik AB. E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury. Nat Med. 2007;13:920–6.CrossRefPubMedGoogle Scholar
  3. Beckwith M, Jorgensen G, Longo DL. The protein product of the proto-oncogene c-cbl forms a complex with phosphatidylinositol 3-kinase p85 and CD19 in anti-IgM-stimulated human B-lymphoma cells. Blood. 1996;88:3502–7.PubMedGoogle Scholar
  4. Bhoj VG, Chen ZJ. Ubiquitylation in innate and adaptive immunity. Nature. 2009;458:430–7.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu RJ, Jang IK, Gutkind JS, Shevach E, Gu H. Cbl-b regulates the CD28 dependence of T-cell activation. Nature. 2000;403:216–20.CrossRefPubMedGoogle Scholar
  6. Chiang JY, Jang IK, Hodes R, Gu H. Ablation of Cbl-b provides protection against transplanted and spontaneous tumors. J Clin Invest. 2007;117:1029–36.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Christie D, Zhu J. Transcriptional regulatory networks for CD4 T cell differentiation. Curr Top Microbiol Immunol. 2014;381:125–72.PubMedPubMedCentralGoogle Scholar
  8. Dou H, Buetow L, Sibbet GJ, Cameron K, Huang DT. Essentiality of a non-RING element in priming donor ubiquitin for catalysis by a monomeric E3. Nat Struct Mol Biol. 2013;20:982–6.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Elly C, Witte S, Zhang Z, Rosnet O, Lipkowitz S, Altman A, Liu YC. Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation. Oncogene. 1999;18:1147–56.CrossRefPubMedGoogle Scholar
  10. Gruber T, Hermann-Kleiter N, Hinterleitner R, Fresser F, Schneider R, Gastl G, Penninger JM, Baier G. PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation. Sci Signal. 2009;2:ra30.CrossRefPubMedGoogle Scholar
  11. Guo H, Qiao G, Ying H, Li Z, Zhao Y, Liang Y, Yang L, Lipkowitz S, Penninger JM, Langdon WY, Zhang J. E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity. Cell Rep. 2012;1:472–82.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Han C, Jin J, Xu S, Liu H, Li N, Cao X. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat Immunol. 2010;11:734–42.CrossRefPubMedGoogle Scholar
  13. Harada Y, Harada Y, Elly C, Ying G, Paik JH, DePinho RA, Liu YC. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med. 2010;207:1381–91.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Heissmeyer V, Macian F, Im SH, Varma R, Feske S, Venuprasad K, Gu H, Liu YC, Dustin ML, Rao A. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol. 2004;5:255–65.CrossRefPubMedGoogle Scholar
  15. Hinterleitner R, Gruber T, Pfeifhofer-Obermair C, Lutz-Nicoladoni C, Tzankov A, Schuster M, Penninger JM, Loibner H, Lametschwandtner G, Wolf D, Baier G. Adoptive transfer of siRNA Cblb-silenced CD8+ T lymphocytes augments tumor vaccine efficacy in a B16 melanoma model. PLoS One. 2012;7:e44295.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Jeon MS, Atfield A, Venuprasad K, Krawczyk C, Sarao R, Elly C, Yang C, Arya S, Bachmaier K, Su L, Bouchard D, Jones R, Gronski M, Ohashi P, Wada T, Bloom D, Fathman CG, Liu YC, Penninger JM. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity. 2004;21:167–77.PubMedCrossRefGoogle Scholar
  17. Kamradt T, Mitchison NA. Tolerance and autoimmunity. N Engl J Med. 2001;344:655–64.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Keane MM, Rivero-Lezcano OM, Mitchell JA, Robbins KC, Lipkowitz S. Cloning and characterization of cbl-b: a SH3 binding protein with homology to the c-cbl proto-oncogene. Oncogene. 1995;10:2367–77.PubMedGoogle Scholar
