Cbl b

Summary

Gene Symbol: Cbl b
Description: Casitas B-lineage lymphoma b
Alias: AI429560, AI851073, Cbl-b, E3 ubiquitin-protein ligase CBL-B, RING-type E3 ubiquitin transferase CBL-B, SH3-binding protein CBL-B, casitas B-lineage lymphoma proto-oncogene b, signal transduction protein CBL-B
Species: mouse
Products:     Cbl b

Top Publications

  1. Chiang Y, Kole H, Brown K, Naramura M, Fukuhara S, Hu R, et al. Cbl-b regulates the CD28 dependence of T-cell activation. Nature. 2000;403:216-20 pubmed
  2. Fang D, Liu Y. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat Immunol. 2001;2:870-5 pubmed
    ..The enhanced activation of Cbl-b(-/-) T cells was suppressed by the inhibition of PI3K. The results suggest a proteolysis-independent function for Cbl-b in the modification of protein recruitment. ..
  3. Suzue N, Nikawa T, Onishi Y, Yamada C, Hirasaka K, Ogawa T, et al. Ubiquitin ligase Cbl-b downregulates bone formation through suppression of IGF-I signaling in osteoblasts during denervation. J Bone Miner Res. 2006;21:722-34 pubmed
  4. Chiang J, Jang I, Hodes R, Gu H. Ablation of Cbl-b provides protection against transplanted and spontaneous tumors. J Clin Invest. 2007;117:1029-36 pubmed
    ..G7 tumor-bearing mice led to efficient eradication of established tumors. Thus, our data indicate that ablation of Cbl-b can be an efficient strategy for eliciting immune responses against both inoculated and spontaneous tumors. ..
  5. Loeser S, Loser K, Bijker M, Rangachari M, van der Burg S, Wada T, et al. Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells. J Exp Med. 2007;204:879-91 pubmed
    ..Inhibition of Cbl-b is a novel approach to stimulate long-lasting immunity against cancer. ..
  6. Wohlfert E, Gorelik L, Mittler R, Flavell R, Clark R. Cutting edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo. J Immunol. 2006;176:1316-20 pubmed
  7. Bachmaier K, Toya S, Gao X, Triantafillou T, Garrean S, Park G, et al. E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury. Nat Med. 2007;13:920-6 pubmed
    ..The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis. ..
  8. Purev E, Neff L, Horne W, Baron R. c-Cbl and Cbl-b act redundantly to protect osteoclasts from apoptosis and to displace HDAC6 from beta-tubulin, stabilizing microtubules and podosomes. Mol Biol Cell. 2009;20:4021-30 pubmed publisher
    ..Thus, both c-Cbl and Cbl-b promote bone resorption via the stabilization of microtubules, allowing the formation of the podosome belt in osteoclasts, and by promoting osteoclast survival. ..
  9. Sohn H, Gu H, Pierce S. Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk. J Exp Med. 2003;197:1511-24 pubmed
    ..Significantly, prolonged phosphorylation of Syk correlated with reduced ubiquitination of Syk indicating that Cbl-b negatively regulates BCR signaling by targeting Syk for ubiquitination. ..

More Information

Publications81

  1. Wohlfert E, Callahan M, Clark R. Resistance to CD4+CD25+ regulatory T cells and TGF-beta in Cbl-b-/- mice. J Immunol. 2004;173:1059-65 pubmed
  2. Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, et al. Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading. Mol Cell Biol. 2009;29:4798-811 pubmed publisher
    ..The inhibition of Cbl-b-mediated ubiquitination may be a new therapeutic strategy for unloading-mediated muscle atrophy. ..
  3. Krawczyk C, Bachmaier K, Sasaki T, Jones R, Snapper S, Bouchard D, et al. Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity. 2000;13:463-73 pubmed
    ..Thus, Cbl-b functions as a negative regulator of receptor clustering and raft aggregation in T cells. ..
  4. Kitaura Y, Jang I, Wang Y, Han Y, Inazu T, Cadera E, et al. Control of the B cell-intrinsic tolerance programs by ubiquitin ligases Cbl and Cbl-b. Immunity. 2007;26:567-78 pubmed
    ..Thus, Cbl proteins control B cell-intrinsic checkpoint of immune tolerance, possibly through coordinating multiple BCR-proximal signaling pathways during anergy induction. ..
