Cbl gene

"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.

Discovery

In 1989 a virally encoded portion of the chromosomal mouse "Cbl" gene was the first member of the Cbl family to be discoveredcite journal | author = Langdon WY, Hartley JW, Klinken SP, Ruscetti SK, Morse HC | title = v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 86 | issue = 4 | pages = 1168–72 | year = 1989 | pmid = 2784003 | doi = 10.1073/pnas.86.4.1168 | issn = ] 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.

tructure

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.cite journal | author = Schmidt MH, Dikic I | title = The Cbl interactome and its functions | journal = Nat. Rev. Mol. Cell Biol. | volume = 6 | issue = 12 | pages = 907–18 | year = 2005 | pmid = 16227975 | doi = 10.1038/nrm1762 | issn = ]

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:
# c-Cbl: ubiquitously expressed, 906 amino acids in length.
# Cbl-b: ubiquitously expressed, 982 amino acids long in length.
# 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 ] .

Functions

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.

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Smit L, Borst J |title=The Cbl family of signal transduction molecules. |journal=Critical reviews in oncogenesis |volume=8 |issue= 4 |pages= 359–79 |year= 1998 |pmid= 9622055 |doi=
*cite journal | author=Lupher ML, Andoniou CE, Bonita D, "et al." |title=The c-Cbl oncoprotein. |journal=Int. J. Biochem. Cell Biol. |volume=30 |issue= 4 |pages= 439–44 |year= 1998 |pmid= 9675877 |doi=
*cite journal | author=Fang N, Fang D, Wang HY, "et al." |title=Regulation of immune responses by E3 ubiquitin-protein ligases. |journal=Curr. Dir. Autoimmun. |volume=5 |issue= |pages= 161–75 |year= 2002 |pmid= 11826757 |doi=

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