  19. Kitaura Y, Jang IK, Wang Y, Han YC, Inazu T, Cadera EJ, Schlissel M, Hardy RR, Gu H. Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b. Immunity. 2007;26:567–78.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Kobashigawa Y, Tomitaka A, Kumeta H, Noda NN, Yamaguchi M, Inagaki F. Autoinhibition and phosphorylation-induced activation mechanisms of human cancer and autoimmune disease-related E3 protein Cbl-b. Proc Natl Acad Sci USA. 2011;108:20579–84.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Krawczyk C, Penninger JM. Molecular controls of antigen receptor clustering and autoimmunity. Trends Cell Biol. 2001;11:212–20.CrossRefPubMedGoogle Scholar
  22. Krawczyk C, Bachmaier K, Sasaki T, Jones RG, Snapper SB, Bouchard D, Kozieradzki I, Ohashi PS, Alt FW, Penninger JM. Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity. 2000;13:463–73.CrossRefPubMedGoogle Scholar
  23. Langdon WY, Hyland CD, Grumont RJ, Morse HR. The c-cbl proto-oncogene is preferentially expressed in thymus and testis tissue and encodes a nuclear protein. J Virol. 1989;63:5420–4.PubMedPubMedCentralGoogle Scholar
  24. Li D, Gal I, Vermes C, Alegre ML, Chong AS, Chen L, Shao Q, Adarichev V, Xu X, Koreny T, Mikecz K, Finnegan A, Glant TT, Zhang J. Cutting edge: Cbl-b: one of the key molecules tuning CD28- and CTLA-4-mediated T cell costimulation. J Immunol. 2004;173:7135–9.CrossRefPubMedGoogle Scholar
  25. Liu YC. Ubiquitin ligases and the immune response. Annu Rev Immunol. 2004;22:81–127.CrossRefPubMedGoogle Scholar
  26. Loeser S, Loser K, Bijker MS, Rangachari M, van der Burg SH, Wada T, Beissert S, Melief CJ, Penninger JM. Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells. J Exp Med. 2007;204:879–91.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ. Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature. 1999;398:84–90.CrossRefPubMedGoogle Scholar
  28. Mueller DL. E3 ubiquitin ligases as T cell anergy factors. Nat Immunol. 2004;5:883–90.CrossRefPubMedGoogle Scholar
  29. Niiro H, Jabbarzadeh-Tabrizi S, Kikushige Y, Shima T, Noda K, Ota S, Tsuzuki H, Inoue Y, Arinobu Y, Iwasaki H, Shimoda S, Baba E, Tsukamoto H, Horiuchi T, Taniyama T, Akashi K. CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells. Blood. 2012;119:2263–73.CrossRefPubMedGoogle Scholar
  30. Paolino M, Penninger JM. E3 ubiquitin ligases in T-cell tolerance. Eur J Immunol. 2009;39:2337–44.CrossRefPubMedGoogle Scholar
  31. Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014;507:508–12.CrossRefPubMedGoogle Scholar
  32. Peschard P, Kozlov G, Lin T, Mirza IA, Berghuis AM, Lipkowitz S, Park M, Gehring K. Structural basis for ubiquitin-mediated dimerization and activation of the ubiquitin protein ligase Cbl-b. Mol Cell. 2007;27:474–85.CrossRefPubMedGoogle Scholar
  33. Qiao G, Li Z, Molinero L, Alegre ML, Ying H, Sun Z, Penninger JM, Zhang J. T-cell receptor-induced NF-kappaB activation is negatively regulated by E3 ubiquitin ligase Cbl-b. Mol Cell Biol. 2008;28:2470–80.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Qiao G, Zhao Y, Li Z, Tang PQ, Langdon WY, Yang T, Zhang J. T cell activation threshold regulated by E3 ubiquitin ligase Cbl-b determines fate of inducible regulatory T cells. J Immunol. 2013;191:632–9.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Qiao G, Ying H, Zhao Y, Liang Y, Guo H, Shen H, Li Z, Solway J, Tao E, Chiang YJ, Lipkowitz S, Penninger JM, Langdon WY, Zhang J. E3 ubiquitin ligase Cbl-b suppresses proallergic T cell development and allergic airway inflammation. Cell Rep. 2014;6:709–23.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Shi ZD, Li XF, Hao L, Zhao Y, Wang YX, Dong BZ, Chen WH, Zhang ZG, Wang YM, Fu Q, Han CH, Li S. Cbl-b gene silencing in splenic T lymphocytes as a therapeutic strategy to target the prostate cancer RM-1 cell tumors in immune competent mice. Eur Rev Med Pharmacol Sci. 2014;18:3819–30.PubMedGoogle Scholar
