Tyrosine phosphorylation of the product of the c-cbl protooncogenesis induced after integrin stimulation

Integrin crosslinking on human B cells induces tyrosine phosphorylation of a set of proteins ranging from 105 to 130 kDa, among which is the focal adhesion kinase p125(FAK). Here we show that the c-CBL protooncogene product p120(c-CBL) is a component of these substrates. β1 integrin stimulation of p120(c-CBL) phosphorylation was observed in both transformed and normal human B cells, and was inbibited by prior treatment of cells with cytochalasin B, which disrupts the actin network. In contrast, tyrosine phosphorylation of p120(c-CBL) following crosslinking of the B cell antigen receptor (BCR) was not affected by cytochalasin B. Integrin stimulation of the promegakaryocytic cell line MO7e also led to a cytoskeleton-dependent tyrosine phosphorylation of p120(c-CBL). In MO7e cells, this stimulation was induced by ligation of either β1 or β2 integrin, whereas only by ligation of β1 integrin in B cells. Tyrosine phosphorylation of p120(c-CBL) links phosphatidylinositol-3 kinase (pI-3K) with the BCR signalling machinery. Although the p85 subunit of PI-3K was increased in p120(c-CBL) immunoprecipitates from BCR-stimulated B cells, this association was only minimally increased by β1 integrin ligation. the function of p120(c-CBL) remains unknown; however, its interactions in vitro and in vivo with Src homology 2 and 3 (SH2 and SH3) domain-containing proteins suggest that p120(c-CBL) has a significant function in signal transduction pathways, and therefore may play a role in integrin signalling in lymphoid and hematopoietic cells.