  5. Qiao G, Li Z, Molinero L, Alegre M, Ying H, Sun Z, et al. T-cell receptor-induced NF-kappaB activation is negatively regulated by E3 ubiquitin ligase Cbl-b. Mol Cell Biol. 2008;28:2470-80 pubmed publisher
  6. Fang N, Fang D, Wang H, Altman A, Liu Y. Regulation of immune responses by E3 ubiquitin-protein ligases. Curr Dir Autoimmun. 2002;5:161-75 pubmed
  7. Heissmeyer V, Macian F, Im S, Varma R, Feske S, Venuprasad K, et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol. 2004;5:255-65 pubmed
    ..Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells. ..
  8. Bachmaier K, Krawczyk C, Kozieradzki I, Kong Y, Sasaki T, Oliveira dos Santos A, et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature. 2000;403:211-6 pubmed
    ..Cbl-b is thus a key regulator of activation thresholds in mature lymphocytes and immunological tolerance and autoimmunity. ..
  9. Gruber T, Hermann Kleiter N, Hinterleitner R, Fresser F, Schneider R, Gastl G, et al. PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation. Sci Signal. 2009;2:ra30 pubmed publisher
    ..Thus, our data establish a nonredundant antagonism between PKC-theta and Cbl-b that regulates T cell activation responses. ..
  10. Jeon M, Atfield A, Venuprasad K, Krawczyk C, Sarao R, Elly C, et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity. 2004;21:167-77 pubmed
    ..Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells. ..
  11. Qiao G, Lei M, Li Z, Sun Y, Minto A, Fu Y, et al. Negative regulation of CD40-mediated B cell responses by E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-B. J Immunol. 2007;179:4473-9 pubmed
    ..Together, our data suggest that Cbl-b attenuates CD40-mediated NF-kappaB and JNK activation, thereby suppressing B cell responses. ..
  12. Oksvold M, Dagger S, Thien C, Langdon W. The Cbl-b RING finger domain has a limited role in regulating inflammatory cytokine production by IgE-activated mast cells. Mol Immunol. 2008;45:925-36 pubmed
    ..Thus the ability of Cbl-b to function as a negative regulator of FcvarepsilonRI signalling that promotes inflammatory cytokine production is largely independent of the RING finger domain. ..
  13. Gustin S, Thien C, Langdon W. Cbl-b is a negative regulator of inflammatory cytokines produced by IgE-activated mast cells. J Immunol. 2006;177:5980-9 pubmed
    ..Thus, Cbl-b functions as a potent negative regulator of cytokines that promote allergic and inflammatory reactions. ..
  14. Krawczyk C, Jones R, Atfield A, Bachmaier K, Arya S, Odermatt B, et al. Differential control of CD28-regulated in vivo immunity by the E3 ligase Cbl-b. J Immunol. 2005;174:1472-8 pubmed
    ..These data provide genetic evidence that CD28-dependent in vivo immune responses and Ig class switching can be genetically uncoupled from germinal center formation and ICOS induction by Cbl-b-Vav1-regulated signaling pathways. ..
  15. Kojo S, Elly C, Harada Y, Langdon W, Kronenberg M, Liu Y. Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1. Proc Natl Acad Sci U S A. 2009;106:17847-51 pubmed publisher
    ..The study identifies an important signaling pathway linking Cbl-b-induced monoubiquitination to NFkappaB activation in NKT cell anergy induction, which may help design approaches for human cancer therapy. ..
  16. 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 pubmed publisher
    ..Thus, TLR-triggered, active CD11b integrin engages in crosstalk with the MyD88 and TRIF pathways and subsequently inhibits TLR signaling in innate immune responses. ..
  17. Gronski M, Boulter J, Moskophidis D, Nguyen L, Holmberg K, Elford A, et al. TCR affinity and negative regulation limit autoimmunity. Nat Med. 2004;10:1234-9 pubmed
    ..Therefore, autoimmune disease is sensitive both to the affinity of the activating ligand and to normal mechanisms that negatively regulate the immune response...
