CBLB (gene) explained

CBL-B is an E3 ubiquitin-protein ligase that in humans is encoded by the CBLB gene.^{[1] [2]} CBLB is a member of the CBL gene family.

Function

CBL-B functions as a negative regulator of T-cell activation.^[3] CBL-B expression in T cells causes ligand-induced T cell receptor down-modulation, controlling the activation degree of T cells during antigen presentation.^{[4] [5]}

Clinical significance

Mutation of the CBLB gene has been associated with autoimmune conditions such as type 1 diabetes.^{[6] [7]}

Interactions

CBLB has been shown to interact with:

• CRKL,
• Epidermal growth factor receptor,^{[8] [9]}
• Grb2,^{[10] [11]}
• NEDD4,^[12]
• PIK3R1,^{[10] [11]} and
• SH3KBP1.^[13]

Further reading

• Book: Fang N, Fang D, Wang HY, etal . Altman A . Regulation of immune responses by E3 ubiquitin-protein ligases . Signal Transduction Pathways in Autoimmunity . Current Directions in Autoimmunity . 5 . 161–75 . 2002 . 11826757 . 10.1159/000060552 . 3-8055-7308-1.
• Ohira M, Morohashi A, Nakamura Y . Neuroblastoma oligo-capping cDNA project: toward the understanding of the genesis and biology of neuroblastoma . Cancer Lett. . 197 . 1–2 . 63–8 . 2003 . 12880961 . 10.1016/S0304-3835(03)00085-5 . etal.
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Res. . 6 . 9 . 791–806 . 1997 . 8889548 . 10.1101/gr.6.9.791 . free .
• Bustelo XR, Crespo P, López-Barahona M . Cbl-b, a member of the Sli-1/c-Cbl protein family, inhibits Vav-mediated c-Jun N-terminal kinase activation . Oncogene . 15 . 21 . 2511–20 . 1997 . 9399639 . 10.1038/sj.onc.1201430 . etal. free .
• Lavagna-Sévenier C, Marchetto S, Birnbaum D, Rosnet O . The CBL-related protein CBLB participates in FLT3 and interleukin-7 receptor signal transduction in pro-B cells . J. Biol. Chem. . 273 . 24 . 14962–7 . 1998 . 9614102 . 10.1074/jbc.273.24.14962 . free .
• Elly C, Witte S, Zhang Z . Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation . Oncogene . 18 . 5 . 1147–56 . 1999 . 10022120 . 10.1038/sj.onc.1202411 . etal. free .
• Zhang Z, Elly C, Qiu L . A direct interaction between the adaptor protein Cbl-b and the kinase zap-70 induces a positive signal in T cells . Curr. Biol. . 9 . 4 . 203–6 . 1999 . 10074432 . 10.1016/S0960-9822(99)80090-6 . 1502923 . etal. free . 1999CBio....9..203Z .
• Ettenberg SA, Keane MM, Nau MM . cbl-b inhibits epidermal growth factor receptor signaling . Oncogene . 18 . 10 . 1855–66 . 1999 . 10086340 . 10.1038/sj.onc.1202499 . etal. free .
• Wong ES, Lim J, Low BC . Evidence for direct interaction between Sprouty and Cbl . J. Biol. Chem. . 276 . 8 . 5866–75 . 2001 . 11053437 . 10.1074/jbc.M006945200 . etal. free .
• Fang D, Wang HY, Fang N . Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells . J. Biol. Chem. . 276 . 7 . 4872–8 . 2001 . 11087752 . 10.1074/jbc.M008901200 . etal. free .
• Ettenberg SA, Magnifico A, Cuello M . Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex . J. Biol. Chem. . 276 . 29 . 27677–84 . 2001 . 11375397 . 10.1074/jbc.M102641200 . etal. free .
• Arron JR, Vologodskaia M, Wong BR . A positive regulatory role for Cbl family proteins in tumor necrosis factor-related activation-induced cytokine (trance) and CD40L-mediated Akt activation . J. Biol. Chem. . 276 . 32 . 30011–7 . 2001 . 11406619 . 10.1074/jbc.M100414200 . etal. free .
• Fang D, Liu YC . Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells . Nat. Immunol. . 2 . 9 . 870–5 . 2001 . 11526404 . 10.1038/ni0901-870 . 23051632 .
• Sattler M, Pride YB, Quinnan LR . Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells . Oncogene . 21 . 9 . 1423–33 . 2002 . 11857085 . 10.1038/sj.onc.1205202 . etal. free .
• Yasuda T, Tezuka T, Maeda A . Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells . J. Exp. Med. . 196 . 1 . 51–63 . 2002 . 12093870 . 10.1084/jem.20020068 . 2194016 . etal.
• Szymkiewicz I, Kowanetz K, Soubeyran P . CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases . J. Biol. Chem. . 277 . 42 . 39666–72 . 2002 . 12177062 . 10.1074/jbc.M205535200 . etal. free .
• Haglund K, Shimokawa N, Szymkiewicz I, Dikic I . Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors . Proc. Natl. Acad. Sci. U.S.A. . 99 . 19 . 12191–6 . 2002 . 12218189 . 10.1073/pnas.192462299 . 129420 . 2002PNAS...9912191H . free .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .

