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Journal of Biochemistry Advance Access published online on November 14, 2008
Journal of Biochemistry, doi:10.1093/jb/mvn153
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© The authors 2008. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

Heparin Binding Epidermal Growth Factor-like Growth Factor and PD169316 Prevent Apoptosis in Mouse Embryonic Stem Cells

Malini Krishnamoorthy2,5, Jamie Heimburg-Molinaro7, Ana M. Bargo3, Rachel J. Nash4,6 and Rodney J. Nash1,5,*

1Department of Animal and Dairy Sciences, 2Department of Biochemistry, 3Department of Statistics, 4Department of Health Promotion and Behavior, The University of Georgia, Athens, GA. 30605, 5Department of Anesthesiology, 6Department of Behavioral Science and Health Education, 7Department of Biochemistry, Emory University School of Medicine, Atlanta, GA. 30322

*To whom correspondence should be addressed. Dr. Rodney Nash PhD, Emory University Anesthesiology Labs, 2268 Crestcliff Dr. Tucker, GA 30084, Phone: 404-31-3046, Fax:404-712-2585, E-mail: rjnash{at}emory.edu

Received October 24, 2008; Accepted November 5, 2008


  Abstract

Apoptosis or programmed cell death is an important outcome of cell fate and is influenced by several factors. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family of growth factors and is synthesized as a membrane-associated precursor molecule (proHB-EGF). Under stressful conditions proHB-EGF is proteolytically cleaved and released as a soluble ligand (sHB-EGF) that activates the EGF receptor. We show that antibody against CD9, a membrane tetraspanin, induces apoptosis in mouse embryonic stem cells through the activation of specific EGF receptor residues (Y-1148 and Y-1173), caspase-3 and MAPK signaling. HB-EGF and the p38 inhibitor PD169316 act in a pro-survival manner by perturbing phosphorylation of EGFR Y-1173, suggesting its importance in inducing apoptosis. Caspase-3 activation was attenuated in the presence of HB-EGF and PD169316. Furthermore, HB-EGF and PD169316 prevent p38 phosphorylation while promoting the phosphorylation of the pro-survival SAPK/JNK and ERK. These results suggest a role for CD9 as an endogenous suppressor of apoptosis, an effect that is mimicked by HB-EGF and PD169316.

Key Words: Apoptosis, CD9, EGFR, HB-EGF, PD169316


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