Plakophilin-1 Localizes to the Nucleus and Interacts with Single-Stranded DNA

Abstract

Plakophilins (Pkp-1, -2, and -3) comprise a family of armadillo repeat-containing proteins first identified as desmosomal plaque components, in which they link desmoplakin to the desmosomal cadherins. In addition to their role in desmosomal cell-cell adhesion, Pkps also localize to the nucleus, where they perform unknown functions. Of the three Pkps, Pkp-1 is most readily detected in the nucleus, where it is localized to the nucleoplasm. Pkp chimeras containing the Pkp-1 head domain and Pkp-3 armadillo repeat domain were localized to the nucleus in A431 cells, whereas Pkp chimeras containing the Pkp-3 head domain and Pkp-1 armadillo repeat domain localized to the desmosome and the cytosol. DNAse I digestion of chromatin in cultured cells results in loss of nuclear Pkp-1, suggesting that Pkp-1 associates specifically with nuclear components. In addition, in vitro assays revealed that the amino-terminal head domains of Pkps-1 and -2 were sufficient to bind single-stranded DNA. Induction of DNA damage induced a partial redistribution of Pkp-1 protein to the nucleolus, and depletion of Pkp-1 resulted in increased survival in response to DNA damage. These data suggest that in addition to mediating desmosome assembly, the nuclear pool of Pkp can influence cell survival by interactions with DNA.

Beyond β-catenin: prospects for a larger catenin network in the nucleus

“…For example, plakophilin 2 associates in some contexts with β-catenin 63 , αT-catenin 114 and the largest subunit of the RNA polymerase III holoenzyme (RPC155) 115 . Plakophilin 1 can bind to single-stranded DNA 116 . Much of the biological significance of these associations, as well as how plakophilins enter the nucleus in the absence of an obvious NLS, remains to be clarified.…”

Proteomic Analysis of Oral Cavity Squamous Cell Carcinoma Specimens Identifies Patient Outcome–Associated Proteins

“…36 In the current study, lower levels of PKP1 protein and RNA were associated with DM and disease-specific survival. Sobolik-Delmaire et al 37 demonstrated that unlike the other members of its family, PKP1 is not a major element in the assembly of desmosomes. Yet it is translocated into the nucleus, where it can bind single-stranded DNA even though it lacks a canonical nuclear localization sequence.…”

Plakophilin 2 Affects Cell Migration by Modulating Focal Adhesion Dynamics and Integrin Protein Expression

“…PKP1 has been shown to associate with single-stranded DNA and may be involved in the response to DNA damage. It also interacts with the translation initiation factor eIF4A1 to promote translation (Sobolik-Delmaire et al, 2010; Wolf et al, 2010). Finally, our data support the hypothesis that PKP2 acts as a signaling scaffold that functionally links RhoA– and protein kinase C–dependent pathways to drive actin reorganization and regulate desmosome assembly (Bass-Zubek et al, 2008; Godsel et al, 2010).…”