{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPIN1 is a unique, phosphorylation‐specific peptidyl–prolyl cis–trans isomerase that catalyzes conformational changes immediately after protein phosphorylation. By binding to phospho–Ser/Thr–Pro motifs, PIN1 modulates the activity, subcellular localization, protein–protein interactions, and stability of a wide range of signaling molecules. For example, PIN1 regulates stress responses by affecting key transcription factors – it promotes the nuclear retention and activity of NF‐κB and remodels the activity of p53 through conformational switches induced upon DNA damage, and it enhances the transcriptional activity of c‐Fos and other AP‐1 members. PIN1 also fine‐tunes RNA polymerase II function and facilitates cleavage events required for Notch activation, partly by engaging the p300 coactivator."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in normal signal transduction, PIN1 is a critical mediator of oncogenesis. Overexpression of PIN1 is observed in numerous human cancers, where it not only up‐regulates cyclin D1 and enhances mutant p53 and p73 oncogenic functions but also stabilizes oncoproteins (such as Myc and Mcl‐1) and promotes the expansion of cancer stem and progenitor cell populations through mechanisms such as Nanog stabilization and Notch signaling. PIN1 further contributes to cellular transformation by promoting epithelial–mesenchymal transition, centrosome amplification, and by interfering with tumor‐suppressive pathways (for example, by negatively regulating Fbw7). Moreover, small molecules such as all‐trans retinoic acid, EGCG, and microRNA regulators have been shown to target PIN1, which highlights its potential as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPIN1 also plays an important role in neurodegenerative disorders. In Alzheimer’s disease, oxidative modifications and somatic mutations in PIN1 diminish its enzyme activity, thereby contributing to tau hyperphosphorylation, deregulated amyloid precursor protein (APP) processing, and the formation of neurofibrillary tangles. Collectively, these alterations underscore a pivotal, yet contrasting, role for PIN1 in protecting against age‐dependent neurodegeneration while its aberrant activation drives multiple oncogenic pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA number of post‐translational modifications and intrinsic structural features regulate PIN1 activity. High‐resolution NMR studies have revealed that the catalytic and WW domains of PIN1 are connected by a flexible linker that permits dynamic interdomain motions. In addition, phosphorylation events – for instance, by death-associated protein kinase 1 – as well as reversible SUMOylation serve to modulate PIN1’s catalytic activity and subcellular localization, thereby fine-tuning its impact on partner proteins and downstream signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "35", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, PIN1 contributes to viral pathogenesis by directly modulating the stability and function of pathogen‐encoded proteins. 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