Article

The Function of Plakophilin 1 in Desmosome Assembly and Actin Filament Organization

Molecular Biology Group of the Medical Faculty, University of Halle, 06097 Halle/Saale, Germany.
The Journal of Cell Biology (Impact Factor: 9.69). 05/2000; 149(1):209-22.
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ABSTRACT Plakophilin 1, a member of the armadillo multigene family, is a protein with dual localization in the nucleus and in desmosomes. To elucidate its role in desmosome assembly and regulation, we have analyzed its localization and binding partners in vivo. When overexpressed in HaCaT keratinocytes, plakophilin 1 localized to the nucleus and to desmosomes, and dramatically enhanced the recruitment of desmosomal proteins to the plasma membrane. This effect was mediated by plakophilin 1's head domain, which interacted with desmoglein 1, desmoplakin, and keratins in the yeast two-hybrid system. Overexpression of the armadillo repeat domain induced a striking dominant negative phenotype with the formation of filopodia and long cellular protrusions, where plakophilin 1 colocalized with actin filaments. This phenotype was strictly dependent on a conserved motif in the center of the armadillo repeat domain. Our results demonstrate that plakophilin 1 contains two functionally distinct domains: the head domain, which could play a role in organizing the desmosomal plaque in suprabasal cells, and the armadillo repeat domain, which might be involved in regulating the dynamics of the actin cytoskeleton.

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    • "PKPs are located at the membrane, in the cytoplasm, and in the nucleus. PKPs act as a structural scaffold for desmosome formation, clustering, and maturation through interactions with the desmosomal cadherins, desmoplakin, intermediate filaments , and perhaps actin (Hatzfeld et al., 2000; Chen et al., 2002; Bonne et al., 2003). In addition, their association with nuclear and regulatory proteins suggests that they can function as signaling modulators important for tissue differentiation, cell–cell contact formation, and migration (Green and Simpson, 2007; Bass-Zubek et al., 2009; Getsios et al., 2009; Godsel et al., 2010; Green et al., 2010; Thomason et al., 2010). "
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    • "Recent studies have shown a functional link between the desmosomal components and the actin cytoskeleton. For instance, plakophi- lin-1, a p120 related desmosomal plaque protein, has been demonstrated to associate with actin and is capable of inducing filopodium formation [18]. Similarly, plakophilin-2 is also reported to be involved in the regulation of Rho activity and actin organisation during intercellular junction assembly [19]. "
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    • "Although plakoglobin has been the focus of early studies as important for junctional cross talk (Lewis et al. 1997), inducible expression of the p120-related protein PKP1 has also been reported to initiate DSM assembly in a classic cadherin-dependent fashion (Wahl 2005). In addition to interacting with desmoplakin and IF, PKPs can associate with actin and cause p120-like rearrangements of the actin cytoskeleton (Hatzfeld et al. 2000) (Chen, Bass-Zubek, and Green, unpublished). PKP2 deficiency also results in major alterations in the actin cytoskeleton and rhoA signaling, likely interfering with AJ-dependent actin remodeling driving DSM assembly (Bass- Zubek, Godsel and Green, unpublished). "
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