  18. Badger Brown K, Gillis L, Bailey M, Penninger J, Barber D. CBL-B is required for leukemogenesis mediated by BCR-ABL through negative regulation of bone marrow homing. Leukemia. 2013;27:1146-54 pubmed publisher
  19. Choi E, Orlova V, Fagerholm S, Nurmi S, Zhang L, Ballantyne C, et al. Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins. Blood. 2008;111:3607-14 pubmed publisher
    ..In conclusion, Cbl-b deficiency activates LFA-1 and LFA-1-mediated inflammatory cell recruitment by stimulating the interaction between the LFA-1 beta-chain and 14-3-3 proteins. ..
  20. Li X, Wei W, Huynh H, Zuo H, Wang X, Wan Y. Nur77 prevents excessive osteoclastogenesis by inducing ubiquitin ligase Cbl-b to mediate NFATc1 self-limitation. elife. 2015;4:e07217 pubmed publisher
  21. Carpino N, Turner S, Mekala D, Takahashi Y, Zang H, Geiger T, et al. Regulation of ZAP-70 activation and TCR signaling by two related proteins, Sts-1 and Sts-2. Immunity. 2004;20:37-46 pubmed
    ..Therefore, Sts-1 and Sts-2 are critical regulators of the signaling pathways that regulate T cell activation. ..
  22. Abe T, Hirasaka K, Kagawa S, Kohno S, Ochi A, Utsunomiya K, et al. Cbl-b is a critical regulator of macrophage activation associated with obesity-induced insulin resistance in mice. Diabetes. 2013;62:1957-69 pubmed publisher
    ..Therefore, inhibition of TLR4 signaling is an attractive therapeutic strategy for treatment of obesity-related insulin resistance. ..
  23. Yu J, Zhao H, Zhang Y, Liu Y, Yao L, Li X, et al. Ubiquitin ligase Cbl-b acts as a negative regulator in discoidin domain receptor 2 signaling via modulation of its stability. FEBS Lett. 2014;588:1509-14 pubmed publisher
    ..Thus, Cbl-b, by promoting the ubiquitination and degradation of DDR2, functions as a negative regulator in the DDR2 signaling pathway. ..
  24. Davidson D, Zhong M, Pandolfi P, Bolland S, Xavier R, Seed B, et al. The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors. Cell Rep. 2016;17:2776-2788 pubmed publisher
    ..Thus, Csk-associating PAG is a critical component of the inhibitory machinery controlling effector T cell activation in cooperation with PTPN22 and Dok adaptors. ..
  25. Feng Q, Baird D, Peng X, Wang J, Ly T, Guan J, et al. Cool-1 functions as an essential regulatory node for EGF receptor- and Src-mediated cell growth. Nat Cell Biol. 2006;8:945-56 pubmed
    ..These findings demonstrate that the regulated phosphorylation of Cool-1 is necessary to maintain the balance between normal signalling by EGFR and Src versus aberrant growth and transformation. ..
  26. Shen F, Lin Q, Gu Y, Childress C, Yang W. Activated Cdc42-associated kinase 1 is a component of EGF receptor signaling complex and regulates EGF receptor degradation. Mol Biol Cell. 2007;18:732-42 pubmed publisher
    ..Taken together, our studies suggest that ACK1 senses signal of EGF and regulates ligand-induced degradation of EGFR...
  27. Huang F, Kitaura Y, Jang I, Naramura M, Kole H, Liu L, et al. Establishment of the major compatibility complex-dependent development of CD4+ and CD8+ T cells by the Cbl family proteins. Immunity. 2006;25:571-81 pubmed
    ..They likely do so by suppressing MHC-independent NF-kappaB activation, possibly through downmodulating pre-TCR signaling in DP thymocytes. ..
  28. Shamim M, Nanjappa S, Singh A, Plisch E, Leblanc S, Walent J, et al. Cbl-b regulates antigen-induced TCR down-regulation and IFN-gamma production by effector CD8 T cells without affecting functional avidity. J Immunol. 2007;179:7233-43 pubmed
    ..These findings have implications in the development of therapies to bolster CD8 T cell function during viral infections or suppress T cell-mediated immunopathology. ..
  29. Bhowmick S, Singh A, Flavell R, Clark R, O Rourke J, Cone R. The sympathetic nervous system modulates CD4(+)FoxP3(+) regulatory T cells via a TGF-beta-dependent mechanism. J Leukoc Biol. 2009;86:1275-83 pubmed publisher
    ..Additionally, targeting Tregs via the SNS may be a novel approach to the prevention or treatment of autoimmune diseases...
