CBLB (gene)

CBL-B is an E3 ubiquitin-protein ligase that in humans is encoded by the CBLB gene.[5][6] CBLB is a member of the CBL gene family.

CBLB
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2AK5, 2BZ8, 2DO6, 2J6F, 2JNH, 2LDR, 2OOA, 2OOB, 3PFV, 3VGO, 3ZNI
Identifiers
Aliases	CBLB, Cbl-b, RNF56, Nbla00127, Cbl proto-oncogene B
External IDs	OMIM: 604491 MGI: 2146430 HomoloGene: 15856 GeneCards: CBLB
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q13.11 Start 105,655,461 bp[1] End 105,869,552 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16|16 B5 Start 52,031,225 bp[2] End 52,208,048 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • calcium ion binding • phosphotyrosine residue binding • metal ion binding • GO:0001948 protein binding • ubiquitin-protein transferase activity • transferase activity • SH3 domain binding • receptor tyrosine kinase binding • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity • zinc ion binding Cellular component • nucleoplasm • cytoplasm • cytosol • cell membrane • membrane raft • cell nucleus Biological process • regulation of signaling • cell surface receptor signaling pathway • protein ubiquitination • NLS-bearing protein import into nucleus • signal transduction • proteolysis • epidermal growth factor receptor signaling pathway • negative regulation of epidermal growth factor-activated receptor activity • regulation of platelet-derived growth factor receptor-alpha signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	868	208650
Ensembl	ENSG00000114423	ENSMUSG00000022637
UniProt	Q13191	Q3TTA7
RefSeq (mRNA)	NM_170662 NM_001321786 NM_001321788 NM_001321789 NM_001321790 NM_001321791 NM_001321793 NM_001321794 NM_001321795 NM_001321796 NM_001321797 NM_001321798 NM_001321799 NM_001321806 NM_001321807 NM_001321808 NM_001321811 NM_001321813 NM_001321816 NM_001321820 NM_001321822	NM_001033238
RefSeq (protein)	NP_001308715 NP_001308717 NP_001308718 NP_001308719 NP_001308720 NP_001308722 NP_001308723 NP_001308724 NP_001308725 NP_001308726 NP_001308727 NP_001308728 NP_001308735 NP_001308736 NP_001308737 NP_001308740 NP_001308742 NP_001308745 NP_001308749 NP_001308751 NP_733762	NP_001028410
Location (UCSC)	Chr 3: 105.66 – 105.87 Mb	Chr 16: 52.03 – 52.21 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

CBL-B functions as a negative regulator of T-cell activation.[7] CBL-B expression in T cells causes ligand-induced T cell receptor down-modulation, controlling the activation degree of T cells during antigen presentation.[8][9]

Clinical significance

Mutation of the CBLB gene has been associated with autoimmune conditions such as type 1 diabetes.[10][11]

Interactions

CBLB has been shown to interact with:

• CRKL,[12]
• Epidermal growth factor receptor,[13][14]
• Grb2,[12][15]
• NEDD4,[16]
• PIK3R1,[12][15] and
• SH3KBP1.[17]

References

1. GRCh38: Ensembl release 89: ENSG00000114423 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022637 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Keane MM, Rivero-Lezcano OM, Mitchell JA, Robbins KC, Lipkowitz S (July 1995). "Cloning and characterization of cbl-b: a SH3 binding protein with homology to the c-cbl proto-oncogene". Oncogene. 10 (12): 2367–77. PMID 7784085.
6. "Entrez Gene: CBLB Cas-Br-M (murine) ecotropic retroviral transforming sequence b".
7. Wallner S, Gruber T, Baier G, Wolf D (2012). "Releasing the brake: targeting Cbl-b to enhance lymphocyte effector functions". Clin. Dev. Immunol. 2012: 692639. doi:10.1155/2012/692639. PMC 3328896. PMID 22550535.
8. Naramura M, Jang IK, Kole H, Huang F, Haines D, Gu H (August 2002). "Pc-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation". Nature Immunology. 3 (12): 1192–9. doi:10.1038/ni855. PMID 12415267.
9. Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D (August 2011). "PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells". EMBO Molecular Medicine. 3 (10): 581–92. doi:10.1002/emmm.201100165. PMC 3191120. PMID 21739608.
10. Hoyne GF, Flening E, Yabas M, Teh C, Altin JA, Randall K, Thien CB, Langdon WY, Goodnow CC (February 2011). "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. doi:10.4049/jimmunol.1002296. PMID 21248249.
11. 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 (March 2008). "Identification and functional analysis of CBLB mutations in type 1 diabetes". Biochem. Biophys. Res. Commun. 368 (1): 37–42. doi:10.1016/j.bbrc.2008.01.032. PMID 18201552.
12. Elly C, Witte S, Zhang Z, Rosnet O, Lipkowitz S, Altman A, Liu YC (February 1999). "Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation". Oncogene. 18 (5): 1147–56. doi:10.1038/sj.onc.1202411. PMID 10022120.
13. Schulze WX, Deng L, Mann M (2005). "Phosphotyrosine interactome of the ErbB-receptor kinase family". Mol. Syst. Biol. 1: E1–E13. doi:10.1038/msb4100012. PMC 1681463. PMID 16729043.
14. Ettenberg SA, Keane MM, Nau MM, Frankel M, Wang LM, Pierce JH, Lipkowitz S (March 1999). "cbl-b inhibits epidermal growth factor receptor signaling". Oncogene. 18 (10): 1855–66. doi:10.1038/sj.onc.1202499. PMID 10086340.
15. Lavagna-Sévenier C, Marchetto S, Birnbaum D, Rosnet O (June 1998). "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. doi:10.1074/jbc.273.24.14962. PMID 9614102.
16. Magnifico A, Ettenberg S, Yang C, Mariano J, Tiwari S, Fang S, Lipkowitz S, Weissman AM (October 2003). "WW domain HECT E3s target Cbl RING finger E3s for proteasomal degradation". J. Biol. Chem. 278 (44): 43169–77. doi:10.1074/jbc.M308009200. PMID 12907674.
17. Szymkiewicz I, Kowanetz K, Soubeyran P, Dinarina A, Lipkowitz S, Dikic I (October 2002). "CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases". J. Biol. Chem. 277 (42): 39666–72. doi:10.1074/jbc.M205535200. PMID 12177062.

