Yksinkertainen RING- tyyppinen E3 ubikitiiniligaasi CBL2 (RNF55)

RING-type single type E3 ubiquitin ligases

c-CBL,

CBL proto-oncogene, CBL2( 11q23.3.) https://www.ncbi.nlm.nih.gov/gene

Also known as

CBL2; NSLL; C-CBL; RNF55; FRA11B

Summary:  This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. 

This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016] Expression Broad expression in testis (RPKM 12.3), lymph node (RPKM 6.0) and 23 other tissues See more Orthologs mouse all

Preferred Names

E3 ubiquitin-protein ligase CBL

Names

Cas-Br-M (murine) ecotropic retroviral transforming sequence

Cbl proto-oncogene, E3 ubiquitin protein ligase

RING finger protein 55

RING-type E3 ubiquitin transferase CBL

casitas B-lineage lymphoma proto-oncogene

fragile site, folic acid type, rare, fra(11)(q23.3)

oncogene CBL2

proto-oncogene c-Cbl

signal transduction protein CBL

Conserved Domains (6) summary

cd09920
Location:256 → 352

SH2_Cbl-b_TKB; Src homology 2 (SH2) domain found in the Cbl-b TKB domain

cd14393
Location:857 → 896

UBA_c-Cbl; UBA domain found in E3 ubiquitin-protein ligase Cbl and similar proteins. Cbl, also called casitas B-lineage lymphoma proto-oncogene, proto-oncogene c-Cbl, RING finger protein 55, or signal transduction protein Cbl, is a multi-domain protein that acts as a key negative regulator of various receptor and non-receptor tyrosine kinases signaling. It contains a tyrosine kinase-binding domain (TKB), a proline-rich domain, a RING domain, and a ubiquitin-associated (UBA) domain. The TKB is responsible for the interactions with many tyrosine kinases, such as the colony-stimulating factor-1 (CSF-1) receptor, Syk/ZAP-70 and Src-family of protein tyrosine kinases. The proline-rich domain can recruit proteins with SH3 domain. Moreover, Cbl functions as an E3 ubiquitin ligase that can bind ubiquitin-conjugating enzymes (E2s) through RING domain.

pfam02262
Location:54 → 175

Cbl_N; CBL proto-oncogene N-terminal domain 1

pfam02761
Location:179 → 262

Cbl_N2; CBL proto-oncogene N-terminus, EF hand-like domain

cd16709
Location:362 → 427

RING-HC_Cbl-b; RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl-b and similar proteins .Structure:3ZNI; Homo sapiens cbl-b binds two Zn2+ ions through its RING-HC finger.

cl26464
Location:480 → 810

Atrophin-1; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteristic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

Region          381..419
                     /region_name="RING-HC finger (C3HC4-type)"
                     /note="RING-HC finger (C3HC4-type) [structural motif]"
                     /db_xref="CDD:319623"
     Site            order(381,384,396,398,401,404,416,419)
                     /site_type="other"
                     /note="Zn binding site [ion binding]"
                     /db_xref="CDD:319623"
 Region          857..896
                     /region_name="UBA_c-Cbl"
                     /note="UBA domain found in E3 ubiquitin-protein ligase Cbl
                     and similar proteins; cd14393"
                     /db_xref="CDD:270576"
ORIGIN      
        1 magnvkkssg agggsgsggs gsggliglmk dafqphhhhh hhlsphppgt vdkkmvekcw
       61 klmdkvvrlc qnpklalkns ppyildllpd tyqhlrtils ryegkmetlg eneyfrvfme
      121 nlmkktkqti slfkegkerm yeensqprrn ltklslifsh mlaelkgifp sglfqgdtfr
      181 itkadaaefw rkafgektiv pwksfrqalh evhpissgle amalkstidl tcndyisvfe
      241 fdiftrlfqp wssllrnwns lavthpgyma fltydevkar lqkfihkpgs yifrlsctrl
      301 gqwaigyvta dgnilqtiph nkplfqalid gfregfylfp dgrnqnpdlt glceptpqdh
      361 ikvtqeqyel ycemgstfql ckicaendkd vkiepcghlm ctscltswqe segqgcpfcr
      421 ceikgtepiv vdpfdprgsg sllrqgaega pspnyddddd eraddtlfmm kelagakver
      481 ppspfsmapq aslppvpprl dllpqrvcvp ssasalgtas kaasgslhkd kplpvpptlr
      541 dlppppppdr pysvgaesrp qrrplpctpg dcpsrdklpp vpssrlgdsw lprpipkvpv
      601 sapsssdpwt greltnrhsl pfslpsqmep rpdvprlgst fsldtsmsmn ssplvgpecd
      661 hpkikpsssa naiyslaarp lpvpklppge qcegeedtey mtpssrplrp ldtsqssrac
      721 dcdqqidsct yeamyniqsq apsitesstf gegnlaaaha ntgpeesene ddgydvpkpp
      781 vpavlarrtl sdisnasssf gwlsldgdpt tnvtegsqvp erppkpfprr inserkagsc
      841 qqgsgpaasa ataspqlsse ienlmsqgys yqdiqkalvi aqnniemakn ilrefvsiss
      901 pahvat
//

