14-3-3 proteins regulate desmosomal adhesion via plakophilins

Abstract

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 to be essential for desmosome dynamics. However, the mechanisms of 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 (PKP1 and PKP3) 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 PKP1 phosphorylated at S155 and destabilized intercellular cohesion of keratinocytes by reducing its incorporation into desmosomes. In contrast, 14-3-3σ (also known as stratifin, encoded by ) interacted preferentially with S285-phosphorylated PKP3 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.

Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulating YAP and Phospho-YAP in Keratinocyte Responses to Mechanical Forces

“…Importantly, our findings have identified that Dsg3 serves as an upstream regulator of YAP/pYAP and forms a complex with and sequesters pYAP to the plasma membrane, a process that involves PKPs, to facilitate AJ assembly ( Figure 10). A recent report has identified that the desmosomal plaque proteins PKP1/3 bind to 14-3-3γ/σ isoforms that are required in desmosome adhesion [45]. Another independent study has shown that PKPs interact directly with the cytoplasmic tail of Dsg1-3 [46].…”

The desmosomal cadherin Desmoglein-3 regulates YAP and phospho-YAP in keratinocyte responses to mechanical forces

“…10). A recent report has identified that the desmosomal plaque proteins PKP1/3 bind to 14-3-3γ/σ isoforms that are required in desmosome adhesion [42]. Another independent study has shown that PKPs interact directly with the cytoplasmic tail of Dsg1-3 [4].…”

Noninvasive analysis of skin proteins in healthy Chinese subjects using an Orbitrap Fusion Tribrid mass spectrometer

“…In this study, we also detected desmoplakin (DP), junction plakoglobin, plakophilin‐1, and envoplakin on the volar forearm skin of the volunteers. DP is an obligate component of desmosomes and is essential for strong intercellular adhesion . In the epidermis, the adhesive strength of desmosomes is controlled by plakophilin (PKP) isoform expression, which facilitates the tissue remodeling that is required during regeneration and wound healing .…”

“…36 In the epidermis, the adhesive strength of desmosomes is controlled by plakophilin (PKP) isoform expression, which facilitates the tissue remodeling that is required during regeneration and wound healing. 36 Envoplakin plays a role in cell-to-cell adhesion, and the plakin repeat domain (PRD) of envoplakin is the key to direct attachment of membranes to the cytoskeleton. 37 Corneodesmolysis is also usually associated with CE maturation and ultimately desquamation.…”

“…DP is an obligate component of desmosomes and is essential for strong intercellular adhesion . In the epidermis, the adhesive strength of desmosomes is controlled by plakophilin (PKP) isoform expression, which facilitates the tissue remodeling that is required during regeneration and wound healing . Envoplakin plays a role in cell‐to‐cell adhesion, and the plakin repeat domain (PRD) of envoplakin is the key to direct attachment of membranes to the cytoskeleton .…”