{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPlakophilin 3 (PKP3) is a multifunctional member of the armadillo‐repeat protein family that is a core structural component of epithelial desmosomes. In its classical role, PKP3 is incorporated into the desmosomal plaque where it binds a broad spectrum of partners—including desmogleins, desmocollins, plakoglobin, desmoplakin, and keratin 18—that together stabilize intercellular adhesion and reinforce the keratin filament network. This multiprotein binding capacity distinguishes PKP3 from other plakophilins and underlies its essential role in establishing robust cell–cell junctions ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "]. \n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its function within desmosomes, PKP3 is present in extra‐junctional pools of the cytoplasm (and even in the nucleus) where it associates with RNA‐binding proteins. In these contexts, PKP3 is a component of ribonucleoprotein complexes—including molecules such as PABPC1, FXR1, G3BP, and UPF1—and participates in the regulation of mRNA stability and translation, particularly under stress conditions where it localizes to stress granules. These findings indicate that PKP3 has roles in posttranscriptional gene regulation that may impact desmosomal protein expression ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "]. \n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysregulation of PKP3 is increasingly implicated in tumor progression. In metastatic cancer cells, transcriptional repression of PKP3 by factors such as ZEB1 correlates with disruption of intercellular adhesion and epithelial–mesenchymal transition, while experimental knockdown of PKP3 in epithelial cell lines leads to decreased desmosome size, reduced cell–cell adhesion, increased cell migration, and enhanced tumor formation and metastasis in vivo. Conversely, increased PKP3 expression, as observed in certain prostate and breast cancers, is associated with a more aggressive phenotype and enhanced cellular proliferation. In addition, PKP3 has been evaluated as a surrogate biomarker for circulating tumor cells in gastrointestinal cancers, and its altered expression has been linked to oncogene‐related pathways—including upregulation of MMP7 via PRL3 or modulation of keratin 8 dynamics—that further potentiate neoplastic progression ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "16"}]}, {"type": "t", "text": "].\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPKP3 also plays a central role in the dynamic regulation of desmosome assembly and intercellular junction maturation. In addition to its structural functions, PKP3 cooperates with small GTPases (such as Rap1) to coordinate desmosome and E‐cadherin junction formation. Its association with regulatory proteins such as stratifin (a 14–3–3 isoform) and modulation by specific phosphorylation events underscore a signaling function, whereby cytoplasmic pools are directed either toward incorporation into stable desmosomes or kept in reserve to facilitate junctional remodeling. Moreover, interactions with desmocollin cytoplasmic domains further illustrate how PKP3 contributes to plaque assembly and the regulation of cellular adhesion dynamics ["}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "20"}]}, {"type": "t", "text": "]. \n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, alternative promoter usage and splicing generate distinct PKP3 isoforms with tissue‐specific expression patterns, such as the PKP3b variant that is preferentially expressed in stratified epithelia. Reviews of PKP3 functions highlight its dual roles in maintaining skin integrity and mediating diverse signaling pathways that govern cell adhesion, proliferation, and even autophagy. As such, both loss and overexpression of PKP3 have been associated with various pathologies—including autoimmune skin diseases (for example in pemphigus vulgaris) and a range of human cancers—positioning PKP3 as a potential diagnostic marker and therapeutic target ["}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "]. \n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stefan Bonné, Barbara Gilbert, Mechthild Hatzfeld, et al. 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