CLONING AND CHARACTERIZATION OF CBL-B : A SH3 BINDING PROTEIN WITH HOMOLOGY TO THE C-CBL PROTO-ONCOGENE

We have cloned a new gene, cbl-b, with homology to the c-cbl proto-oncogene. A large protein is predicted (approx. MW 108,000) that has a proline rich domain, a nuclear localization signal, a C3HC4 zinc finger and a putative leucine zipper. There is striking nucleotide and amino acid homology to the c-cbl proto-oncogene most notably in the structural motifs described above. Cbl-b is expressed in normal and malignant mammary epithelial cells, in a variety of normal tissues, and in hematopoietic tissue and cell lines. Cbl-b expressions is up-regulated with macrophage/monocyte differentiation of the HL60 and U937 cell lines. There is direct association of the cbl-b protein with the Src Homology 3 domains of several proteins including signaling, cytoskeletal and adaptor proteins. Our data suggest that cbl-b encodes a protein which can interact with signal transduction proteins to regulate their function or to be regulated by them. Together, cbl-b and c-cbl are members of a novel family of proto-oncogenes involved in signal transduction.