Plakophilin 3 mediates Rap1-dependent desmosome assembly and adherens junction maturation.
Bottom Line: Moreover, Pkp3 forms a complex with Rap1 GTPase, promoting its activation and facilitating desmosome assembly.We show further that Pkp3 deficiency causes disruption of an E-cadherin/Rap1 complex required for adherens junction sealing.These findings reveal Pkp3 as a coordinator of desmosome and adherens junction assembly and maturation through its functional association with Rap1.
Affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.Show MeSH
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Mentions: The differences in phenotypes of Pkp2 and Pkp3 KD cells suggest that, despite some redundant roles, plakophilins serve as scaffolds for specific signaling molecules. In this role they regulate spatiotemporal distribution as well as the activity status of the signaling complexes they tether in order to accomplish cell–cell junction assembly and maintenance. We show here that Pkp2 and 3 differ in the signaling partners they harness, as well as in the phase of desmosome assembly they regulate. Whereas Pkp3-dependent activation of Rap1 is required for formation of DP-containing desmosome precursors in the cytoplasm as well as size stabilization of nascent desmosomes, Pkp2 helps to transfer already formed precursors from the cytoplasm to sites of cell–cell contacts by harnessing PKC and RhoA activity (Figures 2–6 and see later discussion of Figure 9; Bass-Zubek et al., 2008; Godsel et al., 2010). Therefore Pkp3 ablation leads to an apparent loss of cytoplasmic desmosome precursors, precluding phases 2 and 3 of desmosome assembly. On the other hand, Pkp2 silencing affects only the ultimate phase of the assembly by preventing the transport of the formed precursors to the membrane. The ablation of both Pkps results in failure of phase 1, as no DP is observed at the sites of cell–cell contact (Figure 2).
Affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.