{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUSP9X is a highly conserved deubiquitinase that regulates protein stability and thereby orchestrates a multitude of cellular processes in both normal physiology and disease. In cancer cells, USP9X promotes survival and influences tumor behavior in a context‐dependent manner by removing degradative ubiquitin chains from key effectors. For example, USP9X deubiquitinates and stabilizes the anti‐apoptotic protein MCL1, thereby contributing to chemoresistance in lymphomas and multiple myeloma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", and it also re‐empowers Smad4 function by reversing an inhibitory monoubiquitination in TGFβ signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In pancreatic ductal adenocarcinoma, USP9X loss accelerates transformation and protects against anoikis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", while its deubiquitinating activity on AMPK‐related kinases such as NUAK1 and MARK4 influences kinase activation through the removal of atypical Lys29/33‐linked ubiquitin chains."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " USP9X further participates in specialized autophagy—for instance, in “zymophagy,” it cooperates with VMP1 and the ubiquitin‐binding protein p62 to clear activated zymogen granules"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "—and regulates proteostasis in neurons by deubiquitinating α–synuclein, thereby modulating its degradation pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the nervous system, genetic variants of USP9X have been implicated in intellectual disability by compromising axonal growth and neuronal migration"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", while in chronic myelogenous leukemia, pharmacologic inhibition of USP9X destabilizes oncoproteins such as Bcr–Abl and the survival factor MCL1."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, USP9X interacts with the ubiquitin ligase Itch to prevent its auto‐ubiquitination–mediated degradation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and in multiple myeloma, compensatory upregulation of USP24 upon USP9X depletion highlights the intricacy of survival signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Its ability to stabilize centriolar satellite protein CEP131 is critical for centrosome maintenance in breast cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and by deubiquitinating SMURF1, USP9X enhances cell motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " USP9X also targets the peroxisomal receptor PEX5"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", and its dosage sensitivity plays a role in neurodevelopmental disorders in females"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", while its interaction within the SOX2–associated network in medulloblastoma and glioblastoma underscores its involvement in brain tumor biology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " In colon cancer, USP9X stabilizes the tumor suppressor FBW7, thereby reducing levels of oncogenic c‐Myc"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", and it also associates with MARCH7 to counteract its autoubiquitination."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " Regulation of cell–cell adhesion and trafficking is further exemplified by USP9X’s role in modulating β–catenin and E–cadherin dynamics"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", and by controlling EGFR endocytosis via deubiquitination of the accessory protein Eps15."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Finally, stabilization of the transcriptional co–activator YAP1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "and deubiquitination of Prickle to influence seizure activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct regulation of survival factors, USP9X orchestrates several key signaling cascades that affect oncogenesis and cellular stress responses. In aggressive B–cell lymphomas, USP9X deubiquitinates inhibitors of apoptosis such as XIAP, thereby modulating mitotic checkpoint decisions"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": ", and in non–small cell lung cancer its stabilization of the kinase TTK contributes to tumor cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " USP9X also deubiquitinates ETS1 in melanoma, enhancing its oncogenic function"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": ", while its regulation of Angiomotin–like 2 modulates components of the Hippo pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " Furthermore, by deubiquitinating specific isoforms of PTEN, USP9X impacts a tumor–promoting transcriptional program"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "and, through interactions with TRB3 and Mind Bomb 1, it modulates Notch signaling in basal–like breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": " Its dosage sensitivity is underscored by recurrent loss–of–function mutations in male neurodevelopmental disorders"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": ", and inhibition of USP9X sensitizes pancreatic cancer cells to gemcitabine by reducing autophagy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": " In T–cell acute lymphoblastic leukemia, USP9X mutations contribute to malignant transformation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": ", and its stabilization of β–catenin further promotes glioma cell growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": " Structural insights into its catalytic domain reveal determinants of substrate specificity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": ", and USP9X also stabilizes LATS2 to restrain YAP/TAZ–driven oncogenic programs."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": " Its involvement in maintaining genome stability through CLASPIN deubiquitination"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": "and the observation that low USP9X levels increase chemosensitivity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "further highlight its multifaceted regulatory capacity. USP9X also modulates the stability of PBX1 to influence prostate cancer chemoresistance"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": ", and by regulating the ubiquitination status of DVL2, it helps to specify canonical versus non–canonical WNT signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "38"}]}, {"type": "t", "text": " Additionally, USP9X potentiates TGFβ signaling that supports metastasis in obesity–associated breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Martin Schwickart, Xiaodong Huang, Jennie R Lill, et al. 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