External links

• Human CBLB genome location and CBLB gene details page in the UCSC Genome Browser.

Further reading

• Fang N, Fang D, Wang HY, et al. (2002). "Regulation of immune responses by E3 ubiquitin-protein ligases". In Altman A (ed.). Signal Transduction Pathways in Autoimmunity. Current Directions in Autoimmunity. 5. pp. 161–75. doi:10.1159/000060552. ISBN 3-8055-7308-1. PMID 11826757.
• Ohira M, Morohashi A, Nakamura Y, et al. (2003). "Neuroblastoma oligo-capping cDNA project: toward the understanding of the genesis and biology of neuroblastoma". Cancer Lett. 197 (1–2): 63–8. doi:10.1016/S0304-3835(03)00085-5. PMID 12880961.
• Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Bustelo XR, Crespo P, López-Barahona M, et al. (1997). "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. doi:10.1038/sj.onc.1201430. PMID 9399639.
• Lavagna-Sévenier C, Marchetto S, Birnbaum D, Rosnet O (1998). "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. doi:10.1074/jbc.273.24.14962. PMID 9614102.
• Elly C, Witte S, Zhang Z, et al. (1999). "Tyrosine phosphorylation and complex formation of Cbl-b upon T cell receptor stimulation". Oncogene. 18 (5): 1147–56. doi:10.1038/sj.onc.1202411. PMID 10022120.
• Zhang Z, Elly C, Qiu L, et al. (1999). "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. doi:10.1016/S0960-9822(99)80090-6. PMID 10074432.
• Ettenberg SA, Keane MM, Nau MM, et al. (1999). "cbl-b inhibits epidermal growth factor receptor signaling". Oncogene. 18 (10): 1855–66. doi:10.1038/sj.onc.1202499. PMID 10086340.
• Wong ES, Lim J, Low BC, et al. (2001). "Evidence for direct interaction between Sprouty and Cbl". J. Biol. Chem. 276 (8): 5866–75. doi:10.1074/jbc.M006945200. PMID 11053437.
• Fang D, Wang HY, Fang N, et al. (2001). "Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells". J. Biol. Chem. 276 (7): 4872–8. doi:10.1074/jbc.M008901200. PMID 11087752.
• Ettenberg SA, Magnifico A, Cuello M, et al. (2001). "Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex". J. Biol. Chem. 276 (29): 27677–84. doi:10.1074/jbc.M102641200. PMID 11375397.
• Arron JR, Vologodskaia M, Wong BR, et al. (2001). "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. doi:10.1074/jbc.M100414200. PMID 11406619.
• Fang D, Liu YC (2001). "Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells". Nat. Immunol. 2 (9): 870–5. doi:10.1038/ni0901-870. PMID 11526404.
• Sattler M, Pride YB, Quinnan LR, et al. (2002). "Differential expression and signaling of CBL and CBL-B in BCR/ABL transformed cells". Oncogene. 21 (9): 1423–33. doi:10.1038/sj.onc.1205202. PMID 11857085.
• Yasuda T, Tezuka T, Maeda A, et al. (2002). "Cbl-b positively regulates Btk-mediated activation of phospholipase C-gamma2 in B cells". J. Exp. Med. 196 (1): 51–63. doi:10.1084/jem.20020068. PMC 2194016. PMID 12093870.
• Szymkiewicz I, Kowanetz K, Soubeyran P, et al. (2002). "CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases". J. Biol. Chem. 277 (42): 39666–72. doi:10.1074/jbc.M205535200. PMID 12177062.
• Haglund K, Shimokawa N, Szymkiewicz I, Dikic I (2002). "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. doi:10.1073/pnas.192462299. PMC 129420. PMID 12218189.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "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. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.