Heparin binding epidermal growth factor-like growth factor and PD169316 prevent apoptosis in mouse embryonic stem cells.
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.
Krishnamoorthy
Malini
M
Department of Biochemistry, The University of Georgia, Athens, GA 30605, USA.
Heimburg-Molinaro
Jamie
J
Bargo
Ana M
AM
Nash
Rachel J
RJ
Nash
Rodney J
RJ
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D004622:Embryo, Mammalian / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D066257:Heparin-binding EGF-like Growth Factor; D007093:Imidazoles / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D034622:RNA Interference; D060245:Tetraspanin 29; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D015703:Antigens, CD; C554870:Cd9 protein, mouse; D004791:Enzyme Inhibitors; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D060245:Tetraspanin 29; D048051:p38 Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole