Identification of HB-EGF - Rac1 - c-Myc signalling pathway in growing human keratinocytes

The functions of the autocrine growth factor Heparin Binding-Epidermal Growth Factor (HB-EGF), the Rho guanosine triphosphatase Rac1 and the transcription factor c-Myc have been extensively studied in epidermal keratinocytes. Each of the three proteins has been found to mediate both pro proliferative and pro migratory effects and to accelerate the process of wound healing. Despite the established functions of HB-EGF, Rac1 and c-Myc appear to complement one another, the possible functional connection between the three proteins has never been examined. Herewith we are the first to establish the existence of a functional link between HB-EGF, Rac1 and c-Myc. We have found that siRNA-mediated Rac1 knock down in growing human keratinocytes causes accumulation of the endogenous HB-EGF protein and inhibits c-Myc- Ser62/Thr58 phosphorylation. We have observed for the first time that the treatment with exogenous HB-EGF induces Ser62/Thr58 phosphorylation of c-Myc and this effect is then mediated by Rac1. Our results suggest the existence of HB-EGF-Rac1-c-Myc axis in human keratinocytes proliferation and migration.