5axi

Structural highlights

Function

CBLB_MOUSE 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. Slightly promotes SRC ubiquitination. May be involved in EGFR ubiquitination and internalization. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3.^{[1] [2] [3] [4] [5] [6]}

See Also

• Ubiquitin protein ligase 3D structures

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 Jan 13;403(6766):211-6. PMID:10646608 doi:http://dx.doi.org/10.1038/35003228
2. ↑ 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 Jan 13;403(6766):216-20. PMID:10646609 doi:http://dx.doi.org/10.1038/35003235
3. ↑ 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 Oct;13(4):463-73. PMID:11070165
4. ↑ Fang D, Liu YC. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat Immunol. 2001 Sep;2(9):870-5. PMID:11526404 doi:10.1038/ni0901-870
5. ↑ Sohn HW, Gu H, Pierce SK. Cbl-b negatively regulates B cell antigen receptor signaling in mature B cells through ubiquitination of the tyrosine kinase Syk. J Exp Med. 2003 Jun 2;197(11):1511-24. Epub 2003 May 27. PMID:12771181 doi:http://dx.doi.org/10.1084/jem.20021686
6. ↑ 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 Aug;21(2):167-77. PMID:15308098 doi:http://dx.doi.org/10.1016/j.immuni.2004.07.013
7. ↑ Ohno A, Ochi A, Maita N, Ueji T, Bando A, Nakao R, Hirasaka K, Abe T, Teshima-Kondo S, Nemoto H, Okumura Y, Higashibata A, Yano S, Tochio H, Nikawa T. Structural analysis of the TKB domain of ubiquitin ligase Cbl-b complexed with its small inhibitory peptide, Cblin. Arch Biochem Biophys. 2016 Feb 10;594:1-7. doi: 10.1016/j.abb.2016.02.014. PMID:26874193 doi:http://dx.doi.org/10.1016/j.abb.2016.02.014