Database for Annotation, Visualization and Integrated Discovery 2.1
National Institute of Allergy and Infectious Disease
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Cbl proto-oncogene B(CBLB) Cbl proto-oncogene B(CBLB) Related Genes Homo sapiens
CYTOBAND 3q13.11,
GENERIF_SUMMARY novel E3 ubiquitin-protein ligase; role in regulation of immune response - review, Cbl-b plays a negative role in Crk-L-C3G-mediated Rap1 and LFA-1 activation in T cells., Expression of Cbl-b effectively blocks the ability of Cool-2 to stimulate PAK, providing an additional mechanism, aside from catalyzing receptor ubiquitination, by which Cbl-b acts as a negative regulator for signaling activities requiring PAK activation., Cbl-b is a negative regulator of both Lyn-Syk-LAT and Gab2mediated complementary signaling pathways in FcepsilonRI-mediated mast cell activation, Differences in ubiquitin-binding may reflect distinct regulatory functions of c-Cbl and Cbl-b., genetic interaction between the CTLA4 and CBLB genes in type 1 diabetes, NF-kappaB activity is enhanced by a PI3K signal mediated by Cbl-b and Rho, results suggest that Cbl-b- or atrogin-1-mediated ubiquitination plays an important role in unloading-induced muscle atrophy, and that unloading stress may preferentially inhibit transcriptional responses in skeletal muscle, In a primary analysis, no evidence for an association of the CBLB SNP rs3772534 with disease was found in either sample set in type 1 diabetes., the host ubiquitin ligase Cbl-b interacts with the type III-secreted effector exotoxin T (ExoT) and plays a key role in vivo in limiting bacterial dissemination mediated by ExoT, novel mutations in c-CBL and CBL-b have been identified in human acute myeloid leukemia, F328L mutation is involved in the development of autoimmune diseases including type 1 diabetes, and also provide insight into the structure-function relationship of CBLB protein, two Cbls accounted for total receptor ubiquitination and that while c-Cbl and Cbl-b are each alone sufficient to effect EGFR degradation, both are involved in the physiological, EGF-mediated process of receptor downregulation., Cbls suppress cell death in healthy neurons at least in part by inhibiting the ability of mixed lineage kinases to activate JNK signaling., Overexpressions of c-Cbl, Cbl-b, and EGFR are closely related to the invasion and progression of gastric carcinoma., Cbl-b and itch are key regulators of peripheral T-cell tolerance [review], 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, These data provide further evidence of the association of MS disease with variation within CBLB., Interplay between transgenic Cblb-dependent T cell anergy and other mechanisms prevents organ-specific islet-cell autoimmunity., CBLB mutation is asssociated with chronic myelogenous leukemia., Deregulations of Lck-ZAP-70-Cbl-b cross-talk and miR181a in T cells were found to be associated with cholesterol-dependent-dismantling of HLA-DR rafts in macrophages in leprosy progression., data suggest that Cbl-b may contribute to the deregulated activation of T lymphocytes observed in systemic lupus erythematosus (SLE); a significant association between the 2126(A/G) SNP and SLE was detected, the expression and clinical relevance of c-Cbl, Cbl-b and EGFR in non-small cell lung cancer, c-Cbl as well as Cbl-b may play important roles in Hsp90 inhibitor-induced degradation of Flt3-ITD through the ubiquitin proteasome system, Over expression of TGF-beta and CTLA-4 leads to T cell hyporesponsiveness, a major hallmark of leprosy, by increasing the expression of Cbl-b., Autoinhibition and phosphorylation-induced activation mechanisms of human cancer and autoimmune disease-related E3 protein Cbl-b, Pooled analysis corroborated the effect on multiple sclerosis predisposition of three genes, Data show that bufalin-induced down-regulation of Cbl-b contributed to the up-regulation of TRAIL Receptors DR4 and DR5., FOXP3 mRNA expression correlated with CBLB and ITCH in MS patients., abnormal peripheral tolerance in SLE is caused by a deficiency in Cbl-b, and that this ubiquitin