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Plakophilin 2 couples actomyosin remodeling to desmosomal plaque assembly via RhoA.

Godsel LM, Dubash AD, Bass-Zubek AE, Amargo EV, Klessner JL, Hobbs RP, Chen X, Green KJ - Mol. Biol. Cell (2010)

Bottom Line: Plakophilin 2 (PKP2), an armadillo family member closely related to p120 catenin (p120ctn), is a constituent of the intercellular adhesive junction, the desmosome.We demonstrate that PKP2 knockdown impairs cortical actin remodeling after cadherin ligation, without affecting p120ctn expression or localization.Together with our previous findings, these data suggest that PKP2 may functionally link RhoA- and PKC-dependent pathways to drive actin reorganization and regulate DP-IF interactions required for normal desmosome assembly.

View Article: PubMed Central - PubMed

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

ABSTRACT
Plakophilin 2 (PKP2), an armadillo family member closely related to p120 catenin (p120ctn), is a constituent of the intercellular adhesive junction, the desmosome. We previously showed that PKP2 loss prevents the incorporation of desmosome precursors enriched in the plaque protein desmoplakin (DP) into newly forming desmosomes, in part by disrupting PKC-dependent regulation of DP assembly competence. On the basis of the observation that DP incorporation into junctions is cytochalasin D-sensitive, here we ask whether PKP2 may also contribute to actin-dependent regulation of desmosome assembly. We demonstrate that PKP2 knockdown impairs cortical actin remodeling after cadherin ligation, without affecting p120ctn expression or localization. Our data suggest that these defects result from the failure of activated RhoA to localize at intercellular interfaces after cell-cell contact and an elevation of cellular RhoA, stress fibers, and other indicators of contractile signaling in squamous cell lines and atrial cardiomyocytes. Consistent with these observations, RhoA activation accelerated DP redistribution to desmosomes during the first hour of junction assembly, whereas sustained RhoA activity compromised desmosome plaque maturation. Together with our previous findings, these data suggest that PKP2 may functionally link RhoA- and PKC-dependent pathways to drive actin reorganization and regulate DP-IF interactions required for normal desmosome assembly.

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A schematic representation depicting proposed PKP2-dependent pathways important for desmosomal plaque assembly. The data are consistent with a model in which PKP2 orchestrates DP incorporation into desmosomes through two pathways: 1) by acting as a scaffold that recruits PKCα to DP to modulate its interaction with intermediate filaments (IF; Godsel et al., 2005; Bass-Zubek et al., 2008), and 2) by localizing RhoA at sites of nascent junction assembly and regulating cortical actin remodeling necessary for DP accumulation and junction maturation.
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Figure 10: A schematic representation depicting proposed PKP2-dependent pathways important for desmosomal plaque assembly. The data are consistent with a model in which PKP2 orchestrates DP incorporation into desmosomes through two pathways: 1) by acting as a scaffold that recruits PKCα to DP to modulate its interaction with intermediate filaments (IF; Godsel et al., 2005; Bass-Zubek et al., 2008), and 2) by localizing RhoA at sites of nascent junction assembly and regulating cortical actin remodeling necessary for DP accumulation and junction maturation.

Mentions: We propose that PKP2 functionally links the actin- and previously described IF-dependent arms of the DP assembly pathway (Figure 10, model), by 1) acting as a scaffold that brings PKCα in the vicinity of DP to properly modulate its interaction with IF (Bass-Zubek et al., 2009) and 2) to localize RhoA signaling machinery to sites of nascent junction assembly at cell–cell contact sites. RhoA has been reported as being among the many signaling pathways PKC regulates (Holinstat et al., 2003). The fact that PKP2 has an impact on both RhoA and PKC raised the possibility that they are in the same pathway. However, in SCC9 cells RhoA activity was not affected either by silencing or elevating PKCα activity, nor did these manipulations rescue the changes in actin organization observed upon PKP2 KD (not shown). These results suggest that PKP2 regulates multiple pathways important for cell–cell junction formation and stability, in part by proper localization of these signaling mediators (Figure 10).


