c-Cbl is tyrosine-phosphorylated by interleukin-4 and enhances mitogenic and survival signals of interleukin-4 receptor by linking with the phosphatidylinositol 3'-kinase pathway.

Interleukin-4 (IL-4) is a cytokine that induces both proliferation and differentiation and suppresses apoptosis of B cells. Although IL-4 has been shown to activate the phosphatidylinositol 3' (PI3)-kinase pathway, the role of PI3 kinase in the IL-4 receptor (IL-4R) signaling remains unclear. In this study, we demonstrated that c-Cbl proto-oncogene ...
product is inducibly phosphorylated on tyrosine residues and is associated with the p85 subunit of PI3-kinase by IL-4 stimulation. Overexpression of c-Cbl enhances the PI3-kinase activity and, at the same time, mitogenic activity and survival of cells in the presence of IL-4. However, these effects of c-Cbl were abolished by wortmannin, a specific inhibitor for the PI3 kinase pathway, or by a point mutation at tyrosine 731 of c-Cbl, which is a major binding site for p85. These results indicate that c-Cbl plays a role in linking IL-4R with the PI3 kinase pathway and thus enhancing the mitogenic and survival signals.
Mesh Terms:
Androstadienes, Animals, Apoptosis, Cell Differentiation, Cell Division, Cell Line, Enzyme Inhibitors, Hematopoietic Stem Cells, Interleukin-4, Mice, Phosphatidylinositol 3-Kinases, Phosphorylation, Phosphotyrosine, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Receptors, Interleukin-4, Signal Transduction, Ubiquitin-Protein Ligases, ras Proteins
Blood
Date: Jan. 01, 1998
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