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

Abstract

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.

Keywords: Adherens junctions; Cell adhesion; Cell mechanics; GAPs; GEFs; Hippo pathway; Keratinocytes; Plakophilin 4 (p0071); Rho signaling; YAP/TAZ.

Fig. 1

Overview about PKP4 functions and protein interactions. (A) Schematic depicting the various cellular processes regulated by PKP4. (B) Summary of PKP4 protein interactions involved in intercellular adhesion, intracellular transport, Rho- and Hippo signaling

Fig. 2

PKP4 functions in intracellular transport and recycling. (A) PKP4 interacts with Rab11-expressing endosomes to promote myosin-Vb (MYO5B)-mediated transport. (B) Schematic depicting the role of PKP4 in mediating E-cadherin transport and recycling during AJ formation, at steady state and during recycling. (C) PKP4 stabilizes the interaction of KIF3 motor proteins and the cargo adapter KAP3

Fig. 3

PKP4 functions in the local control of Rho activity. (A) Schematic depicting the role of PKP4 in supporting a GEFH1-RhoA-ROCK-MLC signaling axis to promote cortical actin ring formation and actomyosin-generated tension in basal keratinocytes. (B) During cytokinesis, PKP4 facilitates Ect2-mediated local RhoA activation at the cleavage furrow to enable abscission of the two daughter cells

Fig. 4

Role of PKP4 and Hippo signaling in epidermal keratinocytes. (A) Left panel: schematic depicting the roles of PKP4 in Rho- and Hippo signaling pathways in basal keratinocytes. PKP4 inhibits Hippo signaling. Inactive LATS promotes YAP/TAZ nuclear translocation and activation of YAP/TEAD target gene transcription that control cell proliferation. Right panel: suprabasal keratinocytes lack PKP4 expression. This leads to the activation of the Hippo pathway. The MST kinase phosphorylates LATS, which in turn phosphorylates YAP. Phosphorylated YAP becomes degraded. YAP/TEAD target genes are not expressed which facilitates differentiation. (B) Overview of YAP signaling regulators (upper row), interdependence of YAP signaling with other signaling pathways (middle row) and major effects of YAP signaling in the epidermis (lower row)