Related articles in PubMed

1. An Mtb-Human Protein-Protein Interaction Map Identifies a Switch between Host Antiviral and Antibacterial Responses. Penn BH, et al. Mol Cell, 2018 Aug 16. PMID 30118682,
2. Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL. Tan YC, et al. Sci Rep, 2017 Aug 23. PMID 28835699, Free PMC Article
3. De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy. Guey S, et al. J Med Genet, 2017 Aug. PMID 28343148
4. c-CBL E3 Ubiquitin Ligase Expression Increases Across the Spectrum of Benign and Malignant T-Cell Skin Diseases. Salva KA, et al. Am J Dermatopathol, 2017 Oct. PMID 27805921, Free PMC Article
5. c-CBL regulates melanoma proliferation, migration, invasion and the FAK-SRC-GRB2 nexus. Nihal M, et al. Oncotarget, 2016 Aug 16. PMID 27472394, Free PMC Article

See all (673) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. CBL gene status could be a potential target and indicator for MET inhibitors and future RTK regulation investigations, especially in those that will look into whether CBL should be evaluated before RTK inhibitors are considered.
2. The LMP2A of Epstein-Barr Virus was found to interfer with cofilin degradation in nasopharyngeal cancer cells by accelerating the proteasomal degradation of Cbl and Syk.
3. The host-Mycobacterium tuberculosis (Mtb) interaction map revealed two factors involved in Mtb pathogenesis-the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL.
4. C-CBL is likely to play a tumor suppressive role by antagonizing a robust oncogenic signaling driven by c-Src.
5. Our results suggested that c-Cbl can reverse tamoxifen resistance in HER2-overexpressing breast cancer cells
6. Study provided evidence suggesting that Cbl can positively control GM-CSF-induced JAK2 activation and signaling through JAK2 ubiquitination.
7. Cbl-b and c-Cbl downregulate PD-L1 in EGFR wild-type non-small cell lung cancer
8. Authors observed that delta-catenin plays a key role in EGFR stability and downstream signaling. delta-Catenin competes with c-Cbl for EGFR binding, which results in a reduction of binding between c-Cbl and EGFR and thus decreases the ubiquitination of EGFR.
9. its mutation is genetic predictor of tumor reduction in glucocorticoid-treated patients with chronic myelomonocytic leukemia.
10. c-CBL might play a role in the pathogenesis of inflammatory dermatoses and cutaneous T-cell lymphoma

Submit: New GeneRIF Correction See all GeneRIFs (209)

• Tubibakteerin kalvon lipoproteiini lpqN  ja Ubikitiiniligaasi CBL. Niiden suhde selvitetty. 

https://www.ncbi.nlm.nih.gov/pubmed/30118682/

Mol Cell. 2018 Aug 16;71(4):637-648.e5. doi: 10.1016/j.molcel.2018.07.010.

An Mtb-Human Protein-Protein Interaction Map Identifies a Switch between Host Antiviral and Antibacterial Responses.

Penn BH¹, Netter Z¹, et al.

Abstract

Although macrophages are armed with potent antibacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophage intrinsic bacterial control, and the Mtb strategies to overcome them, are poorly understood. To further study these processes, we used an affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two factors involved in Mtb pathogenesis-

the secreted Mtb protein, LpqN, and

its binding partner, the human ubiquitin ligase CBL.

We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl^-/- macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between antibacterial and antiviral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map for developing a deeper understanding of the intricate interactions between Mtb and its host.

Copyright © 2018 Elsevier Inc. All rights reserved.

 KEYWORDS:

Cbl; LpqN; host-pathogen interaction; macrophage; mycobacterium; protein-protein interaction; tuberculosis; ubiquitin

(29.5. 2019 Asetin tässtä abstraktista suomennoksen infektioista- blogiin)