Plakophilin 3 phosphorylation by ribosomal S6 kinase supports desmosome assembly

Abstract

Desmosome remodeling is crucial for epidermal regeneration, differentiation and wound healing. It is mediated by adapting the composition and by posttranslational modifications of constituent proteins. We have previously demonstrated that plakophilin 1 (PKP1) mediates strong adhesion in suprabasal keratinocytes which is negatively regulated by insulin-like growth factor-1 (IGF1) signaling. The importance of PKP3 for epidermal adhesion is incompletely understood. Here, we identify a major role of epidermal growth factor (EGF) but not IGF1 signaling in PKP3 recruitment to the plasma membrane to facilitate desmosome assembly. We find that ribosomal S6 kinase (RSK) associates with and phosphorylates PKP3 which promotes PKP3 association with desmosomes downstream of the EGF-receptor. Knockdown of RSKs as well as mutation of a RSK phosphorylation site in PKP3 interfered with desmosome formation, maturation and adhesion. Our findings implicate a coordinate action of distinct growth factors in the control of adhesive properties of desmosomes through modulation of PKPs in a context-dependent manner.