| USP9X is an X‑linked ubiquitin-specific cysteine protease of the USP family that reverses ubiquitin conjugation on a broad spectrum of substrates and thereby controls their stability, localization, and participation in signaling pathways governing cell adhesion, polarity, survival, and lineage specification. The protein contains a large N‑terminal substrate- and scaffold-interacting region followed by a conserved C19 peptidase catalytic domain that hydrolyzes Lys11-, Lys63-, Lys48-, and Lys6‑linked polyubiquitin chains on target proteins, allowing USP9X to selectively remove degradative or signaling-linked ubiquitin modifications and to act as a key regulator of protein turnover and complex assembly. Through deubiquitination of SMAD4, AMOT family proteins, β‑catenin complexes, and components of Notch and Wnt pathways, USP9X modulates TGF‑β/BMP, Hippo–YAP, Wnt/β‑catenin, and Notch signaling outputs, influencing transcriptional programs that control proliferation, differentiation, and stem and progenitor cell fate in multiple tissues. In neural development, high USP9X expression in embryonic and neural stem cells and its activity toward substrates involved in cytoskeletal dynamics and ankyrin-repeat proteins support axonal growth, neuronal migration, dendritic spine development, and synaptic connectivity, and partial loss-of-function mutations in USP9X cause a defined neurodevelopmental syndrome with intellectual disability, language impairment, and structural brain anomalies. Within polarized epithelia, USP9X associates with adherens and tight junction complexes and regulates cell–cell contact integrity by stabilizing junctional components, thereby linking deubiquitination to maintenance of epithelial architecture and barrier function and to the integration of polarity cues with downstream Wnt and Notch signaling. In cancer biology, USP9X exerts context-dependent effects by removing ubiquitin from factors such as MCL1, RICTOR, and other survival and growth pathway components, which enhances anti-apoptotic signaling and mTORC2–Akt pathway activity in some tumors, while in other contexts USP9X loss cooperates with oncogenic drivers by disrupting differentiation cues and polarity, illustrating dual tumor-promoting and tumor-suppressive roles that depend on tissue and stage. Deubiquitination of signaling mediators in Notch-driven malignancies, including breast cancer, positions USP9X as an integral component of oncogenic Notch signaling, and pharmacological inhibition of its catalytic activity reduces Notch pathway output and restricts tumor growth in preclinical models, highlighting its tractability as a drug target. USP9X also regulates ribosomal quality control by deubiquitinating factors at stalled ribosomes, contributes to peroxisomal import through PEX5 deubiquitination, and stabilizes epitranscriptomic regulators such as ALKBH3 and ALKBH5, integrating ubiquitin-dependent control of proteostasis with DNA repair and RNA modification pathways that influence genome and transcriptome integrity. |
