title: Physiological epidermal growth factor concentrations activate high affinity receptors to elicit calcium oscillations.
abstract: Signaling mediated by the epidermal growth factor (EGF) is crucial in tissue development, homeostasis and tumorigenesis. EGF is mitogenic at picomolar concentrations and is known to bind its receptor on high affinity binding sites depending of the oligomerization state of the receptor (monomer or dimer). In spite of these observations, the cellular response induced by EGF has been mainly characterized for nanomolar concentrations of the growth factor, and a clear definition of the cellular response to circulating (picomolar) concentrations is still lacking. We investigated Ca2+ signaling, an early event in EGF responses, in response to picomolar doses in COS-7 cells where the monomer/dimer equilibrium is unaltered by the synthesis of exogenous EGFR. Using the fluo5F Ca2+ indicator, we found that picomolar concentrations of EGF induced in 50% of the cells a robust oscillatory Ca2+ signal quantitatively similar to the Ca2+ signal induced by nanomolar concentrations. However, responses to nanomolar and picomolar concentrations differed in their underlying mechanisms as the picomolar EGF response involved essentially plasma membrane Ca2+ channels that are not activated by internal Ca2+ store depletion, while the nanomolar EGF response involved internal Ca2+ release. Moreover, while the picomolar EGF response was modulated by charybdotoxin-sensitive K+ channels, the nanomolar response was insensitive to the blockade of these ion channels.
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, UM2 Aix Marseille Université, Marseille, France; INSERM, U1104, Marseille, France; CNRS, UMR7280, Marseille, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Marquèze-Pouey
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, UM2 Aix Marseille Université, Marseille, France; INSERM, U1104, Marseille, France; CNRS, UMR7280, Marseille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Mailfert
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, UM2 Aix Marseille Université, Marseille, France; INSERM, U1104, Marseille, France; CNRS, UMR7280, Marseille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Rouger
authors.affiliation: INSERM, UMR_S 1072, Marseille, France; Aix-Marseille Université, UNIS, Marseille, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Goaillard
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, UM2 Aix Marseille Université, Marseille, France; INSERM, U1104, Marseille, France; CNRS, UMR7280, Marseille, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Marguet
mesh_terms: D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007700:Kinetics
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D002118:Calcium