{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPeriplakin functions as a key modulator of immune signaling through its interactions with several membrane receptors and intracellular signaling proteins. It binds to the intracellular domains of receptors such as BTN3A1—thereby contributing to the indirect presentation of phosphoantigens to γδ T cells—and to the mu‐opioid receptor, where it disrupts agonist‐induced G protein activation. In addition, periplakin associates with PKB/Akt via a portion of its pleckstrin homology domain without affecting its activation and interacts specifically with the intracellular tail of FcγRI to influence ligand binding, endocytosis, and antigen presentation. Similarly, its binding to the melanin‐concentrating hormone-1 receptor modulates downstream G protein signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its regulatory roles in immune pathways, periplakin acts as an essential cytoskeletal scaffolding protein that coordinates intermediate filament organization. It directly interacts with cytokeratins (such as keratin 8) and vimentin, and engages in functionally significant associations with other plakin proteins like plectin. These interactions facilitate the assembly and dynamic remodeling of the keratin intermediate filament network, which is modulated further by post-translational modifications such as SUMOylation—a process essential for maintaining filament stability and proper cellular localization. Detailed structural studies have revealed that a conserved, basic linker domain within periplakin mediates binding to acidic filament proteins, ensuring robust cytoskeletal tethering and responsiveness to apoptotic cues including caspase cleavage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPeriplakin also has critical tumor-modulatory properties across various epithelial cancers. In esophageal, urothelial, and colorectal cancers its expression is often markedly downregulated, a change that correlates with tumor progression and invasive behavior. In colon carcinoma cells, enforced periplakin expression suppresses proliferation, migratory capacity, epithelial–mesenchymal transition (EMT), and progression by interfering with signaling pathways such as ERK and AKT, while loss of periplakin expression is associated with an adverse clinical outcome. These findings suggest that periplakin serves not only as a promising diagnostic marker for early malignancy but also potentially as a therapeutic target in cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in signaling and cytoskeletal organization, periplakin is implicated in autoimmune processes and pharmacogenetic responses. It is a well-characterized autoantigen in paraneoplastic pemphigus and has been identified as a target of autoantibodies in subsets of asthma patients, suggesting a role in epithelial integrity and immune dysregulation. Furthermore, genetic variants within the PPL gene have been shown to influence the sensitivity of oral squamous cell carcinoma to EGFR inhibitors by altering downstream AKT phosphorylation, highlighting a potential biomarker role in therapeutic responsiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "A Pieter J van den Heuvel, Alida M M de Vries-Smits, Pascale C van Weeren, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Binding of protein kinase B to the plakin family member periplakin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.00069"}], "href": "https://doi.org/10.1242/jcs.00069"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12244133"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12244133"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Giu-Jie Feng, Elaine Kellett, Carol A Scorer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Selective interactions between helix VIII of the human mu-opioid receptors and the C terminus of periplakin disrupt G protein activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M305866200"}], "href": "https://doi.org/10.1074/jbc.M305866200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12810704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12810704"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jeffrey M Beekman, Jantine E Bakema, Jan G J van de Winkel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Direct interaction between FcgammaRI (CD64) and periplakin controls receptor endocytosis and ligand binding capacity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0401217101"}], "href": "https://doi.org/10.1073/pnas.0401217101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15229321"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15229321"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hannah Murdoch, Gui-Jie Feng, Dietmar Bächner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Periplakin interferes with G protein activation by the melanin-concentrating hormone receptor-1 by binding to the proximal segment of the receptor C-terminal tail."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M405215200"}], "href": "https://doi.org/10.1074/jbc.M405215200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15590649"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15590649"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "David A Rhodes, Hung-Chang Chen, Amanda J Price, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Co-assembly of envoplakin and periplakin into oligomers and Ca(2+)-dependent vesicle binding: implications for cornified cell envelope formation in stratified squamous epithelia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M313660200"}], "href": "https://doi.org/10.1074/jbc.M313660200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15033990"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15033990"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Sirpa Aho "}, {"type": "b", "children": [{"type": "t", "text": "Plakin proteins are coordinately cleaved during apoptosis but preferentially through the action of different caspases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Dermatol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.0906-6705.2004.00217.x"}], "href": "https://doi.org/10.1111/j.0906-6705.2004.00217.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15500642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15500642"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Veronika Boczonadi, Lorna McInroy, Arto Määttä "}, {"type": "b", "children": [{"type": "t", "text": "Cytolinker cross-talk: periplakin N-terminus interacts with plectin to regulate keratin organisation and epithelial migration."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2007.07.005"}], "href": "https://doi.org/10.1016/j.yexcr.2007.07.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17662978"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17662978"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Mansi Gujrati, Rohit Mittal, Lakhan Ekal, et al. 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