Cbl gene

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Cas-Br-M (murine) ecotropic retroviral transforming sequence
PDB rendering based on 1b47.
Available structures: 1b47, 1fbv, 1yvh, 2cbl, 2oo9
Identifiers
Symbol(s) CBL; C-CBL; CBL2; RNF55
External IDs OMIM: 165360 MGI: 88279 HomoloGene: 3802
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 867 12402
Ensembl ENSG00000110395 n/a
Uniprot P22681 n/a
Refseq NM_005188 (mRNA)
NP_005179 (protein)		 XM_001001857 (mRNA)
XP_001001857 (protein)
Location Chr 11: 118.58 - 118.68 Mb n/a
Pubmed search [1] [2]

Cbl (named after Casitas B-lineage Lymphoma) is a mammalian gene encoding several proteins involved in cell signalling and protein ubiquitination. Mutations to this gene have been implication in a number of human cancers, particularly acute myeloid leukaemia.

Contents

[edit] Discovery

In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered[1] and was named v-Cbl to distinguish it from normal mouse c-Cbl. The virus used in the experiment was a retrovirus known as Cas-Br-M, and was found to have excised approximately a third of the original c-Cbl gene from mice it was injected into. 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 tumour 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.

[edit] Structure

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

  • N-terminal tyrosine kinase binding domain (TKB domain): determines the protein which it can bind to
  • RING finger domain motif: recruits enzymes involved in ubiquitination
  • Proline-rich region: the site of interaction between Cbl and cytosolic proteins involved in Cbl's adaptor functions
  • C-terminal ubiquitin-associated domain (UBA domain): the site of ubiquitin binding

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.[2]

[edit] Homologues

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 amino acids in length.
  2. Cbl-b: ubiquitously expressed, 982 amino acids long in length.
  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.

Interestingly, 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[2].

[edit] Functions

[edit] Ubiquitin ligase

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.

[edit] References

  1. ^ 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. doi:10.1073/pnas.86.4.1168. PMID 2784003. 
  2. ^ a b Schmidt MH, Dikic I (2005). "The Cbl interactome and its functions". Nat. Rev. Mol. Cell Biol. 6 (12): 907–18. doi:10.1038/nrm1762. PMID 16227975. 

[edit] Further reading

  • Smit L, Borst J (1998). "The Cbl family of signal transduction molecules.". Critical reviews in oncogenesis 8 (4): 359–79. PMID 9622055. 
  • Lupher ML, Andoniou CE, Bonita D, et al. (1998). "The c-Cbl oncoprotein.". Int. J. Biochem. Cell Biol. 30 (4): 439–44. PMID 9675877. 
  • Fang N, Fang D, Wang HY, et al. (2002). "Regulation of immune responses by E3 ubiquitin-protein ligases.". Curr. Dir. Autoimmun. 5: 161–75. PMID 11826757.