Disease relevance of Cblb

• Mice deficient in Cbl-b are highly susceptible to experimental autoimmune encephalomyelitis, suggesting that the dysregulation of signalling pathways modulated by Cbl-b may also contribute to human autoimmune diseases such as multiple sclerosis [1].
• Our results suggest that Cbl-b may mediate denervation-induced osteopenia by inhibiting IGF-I signaling in osteoblasts [2].
• A sustained hyper-expression of CD40L by lupus T cells can be triggered by sub-threshold stimuli, and is associated with impaired phosphorylation of Cbl-b, a critical downregulatory molecule in T cell signal transduction [3].
• Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis [4].

High impact information on Cblb

• Furthermore, in the absence of a key negative regulatory molecule, Cbl-b, 100% of mice develop autoimmunity upon infection with viruses encoding the lower-affinity ligand [5].
• The main TCR signalling pathways, such as tyrosine kinases Zap-70 and Lck, Ras/mitogen-activated kinases, phospholipase Cgamma-1 and Ca2+ mobilization, were not affected in Cbl-b(-/-) T cells [1].
• Here we show that gene-targeted mice lacking the adaptor Cbl-b develop spontaneous autoimmunity characterized by auto-antibody production, infiltration of activated T and B lymphocytes into multiple organs, and parenchymal damage [6].
• Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b [6].
• Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction [7].

Biological context of Cblb

• We now demonstrate that Cbl-b also undergoes tyrosine phosphorylation and membrane translocation in response to insulin in 3T3-L1 adipocytes [8].
• The hyperresponsiveness of Cbl(-/-) and Cbl-b(-/-) lymphocytes and the autoimmune phenotype of Cbl-b(-/-) mice lend strong support for this proposal [9].
• This resistance of Cbl-b(-/-) T(eff) to in vitro regulation is seen at the levels of both DNA synthesis and cell division [10].
• In this study, we show that loss of Cbl-b restores Ig class switching and germinal center formation in Vav1 mutant mice in response to an in vivo viral challenge [11].
• Cbl-b differentially regulates activation-induced apoptosis in T helper 1 and T helper 2 cells [12].

Anatomical context of Cblb

• T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction [13].
• Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl) [14].
• Cbl-b Is a Negative Regulator of Inflammatory Cytokines Produced by IgE-Activated Mast Cells [15].
• Intriguingly, despite restored antiviral in vivo immunity and follicular dendritic cell clusters, loss of Cbl-b did not rescue germinal center formation in CD28-deficient mice [11].
• Specifically, the function and interaction of CD4(+)CD25(+) regulatory T cells (T(reg)) and CD4(+)CD25(-) effector T cells (T(eff)) in Cbl-b(-/-) mice have not been examined [10].

Associations of Cblb with chemical compounds

• In contrast to Cbl-b, c-Cbl deficiency had no detectable effect on Fc epsilon RI-induced histamine release or on the phosphorylation of total cellular proteins or Syk [16].
• Compared with control cells, Cbl-b inactivation resulted in increases in Fc epsilon RI-induced Ca(2+) response and histamine release [16].
• The roles of Cbl-b and c-Cbl in insulin-stimulated glucose transport [8].

Regulatory relationships of Cblb

• Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk [17].
• Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells [18].
• Ubiquitin ligase Cbl-b downregulates bone formation through suppression of IGF-I signaling in osteoblasts during denervation [2].

Other interactions of Cblb

• Among the three members of this family, only c-Cbl and Cbl-b are expressed in hemopoietic cells [16].
• Thus, both c-Cbl and Cbl-b can initiate a phosphatidylinositol 3-kinase/protein kinase B-independent signaling pathway critical to insulin-stimulated GLUT4 translocation [8].
• Resistance to CD4+CD25+ regulatory T cells and TGF-beta in Cbl-b-/- mice [10].
• Here we show that Cbl-b, but not Cbl-3, utilize the same mechanism to down-regulate multiple RTKs [19].
• Moreover, loss of CD28 results in disorganization of follicular dendritic cell clusters, which is also rescued by the Cbl-b mutation [11].

Analytical, diagnostic and therapeutic context of Cblb

• In contrast, in Cbl-b(-/-) mice, bone mass and bone formation were sustained during denervation [2].

References