CBL (gene)

Cbl (named after Casitas B-lineage Lymphoma) is a mammalian gene encoding 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. 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. 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. 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.