  37. Walker LS, Abbas AK. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol. 2002;2:11–9.CrossRefPubMedGoogle Scholar
  38. Waterman H, Levkowitz G, Alroy I, Yarden Y. The RING finger of c-Cbl mediates desensitization of the epidermal growth factor receptor. J Biol Chem. 1999;274:22151–4.CrossRefPubMedGoogle Scholar
  39. Wirnsberger G, Zwolanek F, Asaoka T, Kozieradzki I, Tortola L, Wimmer RA, Kavirayani A, Fresser F, Baier G, Langdon WY, Ikeda F, Kuchler K, Penninger JM. Inhibition of CBLB protects from lethal Candida albicans sepsis. Nat Med. 2016;22:915–23.CrossRefPubMedGoogle Scholar
  40. Xiao Y, Qiao G, Tang J, Tang R, Guo H, Warwar S, Langdon WY, Tao L, Zhang J. Protein tyrosine phosphatase SHP-1 modulates T cell responses by controlling Cbl-b degradation. J Immunol. 2015;195:4218–27.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Xiao Y, Tang J, Guo H, Zhao Y, Tang R, Ouyang S, Zeng Q, Rappleye CA, Rajaram MV, Schlesinger LS, Tao L, Brown GD, Langdon WY, Li BT, Zhang J. Targeting CBLB as a potential therapeutic approach for disseminated candidiasis. Nat Med. 2016;22:906–14.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Yang B, Gay DL, MacLeod MK, Cao X, Hala T, Sweezer EM, Kappler J, Marrack P, Oliver PM. Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells. Nat Immunol. 2008;9:1356–63.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Yasuda T, Tezuka T, Maeda A, Inazu T, Yamanashi Y, Gu H, Kurosaki T, Yamamoto T. Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells. J Exp Med. 2002;196:51–63.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Zeng R, Cannon JL, Abraham RT, Way M, Billadeau DD, Bubeck-Wardenberg J, Burkhardt JK. SLP-76 coordinates Nck-dependent Wiskott-Aldrich syndrome protein recruitment with Vav-1/Cdc42-dependent Wiskott-Aldrich syndrome protein activation at the T cell-APC contact site. J Immunol. 2003;171:1360–8.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Zhang J, Bardos T, Li D, Gal I, Vermes C, Xu J, Mikecz K, Finnegan A, Lipkowitz S, Glant TT. Cutting edge: regulation of T cell activation threshold by CD28 costimulation through targeting Cbl-b for ubiquitination. J Immunol. 2002;169:2236–40.CrossRefPubMedGoogle Scholar
  46. Zhao Y, Guo H, Qiao G, Zucker M, Langdon WY, Zhang J. E3 ubiquitin ligase Cbl-b regulates thymic-derived CD4+CD25+ regulatory T Cell development by targeting Foxp3 for ubiquitination. J Immunol. 2015;194:1639–45.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445–89.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Zhu LL, Luo TM, Xu X, Guo YH, Zhao XQ, Wang TT, Tang B, Jiang YY, Xu JF, Lin X, Jia XM. E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity. J Exp Med. 2016;213:1555–70.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Microbial Infection and ImmunityThe Ohio State UniversityColumbusUSA
  2. 2.Department of NephrologyXiangya Hospital, Central South UniversityChangshaChina