  30. Zhu L, Luo T, Xu X, Guo Y, Zhao X, Wang T, et al. E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity. J Exp Med. 2016;213:1555-70 pubmed publisher
    ..Together, our study indicates that Cbl-b negatively regulates CLR-mediated antifungal innate immunity, which provides molecular insight for designing antifungal therapeutic agents. ..
  31. Stromnes I, Blattman J, Tan X, Jeevanjee S, Gu H, Greenberg P. Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice. J Clin Invest. 2010;120:3722-34 pubmed publisher
    ..Thus, abrogating Cbl-b expression in effector T cells may improve the efficacy of adoptive therapy of some human malignancies. ..
  32. Huang H, Jeon M, Liao L, Yang C, Elly C, Yates J, et al. K33-linked polyubiquitination of T cell receptor-zeta regulates proteolysis-independent T cell signaling. Immunity. 2010;33:60-70 pubmed publisher
    ..Thus, the present study reveals unconventional K33-linked polyubiquitination in nonproteolytic regulation of cell-surface-receptor-mediated signal transduction. ..
  33. Teh C, Daley S, Enders A, Goodnow C. T-cell regulation by casitas B-lineage lymphoma (Cblb) is a critical failsafe against autoimmune disease due to autoimmune regulator (Aire) deficiency. Proc Natl Acad Sci U S A. 2010;107:14709-14 pubmed publisher
  34. Oshikawa G, Nagao T, Wu N, Kurosu T, Miura O. c-Cbl and Cbl-b ligases mediate 17-allylaminodemethoxygeldanamycin-induced degradation of autophosphorylated Flt3 kinase with internal tandem duplication through the ubiquitin proteasome pathway. J Biol Chem. 2011;286:30263-73 pubmed publisher
  35. Zeng S, Xu Z, Lipkowitz S, Longley J. Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl). Blood. 2005;105:226-32 pubmed
    ..The activated KIT in turn induces phosphorylation and activation of Cbl proteins. The Cbl proteins then bind and direct the degradation of activated KIT, leading to down-regulation of KIT signaling. ..
  36. Xiao Y, Qiao G, Tang J, Tang R, Guo H, Warwar S, et al. Protein Tyrosine Phosphatase SHP-1 Modulates T Cell Responses by Controlling Cbl-b Degradation. J Immunol. 2015;195:4218-27 pubmed publisher
    ..Therefore, SHP-1 regulates Cbl-b-mediated T cell responses by controlling its tyrosine phosphorylation and ubiquitination. ..
  37. Kohno S, Ueji T, Abe T, Nakao R, Hirasaka K, Oarada M, et al. Rantes secreted from macrophages disturbs skeletal muscle regeneration after cardiotoxin injection in Cbl-b-deficient mice. Muscle Nerve. 2011;43:223-9 pubmed publisher
    ..Cbl-b is an important regulatory factor for cytotoxic T-cell infiltration via RANTES production in macrophages. ..
  38. Nakajima A, Sanjay A, Chiusaroli R, Adapala N, Neff L, Itzsteink C, et al. Loss of Cbl-b increases osteoclast bone-resorbing activity and induces osteopenia. J Bone Miner Res. 2009;24:1162-72 pubmed publisher
    ..e., functions that cannot be compensated by the other homolog). One of Cbl-b's unique functions in osteoclasts is to downregulate bone resorption. ..
  39. Schmitz M. Activation of T cells: releasing the brakes by proteolytic elimination of Cbl-b. Sci Signal. 2009;2:pe38 pubmed publisher
  40. WILSON B, Wang X, Shen X, McKenna E, Lemieux M, Cho Y, et al. Epigenetic antagonism between polycomb and SWI/SNF complexes during oncogenic transformation. Cancer Cell. 2010;18:316-28 pubmed publisher
    ..Finally, using conditional mouse models, we show that inactivation of Ezh2 blocks tumor formation driven by Snf5 loss. ..
