{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWWP2 is a versatile HECT‐type E3 ubiquitin ligase that orchestrates protein homeostasis by directly attaching ubiquitin to key regulatory substrates via its multiple WW domains and catalytic HECT domain. In doing so, it governs diverse cellular processes ranging from signal transduction and DNA repair to differentiation and stress responses. For example, studies have shown that WWP2 can mediate the degradation of factors important for cell‐fate decisions and viral infections, underscoring its role as a central hub in protein turnover and cellular quality control."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of oncogenic signaling and tumor progression, WWP2 has been implicated in the downregulation of tumor suppressors and the modulation of key signaling pathways. For instance, by interacting with and promoting the degradation of PTEN it helps to tip the balance in favor of Akt‐driven cell survival, while its ability to mono‐ubiquitinate the membrane‐tethered Notch3 fragment attenuates Notch signaling in ovarian cancer. In addition, various WWP2 isoforms differentially regulate TGFβ/Smad activity to shape epithelial–mesenchymal transition, and its targeting of cell cycle regulators such as p27 has been linked to the promotion of proliferation across several malignancies including liver, gastric, lung, and hematologic cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWWP2 also plays critical roles in stem cell maintenance and differentiation. In human embryonic stem cells its activity toward the pluripotency factor OCT4 is essential for modulating self‐renewal, while in developing tissues it regulates chromatin remodeling through substrates such as SRG3 and exerts non‐proteolytic mono‐ubiquitination of RUNX2 to promote osteogenic transactivation. In addition, studies in amniotic epithelial cells indicate that microRNA–mediated suppression of WWP2 contributes to the maintenance of Oct4 expression and stem cell pluripotency."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond development and cancer, WWP2 modulates cellular stress responses and quality‐control mechanisms. It participates in the DNA damage response by targeting the large subunit of RNA polymerase II for K48–linked ubiquitination, thereby facilitating removal of stalled transcription complexes. Moreover, by ubiquitinating key regulators—including autophagy receptors—and by targeting p53 in the setting of acute kidney injury, WWP2 helps maintain proteostatic balance under stress conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "20"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the cardiovascular system, WWP2 exerts profound effects on vascular remodeling and endothelial homeostasis. Its ability to promote the degradation of substrates such as Septin4 and PDCD4 is linked to the suppression of oxidative‐stress–induced endothelial injury and atherosclerosis, while myeloid‐specific ablation of WWP2 has been shown to ameliorate cardiac fibrosis. These findings highlight a key role for WWP2 in regulating inflammatory and fibrotic responses within the vasculature."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "24"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, WWP2 has been implicated in viral egress and is subject to fine regulation by post‐translational modifications and noncoding RNAs. It is recruited by viral proteins—such as the adenovirus penton base and Koala retrovirus components—to facilitate budding."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " Furthermore, its activity can be modulated by tyrosine phosphorylation mediated by ACK1 and by epigenetic m6A modifications that enhance its stability in the context of hepatocellular carcinoma. 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