title: Heparin binding epidermal growth factor-like growth factor and PD169316 prevent apoptosis in mouse embryonic stem cells.
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.
authors.affiliation: Department of Biochemistry, The University of Georgia, Athens, GA 30605, USA.
authors.forename: Malini
authors.initials: M
authors.lastname: Krishnamoorthy
authors.forename: Jamie
authors.initials: J
authors.lastname: Heimburg-Molinaro
authors.forename: Ana M
authors.initials: AM
authors.lastname: Bargo
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Nash
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Nash
mesh_terms: 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
chemical_list: 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