Notes and References

1. 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 . 10 . 12 . 2367–77 . July 1995 . 7784085 .
2. Web site: Entrez Gene: CBLB Cas-Br-M (murine) ecotropic retroviral transforming sequence b.
3. Wallner S, Gruber T, Baier G, Wolf D . Releasing the brake: targeting Cbl-b to enhance lymphocyte effector functions . Clin. Dev. Immunol. . 2012 . 692639 . 2012 . 22550535 . 3328896 . 10.1155/2012/692639 . free .
4. Naramura M, Jang IK, Kole H, Huang F, Haines D, Gu H . Pc-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. . Nature Immunology . 3 . 12 . 1192–9 . August 2002 . 12415267 . 10.1038/ni855. 13354434 .
5. Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D . PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells . EMBO Molecular Medicine . 3 . 10 . 581–92 . August 2011 . 21739608 . 10.1002/emmm.201100165 . 3191120.
6. Hoyne GF, Flening E, Yabas M, Teh C, Altin JA, Randall K, Thien CB, Langdon WY, Goodnow CC . Visualizing the role of Cbl-b in control of islet-reactive CD4 T cells and susceptibility to type 1 diabetes . J. Immunol. . 186 . 4 . 2024–32 . February 2011 . 21248249 . 10.4049/jimmunol.1002296. free . 1885/66821 . free .
7. Yokoi N, Fujiwara Y, Wang HY, Kitao M, Hayashi C, Someya T, Kanamori M, Oiso Y, Tajima N, Yamada Y, Seino Y, Ikegami H, Seino S . Identification and functional analysis of CBLB mutations in type 1 diabetes . Biochem. Biophys. Res. Commun. . 368 . 1 . 37–42 . March 2008 . 18201552 . 10.1016/j.bbrc.2008.01.032 .
8. Schulze WX, Deng L, Mann M . Phosphotyrosine interactome of the ErbB-receptor kinase family . Mol. Syst. Biol. . 1 . E1–E13 . 2005 . 16729043 . 1681463 . 10.1038/msb4100012 .
9. Ettenberg SA, Keane MM, Nau MM, Frankel M, Wang LM, Pierce JH, Lipkowitz S . cbl-b inhibits epidermal growth factor receptor signaling . Oncogene . 18 . 10 . 1855–66 . March 1999 . 10086340 . 10.1038/sj.onc.1202499 . free .
10. 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 . 18 . 5 . 1147–56 . February 1999 . 10022120 . 10.1038/sj.onc.1202411 . free .
11. Lavagna-Sévenier C, Marchetto S, Birnbaum D, Rosnet O . The CBL-related protein CBLB participates in FLT3 and interleukin-7 receptor signal transduction in pro-B cells . J. Biol. Chem. . 273 . 24 . 14962–7 . June 1998 . 9614102 . 10.1074/jbc.273.24.14962 . free .
12. Magnifico A, Ettenberg S, Yang C, Mariano J, Tiwari S, Fang S, Lipkowitz S, Weissman AM . WW domain HECT E3s target Cbl RING finger E3s for proteasomal degradation . J. Biol. Chem. . 278 . 44 . 43169–77 . October 2003 . 12907674 . 10.1074/jbc.M308009200 . free .
13. Szymkiewicz I, Kowanetz K, Soubeyran P, Dinarina A, Lipkowitz S, Dikic I . CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases . J. Biol. Chem. . 277 . 42 . 39666–72 . October 2002 . 12177062 . 10.1074/jbc.M205535200 . free .