Working Paper Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 8 November 2019 / Approved: 10 November 2019 / Online: 10 November 2019 (10:28:11 CET)

How to cite: Uttagomol, J.; Ahmad, U.S.; Rehman, A.; Huang, Y.; Laly, A.C.; Kang, A.; Soetaert, J.; Chance, R.; Teh, M.; Connelly, J.T.; Wan, H. Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulating YAP and Phospho-YAP in Keratinocyte Responses to Mechanical Forces . Preprints 2019, 2019110105 Uttagomol, J.; Ahmad, U.S.; Rehman, A.; Huang, Y.; Laly, A.C.; Kang, A.; Soetaert, J.; Chance, R.; Teh, M.; Connelly, J.T.; Wan, H. Evidence for the Desmosomal Cadherin Desmoglein-3 in Regulating YAP and Phospho-YAP in Keratinocyte Responses to Mechanical Forces . Preprints 2019, 2019110105

Abstract

Desmoglein 3 (Dsg3) plays a crucial role in cell-cell adhesion and tissue integrity. Increasing evidence suggests that Dsg3 acts as a regulator of cellular mechanotransduction, but little is known about its direct role in mechanical force transmission. The present study investigated the impact of cyclic strain and substrate stiffness on Dsg3 expression and its role in mechanotransduction in keratinocytes. A direct comparison was made with E-cadherin, a well-characterized mechanosensor. Exposure of oral and skin keratinocytes to equiaxial cyclic strain promoted changes in expression and localization of junction assembly proteins. Knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. Importantly, the study demonstrated that Dsg3 regulates the expression and localization of YAP, a mechanosensor and an effector of the Hippo pathway. Furthermore, we showed that Dsg3 forms a complex with phospho-YAP and sequestered it to the plasma membrane, while Dsg3 depletion had an impact on both YAP and phospho-YAP in their response to mechanical forces, increasing the sensitivity of keratinocytes to strain- or substrate rigidity-induced nuclear relocation of YAP and phospho-YAP. PKP1 seemed to be crucial in recruiting the complex containing Dsg3/phospho-YAP to the cell surface since its silencing affected both Dsg3 junctional assembly with concomitant loss of phospho-YAP at cell periphery. Finally, we demonstrated that this Dsg3/YAP pathway has an influence on the expression of YAP1 target genes and cell proliferation. Together, these findings provide evidence of a novel role for Dsg3 in keratinocyte mechanotransduction.

Subject Areas

desmoglein; desmosome; adherens junction; YAP; Phospho-YAP; keratinocyte; cyclic strain; substrate stiffness

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.