THE PROTEIN PRODUCT OF THE C-CBL PROTOONCOGENE IS PHOSPHORYLATED AFTER B-CELL RECEPTOR STIMULATION AND BINDS THE SH3 DOMAIN OF BRUTONS TYROSINE KINASE

X-linked agammaglobulinemia, a B cell immunodeficiency, is caused by m utations in the Bruton's tyrosine kinase (Btk) gene. The absence of a functional Btk protein leads to a failure of B cell differentiation an d antibody production. B cell receptor stimulation leads to the phosph orylation of the Btk protein and it is, therefore, likely that Btk is involved in B cell receptor signaling. As a nonreceptor tyrosine kinas e, Btk is likely to interact with several proteins within the context of a signal transduction pathway. To understand such interactions, we have generated glutathione S-transferase fusion proteins corresponding to different domains of the human Btk protein. We have identified a 1 20-kD protein present in human B cells as being bound by the SH3 domai n of Btk and which, after B cell receptor stimulation, is one of the m ajor substrates of tyrosine phosphorylation. We have shown that this 1 20-kD protein is the protein product of c-cbl, a protooncogene, which is known to be phosphorylated in response to T cell receptor stimulati on and to interact with several other tyrosine kinases. Association of the SH3 domain of Btk with p120(cbl) provides evidence for an analogo us role for p120(cbl) in B cell signaling pathways. The p120(cbl) prot ein is the first identified ligand of the Btk SH3 domain.