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

H Ueno; K Sasaki; H Honda; T Nakamoto; T Yamagata; K Miyagawa; K Mitani; Y Yazaki; H Hirai

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

Blood. 1998 Jan 1;91(1):46-53.

Authors

H Ueno¹, K Sasaki, H Honda, T Nakamoto, T Yamagata, K Miyagawa, K Mitani, Y Yazaki, H Hirai

Affiliation

¹ Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.

PMID: 9414268

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androstadienes / pharmacology
Animals
Apoptosis / drug effects
Cell Differentiation / drug effects
Cell Division / drug effects
Cell Line
Enzyme Inhibitors / pharmacology
Hematopoietic Stem Cells / drug effects
Interleukin-4 / pharmacology*
Interleukin-4 / physiology
Mice
Phosphatidylinositol 3-Kinases / physiology*
Phosphorylation / drug effects
Phosphotyrosine / metabolism
Protein Processing, Post-Translational* / drug effects
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-cbl
Receptors, Interleukin-4 / drug effects*
Receptors, Interleukin-4 / physiology
Signal Transduction / drug effects
Ubiquitin-Protein Ligases*
Wortmannin
ras Proteins / metabolism

Substances

Androstadienes
Enzyme Inhibitors
Proto-Oncogene Proteins
Receptors, Interleukin-4
Interleukin-4
Phosphotyrosine
Proto-Oncogene Proteins c-cbl
Ubiquitin-Protein Ligases
Phosphatidylinositol 3-Kinases
ras Proteins
Cbl protein, mouse
Wortmannin