Desmosomes are essential for strong intercellular adhesion and are abundant in tissues exposed to mechanical strain. At the same time, desmosomes need to be dynamic to allow for remodeling of epithelia during differentiation or wound healing. Phosphorylation of desmosomal plaque proteins appears essential for desmosome dynamics. However, the mechanisms how context-dependent post-translational modifications regulate desmosome formation, dynamics or stability are incompletely understood. Here, we show that growth factor signaling regulates the phosphorylation-dependent association of plakophilins 1 and 3 with 14-3-3 protein isoforms and uncover unique and partially antagonistic functions of members of the 14-3-3 family in the regulation of desmosomes. 14-3-3γ associated primarily with cytoplasmic plakophilin 1 phosphorylated at S155 and destabilized intercellular cohesion of keratinocytes by reducing its incorporation into desmosomes. In contrast, stratifin/14-3-3σ interacted preferentially with S285-phosphorylated plakophilin 3 to promote its accumulation at tricellular contact sites, leading to stable desmosomes. Taken together, our study identifies a new layer of regulation of intercellular adhesion by 14-3-3 proteins.

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