CBL (gene)

In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered 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, 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 ==

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. == 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 and 913 amino acids in length in humans and mice respectively • Cbl-b: ubiquitously expressed, 982 amino acids long. • 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. == Function ==

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. == Interactions ==

Cbl gene has been shown to interact with: • Abl gene, • ARHGEF7, • C-Met, • CD2AP, • CSF1R. • CRK, • CRKL, • EGFR, • FRS2, • FYN, • Grb2, • HCK, • IGF1R, • LCP2, • NCK1, • PIK3R1, • PIK3R2, • PLCG1, • PTK2B, • PTPN11, • SH2B2, • SH3KBP1 • SHC1, • SLA2, • SORBS1, • SORBS2, • Syk, • UBE2L3, • VAV1, • YWHAB, and • ZAP-70, == References ==