IDENTIFICATION OF THE MAJOR TYROSINE KINASE SUBSTRATE IN SIGNALING COMPLEXES FORMED AFTER ENGAGEMENT OF FC-GAMMA RECEPTORS

We have recently identified the protein product of the c-cbl proto oncogene as an SH3 binding protein expressed in macrophages. To investigate the possibility that p120(c-cbl) is involved in signaling pathways initiated by cell surface receptors for IgG (Fc gamma R), lysates of HL60 cells were examined for tyrosine phosphorylation of p120(c-cbl) upon Fc gamma R engagement. Our findings demonstrate that p120(c-cbl) is tyrosine-phosphorylated upon Fc gamma R engagement and that this molecule represents the major tyrosine kinase substrate in this signaling pathway. Protein complexes containing p120(c-cbl), p72(syk), and p56(lyn) were observed either in resting or activated cells. In vitro studies showed that the direct association between p120(c-cbl) and p56(lyn) was mediated by the SH3 domain of p56(lyn).