{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWWP1 is a multifunctional HECT‐type E3 ubiquitin ligase whose activity is intricately regulated by its multidomain architecture. Structural studies have revealed that WWP1 possesses a two‐lobed HECT domain connected by a flexible hinge and is flanked by an N‐terminal C2 domain and multiple WW domains that recognize PY motifs in substrates. Intramolecular interactions—including those mediated by peptide linkers—lock the enzyme in an inactive conformation, a brake that can be released by post‐translational modifications or interacting partners, thereby enabling substrate ubiquitylation. Moreover, studies in diverse systems have indicated that WWP1 may also interface with components of signaling pathways such as Notch, underscoring its capacity to relay positional cues in the cell."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThrough specific recognition of PY motifs via its WW domains, WWP1 orchestrates ubiquitination of a broad array of substrates that are essential for cellular homeostasis and signaling. It negatively regulates the transforming growth factor‐β (TGF‐β) pathway by binding Smad7 and promoting ubiquitination and degradation of TGF‐β receptors and associated components."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": " WWP1 also targets key transcription factors such as KLF5—with its activity modulated by TAZ"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "—and p63, where it directs the degradation of distinct isoforms to elicit context‐dependent effects on apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In addition, WWP1 modulates p53 function by increasing its stability while sequestering it in the cytoplasm"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and it regulates ErbB4 signaling by catalyzing its ubiquitination."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Furthermore, WWP1 has been implicated in the turnover of other proteins such as spartin"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", in controlling cell cycle and senescence via p27^Kip1 ubiquitination"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", and in assembling distinct polyubiquitin chains with defined lysine linkages."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " Beyond its actions on endogenous substrates, WWP1 is co‐opted by viruses: it interacts with viral proteins including the adenovirus penton base"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", HTLV-1 Gag"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ", and Ebola VP40"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "25"}]}, {"type": "t", "text": ", thereby influencing viral egress. Additional layers of regulation involve microRNAs—for instance, miR-21 suppresses EPC proliferation via downregulation of WWP1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "—while aberrant ubiquitin ligase activity has been linked to NF-κB signaling modulation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "can be extended by findings showing a role for miR-30a-5p in glioma via targeting WWP1, see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " Collectively, these studies illustrate that WWP1 functions as a central node integrating ubiquitin-mediated post-translational regulation across diverse signaling cascades."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "14"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "12"}, {"type": "fg_fs", "start_ref": "15", "end_ref": "17"}, {"type": "fg_f", "ref": "13"}, {"type": "fg_f", "ref": "23"}, {"type": "fg_f", "ref": "18"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "22"}, {"type": "fg_f", "ref": "26"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "20"}, {"type": "fg_f", "ref": "24"}, {"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant regulation of WWP1 has been strongly implicated in tumorigenesis across a spectrum of malignancies. Elevated expression and genomic amplification of WWP1 have been reported in breast, prostate, gastric, hepatocellular, and oral cancers as well as in certain hematological neoplasms—associations that correlate with aggressive tumor behavior, metastasis, chemoresistance, and poor clinical outcome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "31"}, {"type": "fg_f", "ref": "19"}, {"type": "fg_fs", "start_ref": "32", "end_ref": "34"}]}, {"type": "t", "text": " In these contexts, dysregulated WWP1 activity perturbs key signaling cascades by inappropriately degrading tumor suppressors—such as components of the TGF‐β and PTEN pathways—and by altering the homeostasis of transcription factors like p63, p53, and KLF5. Moreover, microRNA-mediated alterations in WWP1 expression (for example by miR-30a-5p, miR-21, or miR-452) further contribute to malignant progression and metastasis, while emerging evidence also links WWP1 with cardiac remodeling and metabolic adaptations, thereby expanding its disease relevance beyond cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "31"}, {"type": "fg_f", "ref": "19"}, {"type": "fg_fs", "start_ref": "32", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mark A Verdecia, Claudio A P Joazeiro, Nicholas J Wells, et al. 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