  41. Hundt M, Tabata H, Jeon M, Hayashi K, Tanaka Y, Krishna R, et al. Impaired activation and localization of LAT in anergic T cells as a consequence of a selective palmitoylation defect. Immunity. 2006;24:513-22 pubmed
  42. Zhang W, Shao Y, Fang D, Huang J, Jeon M, Liu Y. Negative regulation of T cell antigen receptor-mediated Crk-L-C3G signaling and cell adhesion by Cbl-b. J Biol Chem. 2003;278:23978-83 pubmed
    ..Thus, Cbl-b plays a negative role in Crk-L-C3G-mediated Rap1 and LFA-1 activation in T cells. ..
  43. McGargill M, Wen B, Walsh C, Hedrick S. A deficiency in Drak2 results in a T cell hypersensitivity and an unexpected resistance to autoimmunity. Immunity. 2004;21:781-91 pubmed
    ..These results expose a new pathway regulating T cell activation and highlight the intricacies of induced autoimmune disease. ..
  44. Harada Y, Harada Y, Elly C, Ying G, Paik J, Depinho R, et al. 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 pubmed publisher
    ..This study reveals that Foxo factors promote transcription of the Foxp3 gene in induced T reg cells, and thus provides new mechanistic insight into Foxo-mediated T cell regulation. ..
  45. Adapala N, Barbe M, Tsygankov A, Lorenzo J, Sanjay A. Loss of Cbl-PI3K interaction enhances osteoclast survival due to p21-Ras mediated PI3K activation independent of Cbl-b. J Cell Biochem. 2014;115:1277-89 pubmed publisher
    ..Hence, Cbl and Cbl-b play mutually exclusive roles in osteoclasts. Whereas Cbl-PI3K interaction regulates differentiation and survival, bone resorption is predominantly regulated by Cbl-b in osteoclasts. ..
  46. Wallner S, Lutz Nicoladoni C, Tripp C, Gastl G, Baier G, Penninger J, et al. The role of the e3 ligase cbl-B in murine dendritic cells. PLoS ONE. 2013;8:e65178 pubmed publisher
    ..We conclude that in contrast to c-Cbl, Cbl-b plays only a limited role in the induction of Ag-specific T cell responses by murine BMDCs in vitro and in vivo...
  47. Bhowmick S, Clark R, Brocke S, Cone R. Antigen-specific splenic CD4+ and CD8+ regulatory T cells generated via the eye, suppress experimental autoimmune encephalomyelitis either at the priming or at the effector phase. Int Immunol. 2011;23:119-28 pubmed publisher
    ..Hence, it is important to consider the phenotype of Treg cells while designing effective cell-based therapies against autoimmune disorders. ..
  48. Zhang R, Zhang N, Mueller D. Casitas B-lineage lymphoma b inhibits antigen recognition and slows cell cycle progression at late times during CD4+ T cell clonal expansion. J Immunol. 2008;181:5331-9 pubmed
    ..These observations now suggest a novel role for Cbl-b in triggering the exit from cell cycle at the end of a CD4(+) T cell clonal expansion. ..
  49. Daniel J, Dangelmaier C, Mada S, Buitrago L, Jin J, Langdon W, et al. Cbl-b is a novel physiologic regulator of glycoprotein VI-dependent platelet activation. J Biol Chem. 2010;285:17282-91 pubmed publisher
    ..These data indicate that Cbl-b plays a positive modulatory role in GPVI-dependent platelet signaling, which translates to an important regulatory role in hemostasis and thrombosis in vivo. ..
  50. Goetz B, An W, Mohapatra B, Zutshi N, Iseka F, Storck M, et al. A novel CBL-Bflox/flox mouse model allows tissue-selective fully conditional CBL/CBL-B double-knockout: CD4-Cre mediated CBL/CBL-B deletion occurs in both T-cells and hematopoietic stem cells. Oncotarget. 2016;7:51107-51123 pubmed publisher
  51. Zhang J, Chiang Y, Hodes R, Siraganian R. Inactivation of c-Cbl or Cbl-b differentially affects signaling from the high affinity IgE receptor. J Immunol. 2004;173:1811-8 pubmed
    ..These results suggest that Cbl-b and c-Cbl have divergent effects on Fc epsilon RI signal transduction and that Cbl-b, but not c-Cbl, functions as a negative regulator of Fc epsilon RI-induced degranulation. ..
