The Apoptosis-inducing Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF) Analog E21R Functions through Specific Regions of the Heterodimeric GM-CSF Receptor and Requires Interleukin-1β-converting Enzyme-like Proteases

• Published in: The Journal of biological chemistry 1997-04, Vol.272 (15), p.9877-9883
• Main Authors: Iversen, Per O., Hercus, Timothy R., Zacharakis, Betty, Woodcock, Joanna M., Stomski, Frank C., Kumar, Sharad, Nelson, Brad H., Miyajima, Atsushi, Lopez, Angel F.
• Format: Article
• Language: English
• ISSN: 0021-9258
• DOI: 10.1074/jbc.272.15.9877

The granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R induces apoptosis of hemopoietic cells. We examined the GM-CSF receptor subunit requirements and the signaling molecules involved. Using Jurkat T cells transfected with the GM-CSF receptor we found that both receptor subunits were necessary for E21R-induced apoptosis. Specifically, the 16 membrane-proximal residues of the alpha subunit were sufficient for apoptosis. This sequence could be replaced by the corresponding sequence from the interleukin-2 receptor common gamma subunit, identifying this as a conserved cytokine motif necessary for E21R-induced apoptosis. Cells expressing the alpha subunit and truncated beta c mutants showed that the 96 membrane-proximal residues of beta c were sufficient for apoptosis. E21R, in contrast to GM-CSF, did not alter tyrosine phosphorylation of beta c, suggesting that receptor-associated tyrosine kinases were not activated. Consistent with this, E21R decreased the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase). E21R-induced apoptosis was independent of Fas/APO-1 (CD95) and required interleukin-1 beta -converting enzyme (ICE)-like proteases. In contrast, Bcl-2, which protects cells from growth factor deprivation-induced cell death, did not prevent this apoptosis. These findings demonstrate the GM-CSF receptor and ICE-like protease requirements for E21R-induced apoptosis.