Plakophilin 2 couples actomyosin remodeling to desmosomal plaque assembly via RhoA.

Godsel LM, Dubash AD, Bass-Zubek AE, Amargo EV, Klessner JL, Hobbs RP, Chen X, Green KJ - Mol. Biol. Cell (2010)

A schematic representation depicting proposed PKP2-dependent pathways important for desmosomal plaque assembly. The data are consistent with a model in which PKP2 orchestrates DP incorporation into desmosomes through two pathways: 1) by acting as a scaffold that recruits PKCα to DP to modulate its interaction with intermediate filaments (IF; Godsel et al., 2005; Bass-Zubek et al., 2008), and 2) by localizing RhoA at sites of nascent junction assembly and regulating cortical actin remodeling necessary for DP accumulation and junction maturation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2921118&req=5

Figure 10: A schematic representation depicting proposed PKP2-dependent pathways important for desmosomal plaque assembly. The data are consistent with a model in which PKP2 orchestrates DP incorporation into desmosomes through two pathways: 1) by acting as a scaffold that recruits PKCα to DP to modulate its interaction with intermediate filaments (IF; Godsel et al., 2005; Bass-Zubek et al., 2008), and 2) by localizing RhoA at sites of nascent junction assembly and regulating cortical actin remodeling necessary for DP accumulation and junction maturation.
Mentions: We propose that PKP2 functionally links the actin- and previously described IF-dependent arms of the DP assembly pathway (Figure 10, model), by 1) acting as a scaffold that brings PKCα in the vicinity of DP to properly modulate its interaction with IF (Bass-Zubek et al., 2009) and 2) to localize RhoA signaling machinery to sites of nascent junction assembly at cell–cell contact sites. RhoA has been reported as being among the many signaling pathways PKC regulates (Holinstat et al., 2003). The fact that PKP2 has an impact on both RhoA and PKC raised the possibility that they are in the same pathway. However, in SCC9 cells RhoA activity was not affected either by silencing or elevating PKCα activity, nor did these manipulations rescue the changes in actin organization observed upon PKP2 KD (not shown). These results suggest that PKP2 regulates multiple pathways important for cell–cell junction formation and stability, in part by proper localization of these signaling mediators (Figure 10).

Bottom Line: Plakophilin 2 (PKP2), an armadillo family member closely related to p120 catenin (p120ctn), is a constituent of the intercellular adhesive junction, the desmosome.We demonstrate that PKP2 knockdown impairs cortical actin remodeling after cadherin ligation, without affecting p120ctn expression or localization.Together with our previous findings, these data suggest that PKP2 may functionally link RhoA- and PKC-dependent pathways to drive actin reorganization and regulate DP-IF interactions required for normal desmosome assembly.

View Article: PubMed Central - PubMed

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

ABSTRACT
Plakophilin 2 (PKP2), an armadillo family member closely related to p120 catenin (p120ctn), is a constituent of the intercellular adhesive junction, the desmosome. We previously showed that PKP2 loss prevents the incorporation of desmosome precursors enriched in the plaque protein desmoplakin (DP) into newly forming desmosomes, in part by disrupting PKC-dependent regulation of DP assembly competence. On the basis of the observation that DP incorporation into junctions is cytochalasin D-sensitive, here we ask whether PKP2 may also contribute to actin-dependent regulation of desmosome assembly. We demonstrate that PKP2 knockdown impairs cortical actin remodeling after cadherin ligation, without affecting p120ctn expression or localization. Our data suggest that these defects result from the failure of activated RhoA to localize at intercellular interfaces after cell-cell contact and an elevation of cellular RhoA, stress fibers, and other indicators of contractile signaling in squamous cell lines and atrial cardiomyocytes. Consistent with these observations, RhoA activation accelerated DP redistribution to desmosomes during the first hour of junction assembly, whereas sustained RhoA activity compromised desmosome plaque maturation. Together with our previous findings, these data suggest that PKP2 may functionally link RhoA- and PKC-dependent pathways to drive actin reorganization and regulate DP-IF interactions required for normal desmosome assembly.

Show MeSH
Related in: MedlinePlus