  52. Adapala N, Holland D, Scanlon V, Barbe M, Langdon W, Tsygankov A, et al. Loss of Cbl-PI3K interaction in mice prevents significant bone loss following ovariectomy. Bone. 2014;67:1-9 pubmed publisher
    ..These data indicate that while lack of Cbl or Cbl-b distinctly affects bone remodeling, only the loss of Cbl-PI3K interaction protects mice from significant bone loss following ovariectomy. ..
  53. Cho J, Kim H, Ju Y, Kye Y, Lee G, Lee S, et al. CD45-mediated control of TCR tuning in naïve and memory CD8+ T cells. Nat Commun. 2016;7:13373 pubmed publisher
    ..Inhibition by high CD45 on CD8+ T cells may protect against overt TCR auto-MHC reactivity, while enhanced sensitivity to cytokines ensures strong responses to foreign antigens. ..
  54. Veselits M, Tanaka A, Lipkowitz S, O Neill S, Sciammas R, Finnegan A, et al. Recruitment of Cbl-b to B cell antigen receptor couples antigen recognition to Toll-like receptor 9 activation in late endosomes. PLoS ONE. 2014;9:e89792 pubmed publisher
    ..These data indicate that Cbl-b acts as a scaffolding molecule to coordinate the delivery of the BCR and TLR9 into subcellular compartments required for productively delivering BCR-captured ligands to TLR9. ..
  55. Mohapatra B, Zutshi N, An W, Goetz B, Arya P, Bielecki T, et al. An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance. Development. 2017;144:1072-1086 pubmed publisher
    ..Our studies reveal a novel, cell-autonomous requirement of CBL and CBL-B in epithelial stem cell maintenance during organ development and remodeling through modulation of mTOR signaling. ..
  56. Choi Y, Han Y, Lee S, Jin Y, Bahn M, Hur K, et al. Cbl-b and c-Cbl negatively regulate osteoblast differentiation by enhancing ubiquitination and degradation of Osterix. Bone. 2015;75:201-9 pubmed publisher
    ..Taken together, we propose novel regulatory roles of Cbl-b and c-Cbl during osteoblast differentiation in which Cbl-b and c-Cbl regulate the degradation of Osterix through the ubiquitin-proteasome pathway. ..
  57. McGargill M, Choy C, Wen B, Hedrick S. Drak2 regulates the survival of activated T cells and is required for organ-specific autoimmune disease. J Immunol. 2008;181:7593-605 pubmed
    ..We present a model whereby T cell survival depends on a balance of TCR and costimulatory signals to explain how the absence of Drak2 affects autoimmune disease without generalized suppression of the immune system. ..
  58. Hoyne G, Flening E, Yabas M, Teh C, Altin J, Randall K, et al. Visualizing the role of Cbl-b in control of islet-reactive CD4 T cells and susceptibility to type 1 diabetes. J Immunol. 2011;186:2024-32 pubmed publisher
    ..These results reveal a role for peripheral T cell anergy in organ-specific self-tolerance and illuminate the interplay between Cblb-dependent anergy and other mechanisms for preventing organ-specific autoimmunity. ..
  59. Zhou S, Chen W, Shi Z, Wang S, Li L, Wen X, et al. Silencing the expression of Cbl-b enhances the immune activation of T lymphocytes against RM-1 prostate cancer cells in vitro. J Chin Med Assoc. 2014;77:630-6 pubmed publisher
    ..This study suggests a potentially novel immunotherapeutic strategy against prostate cancer. ..
  60. Pellegrini M, Calzascia T, Elford A, Shahinian A, Lin A, Dissanayake D, et al. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat Med. 2009;15:528-36 pubmed publisher
    ..The ability of adjuvant IL-7 to antagonize inhibitory networks at the cellular and molecular level has major implications for immunotherapy in the treatment of tumors. ..
  61. Zhao D, Zhang M, Wang M, Liu B, Wang X, Yang J, et al. Up-regulation of Cbl-b is associated with LSECtin-mediated inhibition of different CD4+ T-cell subsets. Immunobiology. 2013;218:602-8 pubmed publisher
    ..Taken together, these data demonstrate that LSECtin-mediated signaling up-regulates the threshold of CD4(+) T cell activation via tuning the expression of Cbl-b. ..
