The cbl oncogene: a novel substrate of protein tyrosine kinases.

Abstract

The cbl oncogene was first identified as part of a transforming retrovirus which arose in a mouse pre-B cell lymphoma. Its protein product, p120cbl, is cytoplasmic and has several distinctive domains including a highly basic region, a RING finger motif and a large proline-rich domain. A mutation to cbl in the 70Z/3 pre-B cell lymphoma produces an oncogenic protein which exhibits a marked enhancement of tyrosine phosphorylation. Parallel studies have demonstrated that p120cbl is a substrate of protein Tyrosine kinases activated by engagement of the T cell antigen receptor and that cbl is phosphorylated by oncogenic forms of the Abl tyrosine kinase. These studies also demonstrated a constitutive association between cbl and the SHS domains of the Grb2 and Nck adaptor proteins in a range of haemopoietic cell lines. More recently it has been found that cbl is rapidly phosphorylated following stimulation of the EGF receptor, Fcy receptor, c-Kit receptor and CSF-1 receptor. A genetic analysis in Caenorhabditis elegans has identified a cbl homologue, called sli-1, that negatively regulates the LET-23 tyrosine kinase receptor. These characteristics indicate a central role for cbl in the regulation of intracellular signals that are mediated by growth factors and antigenic stimuli which activate protein tyrosine kinases.