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CBL (gene)

From Wikipedia - Reading time: 17 min

"CBL2" redirects here. For the airport in Canada, see Severn Bridge/Buck Lake Water Aerodrome.
CBL
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCBL, C-CBL2, FRA11B, NSLL, RNF55, Cbl proto-oncogene
External IDsOMIM: 165360; MGI: 88279; HomoloGene: 3802; GeneCards: CBL; OMA:CBL - orthologs
Orthologs
SpeciesHumanMouse
Entrez

867

12402

Ensembl

ENSG00000110395

ENSMUSG00000034342

UniProt

P22681

P22682

RefSeq (mRNA)

NM_005188

NM_007619

RefSeq (protein)

NP_005179

NP_031645

Location (UCSC)Chr 11: 119.21 – 119.31 MbChr 9: 44.05 – 44.15 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cbl (named after Casitas B-lineage Lymphoma) is a mammalian gene family. CBL gene, a part of the Cbl family, encodes the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.[5]

Discovery

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In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered[6] and was named v-Cbl to distinguish it from normal mouse c-Cbl. The virus used in the experiment was a mouse-tropic strain of Murine leukemia virus isolated from the brain of a mouse captured at Lake Casitas, California known as Cas-Br-M,[7] and was found to have excised approximately a third of the original c-Cbl gene from a mouse into which it was injected. Sequencing revealed that the portion carried by the retrovirus encoded a tyrosine kinase binding domain, and that this was the oncogenic form as retroviruses carrying full-length c-Cbl did not induce tumor formation. The resultant transformed retrovirus was found to consistently induce a type of pre-B lymphoma, known as Casitas B-lineage lymphoma, in infected mice.

Structure

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Full length c-Cbl has been found to consist of several regions encoding for functionally distinct protein domains:

This domain structure and the tyrosine and serine-rich content of the protein product is typical of an "adaptor molecule" used in cell signalling pathways.[8]

Homologues

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Three mammalian homologues have been characterized, which all differ in their ability to function as adaptor proteins due to the differing lengths of their C-terminal UBA domains:

  1. c-Cbl: ubiquitously expressed, 906 and 913 amino acids in length in humans and mice respectively
  2. Cbl-b: ubiquitously expressed, 982 amino acids long.
  3. Cbl-c: lacks the UBA domain and is therefore only 474 amino acids in length. It is primarily expressed in epithelial cells however its function is poorly understood.

Both c-Cbl and Cbl-b have orthologues in D. melanogaster (D-Cbl) and C. elegans (Sli-1), hinting at a long evolutionary path for these proteins.[8]

Function

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Ubiquitin ligase

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Ubiquitination is the process of chemically attaching ubiquitin monomers to a protein, thereby targeting it for degradation. As this is a multi-step process, several different enzymes are involved, the final one being a member of the E3 family of ligases. Cbl functions as an E3 ligase, and therefore is able to catalyse the formation of a covalent bond between ubiquitin and Cbl's protein substrate - typically a receptor tyrosine kinase. The RING-finger domain mediates this transfer, however like other E3 ligases of the RING type no intermediate covalent bond is formed between ubiquitin and the RING-finger domain. The stepwise attachment of ubiquitin to the substrate receptor tyrosine kinase can lead to its removal from the plasma membrane and subsequent trafficking to the lysosome for degradation.

Interactions

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Cbl gene has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000110395 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034342 – 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.
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  6. ^ Langdon WY, Hartley JW, Klinken SP, Ruscetti SK, Morse HC (1989). "v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas". Proc. Natl. Acad. Sci. U.S.A. 86 (4): 1168–72. Bibcode:1989PNAS...86.1168L. doi:10.1073/pnas.86.4.1168. PMC 286647. PMID 2784003.
  7. ^ Hartley JW, Rowe WP (July 1976). "Naturally occurring murine leukemia viruses in wild mice: characterization of a new "amphotropic" class". Journal of Virology. 19 (1): 21. doi:10.1128/JVI.19.1.19-25.1976. PMC 354828. PMID 59816.
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