  62. Ou R, Zhang M, Huang L, Moskophidis D. Control of virus-specific CD8+ T-cell exhaustion and immune-mediated pathology by E3 ubiquitin ligase Cbl-b during chronic viral infection. J Virol. 2008;82:3353-68 pubmed publisher
    ..In conclusion, our results suggest that Cbl-b is critically involved in T-cell exhaustion and prevention of lethal disease. ..
  63. Paolino M, Thien C, Gruber T, Hinterleitner R, Baier G, Langdon W, et al. Essential role of E3 ubiquitin ligase activity in Cbl-b-regulated T cell functions. J Immunol. 2011;186:2138-47 pubmed publisher
    ..Thus, modulation of the E3 ligase activity of Cbl-b might be a novel modality to control T cell immunity in vaccination, cancer biology, or autoimmunity. ..
  64. Liu Y, Li Y, Zhang L, Li M, Li C, Xue C, et al. NF-κB downregulates Cbl-b through binding and suppressing Cbl-b promoter in T cell activation. J Immunol. 2015;194:3778-83 pubmed publisher
    ..These results indicated that NF-κB downregulated Cbl-b by binding and suppressing Cbl-b promoter in T cell activation. Our findings provide a novel role for NF-κB signaling in T cell activation. ..
  65. Qiao G, Zhao Y, Li Z, Tang P, Langdon W, Yang T, et al. T cell activation threshold regulated by E3 ubiquitin ligase Cbl-b determines fate of inducible regulatory T cells. J Immunol. 2013;191:632-9 pubmed publisher
    ..Furthermore, we show that Akt-2 but not Akt-1 regulates Foxp3 expression downstream of Cbl-b. Therefore, we demonstrate that Cbl-b regulates the fate of iTregs via controlling the threshold for T cell activation. ..
  66. Hirasaka K, Kohno S, Goto J, Furochi H, Mawatari K, Harada N, et al. Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice. Diabetes. 2007;56:2511-22 pubmed
    ..Cbl-b is a negative regulator of macrophage infiltration and activation, and macrophage activation by Cbl-b deficiency contributes to the peripheral insulin resistance and glucose intolerance via cytokines secreted from macrophages. ..
  67. Naramura M, Jang I, Kole H, Huang F, Haines D, Gu H. c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat Immunol. 2002;3:1192-9 pubmed
    ..These findings show that Cbl family proteins negatively regulate T cell activation by promoting clearance of engaged TCR from the cell surface, a process that is apparently essential for the termination of TCR signals. ..
  68. Salingcarnboriboon R, Pavasant P, Noda M. Cbl-b enhances Runx2 protein stability and augments osteocalcin promoter activity in osteoblastic cell lines. J Cell Physiol. 2010;224:743-7 pubmed publisher
    ..Moreover, the upregulation of downstream genes of Runx2 such as osteocalcin and alkaline phosphatase mRNA was also observed. These data propose the involvement of Cbl-b in the regulation of osteoblast-related genes expression. ..
  69. Oh S, Park J, Zheng T, Kim Y, Wu F, Cho S, et al. Cbl-b regulates airway mucosal tolerance to aeroallergen. Clin Exp Allergy. 2011;41:434-42 pubmed publisher
  70. Yee N, Hamerman J. ?(2) integrins inhibit TLR responses by regulating NF-?B pathway and p38 MAPK activation. Eur J Immunol. 2013;43:779-92 pubmed publisher
    ..Thus, ?(2) integrins limit TLR signaling by inhibiting NF-?B pathway activation and promoting p38 MAPK activation, thereby fine-tuning TLR-induced inflammatory responses. ..
  71. Balachandran P, Dragone L, Garrity Ryan L, Lemus A, Weiss A, Engel J. The ubiquitin ligase Cbl-b limits Pseudomonas aeruginosa exotoxin T-mediated virulence. J Clin Invest. 2007;117:419-27 pubmed
    ..To the best of our knowledge, this represents the first identification of a mammalian gene product that is specifically required for in vivo resistance to disease mediated by a type III-secreted effector. ..
  72. Zhang J, Bardos T, Li D, Gal I, Vermes C, Xu J, et al. Cutting edge: regulation of T cell activation threshold by CD28 costimulation through targeting Cbl-b for ubiquitination. J Immunol. 2002;169:2236-40 pubmed
    ..Our results demonstrate that CD28 costimulation regulates the threshold for T cell activation, at least in part, by promoting Cbl-b ubiquitination and degradation. ..