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Journal of Biochemistry Advance Access originally published online on November 14, 2008
Journal of Biochemistry 2009 145(2):177-184; 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 Krishnamoorthy1,2, Jamie Heimburg-Molinaro3, Ana M. Bargo4, Rachel J. Nash5,6 and Rodney J. Nash2,7,*

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

*To whom correspondence should be addressed. Tel: +1-404-316-3046, Fax: +1-404-712-1351, E-mail: rjnash{at}emory.edu

Received October 24, 2008; Accepted November 24, 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 signalling. 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

Abbreviations: CD9, cluster of differentiation 9; EGF, epidermal growth factor; EGFR, EGF receptor; ES, embryonic stem; HB-EGF, heparin-binding epidermal growth factor-like growth factor; JNK/SAPK, c-Jun NH2-terminal kinase/stress-activated protein kinase; MAPK, mitogen-activated protein kinase; mESCs, mouse embryonic stem cells; RAJO, resistance as juxtacrine orientated


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