Emerging functions of Plakophilin 4 in the control of cell contact dynamics.

Plakophilin 4 (PKP4, also called p0071) is a unique armadillo family protein localized at adherens junctions that acts as a scaffold protein capable of clustering cadherins. PKP4 also regulates cadherin recycling which is vital to enable junction dynamics. In addition, PKP4 controls the mechanical properties of cells by regulating actin filament organization through small Rho-GTPases. In this setting, PKP4 controls the localization and activity of specific guanine exchange factors (GEFs) and of their opponents, the GTPase activating proteins (GAPs). Through the formation of multiprotein complexes with Rho-GTPases, their regulators and their effectors, PKP4 controls the spatio-temporal activity of Rho signaling to regulate cell adhesion and cell mechanics. In keratinocytes, PKP4 prevents differentiation and at the same time dampens proliferation. This is, in part achieved through an interaction with the Hippo pathway, which controls the activity of the transcriptional co-factors YAP and TAZ. In a feedback loop, YAP/TAZ modulate PKP4 localization and function. Here, we review the various functions of PKP4 in cell signaling, cell mechanics, cell adhesion and growth control. We discuss how these functions converge in the regulation of cell adhesion dynamics to allow cells to adapt to their changing environment and enable proliferation, delamination but, at the same time, guarantee cell barrier function.