ligase plays a key role in regulating T-cell receptor signaling during the induction of peripheral tolerance., that icotinib-induced upregulation of Cbl-b is responsible, at least in part, for the antitumor effect of icotinib via the inhibition of phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase pathways in EGFR-mutated NSCLC cells., By up-regulating the expression of c-Cbl and Cbl-b, which leads to inhibition of PI3K/Akt signaling and down-regulation of P-gp expression, beta-elemene is capable of enhancing the efficacy of doxorubicin in leukemia and gastric cancer cells., Cbl-b knockdown caused significant increase of phosphorylation of EGFR, ERK and Akt, decrease of mitochondrial membrane potential, and increase of expression ratio of Bcl-2/Bax., Ubiquitin ligase Cbl-b represses IGF-I-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells., The data suggest a role of the CBLB rs12487066 variant in the interactions of a genetic risk factor and IFN function during viral infections in multiple sclerosis., Low CBLB expression is associated with glioma cell invasion., Our results suggest that celecoxib-mediated upregulation of Cbl-b is responsible, at least in part, for the additive antitumor effect of celecoxib and rapamycin via inhibition of rapamycin-induced Akt activation., Translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of multidrug resistance through the ubiquitination and degradation of c-Src., findings suggest that Cbl-b limits NGF-TrkA signaling to control the length of neurites., Results suggest that Cbl-b improves the prognosis of RANK-expressing breast cancer patients by inhibiting RANKL-induced breast cancer cell migration and metastasis., results show that Cbl-b suppresses human ORMDL3 expression through STAT6, H19 non coding RNA-derived miR-675 enhances tumorigenesis and metastasis of breast cancer cells by downregulating c-Cbl and Cbl-b., direct interaction between Cblin and the TKB domain of Cbl-b,
SP_COMMENT domain:The N-terminus is composed of the phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. The PTB domain, which is also called TKB (tyrosine kinase binding) domain, is composed of three different subdomains: a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain., domain:The RING-type zinc finger domain mediates binding to an E2 ubiquitin-conjugating enzyme., domain:The UBA domain interacts with poly-ubiquitinated proteins., function:E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T-cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. May also be involved in EGFR ubiquitination and internalization., miscellaneous:This protein has one functional calcium-binding site., pathway:Protein modification; protein ubiquitination., PTM:Auto-ubiquitinated upon EGF-mediated cell activation or upon T-cell costimulation by CD28; which promotes proteasomal degradation., PTM:Phosphorylated on tyrosine residues upon TCR or BCR activation, and upon various types of cell stimulation., sequence caution:Translated as Arg., similarity:Contains 1 CBL N-terminal domain., similarity:Contains 1 RING-type zinc finger., similarity:Contains 1 SH2 domain., similarity:Contains 1 UBA domain., similarity:Contains 2 EF-hand-like domains., subcellular location:Upon EGF stimulation, associates with endocytic vesicles., subunit:Interacts with SH3 domain-containing proteins LCK, CRK and SORBS1. Interacts with LCP2 and ZAP70. May interact with CBL (By similarity). Interacts with SH3 domain-containing proteins VAV1, FYN, FGR, PLCG1, GRB2, CRKL, PIK3R1 and SH3KBP1/CIN85. Identified in heterotrimeric complexes with SH3KBP1/CIN85, CD2AP and ARHGEF7, where one CBLB peptide binds two copies of the other protein. Interacts with poly-ubiquitinated proteins. Dimerization is required for the binding of poly-ubiquitin, but not for the binding of mono-ubiquitin., tissue specificity:Expressed in placenta, heart, lung, kidney, spleen, ovary and testis, as well as fetal brain and liver and hematopoietic cell lines, but not in adult brain, liver, pancreas, salivary gland, or skeletal muscle. Present in lymphocytes (at protein level).,