{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUSP6 is a deubiquitinating enzyme whose aberrant overexpression is driven by recurrent gene rearrangements in a spectrum of mesenchymal neoplasms such as aneurysmal bone cysts and nodular fasciitis. In these lesions, USP6 (also known as TRE17) becomes transcriptionally deregulated via promoter swapping events—for example, with CDH11 or MYH9—resulting in its high-level expression specifically within the neoplastic mesenchymal cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFunctionally, the USP6 enzyme exerts its oncogenic influence by deubiquitinating key substrates. In aneurysmal bone cysts, its overexpression is sufficient to induce the transcription of matrix metalloproteinases (notably MMP-9 and MMP-10) via activation of the NF‑κB pathway—in part through its association with and activation of IκB kinase—thereby contributing to aggressive osteolysis and tumor growth. In parallel, USP6 activates the Wnt signaling cascade by deubiquitinating Frizzled receptors, which increases their accumulation at the cell surface and enhances downstream signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUSP6 also modulates small GTPase signaling. Studies demonstrate that TRE17/USP6 binds directly to Arf6 (in its GDP-bound state) and, rather than acting as a classical GTPase-activating protein, it facilitates Arf6 activation—an action that likely primes the recruitment of membrane-associated guanine nucleotide exchange factors. Furthermore, USP6 appears to be functionally intertwined with Rac1 and Cdc42 pathways involved in actin remodeling, and its activity is further modulated by direct binding to calmodulin, which influences its own monoubiquitination."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to these roles, USP6 helps stabilize key signaling molecules through its deubiquitinating activity. It directly deubiquitinates Jak1, stabilizing the protein and triggering activation of the Jak‑STAT3 cascade—a pathway that not only drives tumorigenesis in benign bone and soft tissue tumors but also modulates the local immune microenvironment (with implications observed in Ewing sarcoma). Similarly, USP6 deubiquitinates c‑Jun, resulting in enhanced AP‑1–mediated transcription and increased invasive capacity of cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its oncogenic functions, USP6 has roles in normal cell physiology. Neuronal expression of USP6 improves synaptic function by deubiquitinating and stabilizing N‑methyl-D-aspartate receptors (NMDARs), thereby promoting receptor surface accumulation and enhancing cognitive performance. Moreover, USP6 can counteract the activity of specific E3 ubiquitin ligases (such as MARCH family members) to preserve the stability of key plasma membrane proteins like major histocompatibility complex class I molecules."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andre M Oliveira, Antonio R Perez-Atayde, Carrie Y Inwards, et al. "}, {"type": "b", "children": [{"type": "t", "text": "USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/S0002-9440(10)63432-3"}], "href": "https://doi.org/10.1016/S0002-9440(10"}, {"type": "t", "text": "63432-3) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15509545"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15509545"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Andre M Oliveira, Bae-Li Hsi, Stanislawa Weremowicz, et al. 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