THE PROTEIN PRODUCT OF THE PROTOONCOGENE C-CBL FORMS A COMPLEX WITH PHOSPHATIDYLINOSITOL 3-KINASE P85 AND CD19 IN ANTI-IGM-STIMULATED HUMANB-LYMPHOMA CELLS

Multiple signal transduction cascades, consisting of multiple interact ing proteins, are activated following stimulation through most cell su rface receptors, including the immunoglobulin receptor of B lymphocyte s. In this report, we investigated the multimolecular complexes formed following anti-Ig stimulation of a human B-lymphoma cell line, result ing in activation of phosphatidylinositol 3-kinase (PI3K). PI3K is a l ipid kinase that consists of an 85-kD regulatory subunit, bound to a 1 10-kD catalytic subunit. CD19 is a 95-kD B-cell surface marker that co ntains a consensus binding motif for PI3Kp85 in the cytoplasmic domain and recruits PI3K activity in activated B cells. The protein product of the c-cbl protooncogene is a 129-kD protein that is expressed in ea rly B-lineage cells and in myeloid cells and is phosphorylated on tyro sine following receptor-mediated signaling in T and B lymphocytes, We demonstrate here that phosphorylated c-cbl complexes with CD19 and wit h PI3Kp85 via its C-terminal SH2 domain, and that both c-cbl and CD19 are associated with active P13K in anti-Ig-stimulated cells, Although we cannot differentiate between a three-component, c-cbl/CD19/p85 comp lex and individual two-component complexes, these studies suggest that c-cbl may function as a docking protein, possibly linking distinct si gnal transduction pathways.