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Plakophilin 3 mediates Rap1-dependent desmosome assembly and adherens junction maturation.

Todorovic V, Koetsier JL, Godsel LM, Green KJ - Mol. Biol. Cell (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.

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Model for the role of Pkp3 in cell–cell junction formation. Left, activation of cAMP pathway upon cell–cell contact in high calcium leads to rapid recruitment of Pkp3-Rap1 complex to E-cad. At the same time, juxtamembrane DP coalesces at the sites of cell–cell contacts, requiring either Pkp2 or Pkp3, forming nascent desmosomes. Functional Pkp3-Rap1-E-cad complex drives adherens junction maturation by pulling the cells closer together and desmosome assembly by signaling the formation of cytoplasmic DP particles. On the other hand, Pkp3 acts as a spacer, preventing the aberrant coalescence of nascent desmosomes at the membrane. Pkp2 harnesses the activity of PKCα and RhoA to facilitate actin-dependent transport of cytoplasmic DP particles to the membrane. Right, model of steady-state adherens and desmosome junctions demonstrating mature cortical actin distribution and correctly sealed adherens junctions in the presence of Pkp3. In the absence of Pkp3 (not shown), Pkp3-Rap1-E-cad complex fails to assemble, leading to immature adherens junctions and failure of DP cytoplasmic particles to form. In addition, aberrant coalescence of nascent desmosomes occurs at the membrane.
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Figure 9: Model for the role of Pkp3 in cell–cell junction formation. Left, activation of cAMP pathway upon cell–cell contact in high calcium leads to rapid recruitment of Pkp3-Rap1 complex to E-cad. At the same time, juxtamembrane DP coalesces at the sites of cell–cell contacts, requiring either Pkp2 or Pkp3, forming nascent desmosomes. Functional Pkp3-Rap1-E-cad complex drives adherens junction maturation by pulling the cells closer together and desmosome assembly by signaling the formation of cytoplasmic DP particles. On the other hand, Pkp3 acts as a spacer, preventing the aberrant coalescence of nascent desmosomes at the membrane. Pkp2 harnesses the activity of PKCα and RhoA to facilitate actin-dependent transport of cytoplasmic DP particles to the membrane. Right, model of steady-state adherens and desmosome junctions demonstrating mature cortical actin distribution and correctly sealed adherens junctions in the presence of Pkp3. In the absence of Pkp3 (not shown), Pkp3-Rap1-E-cad complex fails to assemble, leading to immature adherens junctions and failure of DP cytoplasmic particles to form. In addition, aberrant coalescence of nascent desmosomes occurs at the membrane.

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).


Plakophilin 3 mediates Rap1-dependent desmosome assembly and adherens junction maturation.

Todorovic V, Koetsier JL, Godsel LM, Green KJ - Mol. Biol. Cell (2014)

Model for the role of Pkp3 in cell–cell junction formation. Left, activation of cAMP pathway upon cell–cell contact in high calcium leads to rapid recruitment of Pkp3-Rap1 complex to E-cad. At the same time, juxtamembrane DP coalesces at the sites of cell–cell contacts, requiring either Pkp2 or Pkp3, forming nascent desmosomes. Functional Pkp3-Rap1-E-cad complex drives adherens junction maturation by pulling the cells closer together and desmosome assembly by signaling the formation of cytoplasmic DP particles. On the other hand, Pkp3 acts as a spacer, preventing the aberrant coalescence of nascent desmosomes at the membrane. Pkp2 harnesses the activity of PKCα and RhoA to facilitate actin-dependent transport of cytoplasmic DP particles to the membrane. Right, model of steady-state adherens and desmosome junctions demonstrating mature cortical actin distribution and correctly sealed adherens junctions in the presence of Pkp3. In the absence of Pkp3 (not shown), Pkp3-Rap1-E-cad complex fails to assemble, leading to immature adherens junctions and failure of DP cytoplasmic particles to form. In addition, aberrant coalescence of nascent desmosomes occurs at the membrane.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 9: Model for the role of Pkp3 in cell–cell junction formation. Left, activation of cAMP pathway upon cell–cell contact in high calcium leads to rapid recruitment of Pkp3-Rap1 complex to E-cad. At the same time, juxtamembrane DP coalesces at the sites of cell–cell contacts, requiring either Pkp2 or Pkp3, forming nascent desmosomes. Functional Pkp3-Rap1-E-cad complex drives adherens junction maturation by pulling the cells closer together and desmosome assembly by signaling the formation of cytoplasmic DP particles. On the other hand, Pkp3 acts as a spacer, preventing the aberrant coalescence of nascent desmosomes at the membrane. Pkp2 harnesses the activity of PKCα and RhoA to facilitate actin-dependent transport of cytoplasmic DP particles to the membrane. Right, model of steady-state adherens and desmosome junctions demonstrating mature cortical actin distribution and correctly sealed adherens junctions in the presence of Pkp3. In the absence of Pkp3 (not shown), Pkp3-Rap1-E-cad complex fails to assemble, leading to immature adherens junctions and failure of DP cytoplasmic particles to form. In addition, aberrant coalescence of nascent desmosomes occurs at the membrane.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.

Show MeSH
Related in: MedlinePlus