{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nYWHAE, which encodes the 14-3-3ε adaptor protein, is prominently implicated in oncogenic transformation and tumor classification. In uterine sarcomas such as endometrial stromal sarcoma (ESS) and undifferentiated round cell sarcoma, recurrent YWHAE rearrangements—most notably as fusion events with FAM22 family members—define a subset with high‐grade morphology, aggressive behavior, and distinct gene‐expression profiles. Moreover, in pediatric renal and soft tissue tumors, YWHAE fusions are found to be mutually exclusive with BCOR alterations, and duplications involving YWHAE in the 17p13.3 region have been linked to neurodevelopmental phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its oncogenic fusions, 14-3-3ε plays a multifaceted role in intracellular signaling. It contributes to antiviral innate immune responses by forming part of a RIG-I translocon complex that facilitates the relocation of RIG-I to membranes and subsequent MAVS-dependent signaling. Furthermore, 14-3-3ε interacts with regulatory proteins such as Chibby to promote the nuclear export of β-catenin and modulates the activity of heat shock factor 1 (HSF1) in response to extracellular signal–regulated kinase (ERK) activation, thereby adjusting cellular stress responses. Such interactions underscore its role in coupling stress, immunity, and apoptosis regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nYWHAE also exerts crucial regulatory functions in the control of apoptosis, cell migration, and neurodevelopment. Proteolytic processing of 14-3-3ε by caspase-3 during apoptotic signaling alters its binding affinity for pro-apoptotic partners such as Bad, thereby modulating mitochondrial cytochrome c release. In parallel, its interaction with kinases (for example, via MK5) can temper cell migration by affecting downstream effectors like HSP27. Furthermore, genetic studies have linked variations in YWHAE with neuropsychiatric conditions—including susceptibility to schizophrenia and associations with suicidal behavior—highlighting its importance in neural development and signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther, elevated or altered levels of 14-3-3ε have been associated with enhanced tumor progression and metastasis in several cancers. In hepatocellular carcinoma and gastric cancer, its expression correlates with increased cell survival, migratory capacity, and resistance to chemotherapeutic agents, partly through upregulation of factors such as focal adhesion kinase (FAK) and modulation of ion channel activity (e.g. HERG channels in cardiac tissues). Deletions of the YWHAE gene have also been linked to disrupted G2 checkpoint function in lung cancers, underlining its role as a critical regulator of cell cycle progression and oncogenic signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cancer and stress signaling, 14-3-3ε partakes in diverse cellular processes that influence development and tissue homeostasis. It associates with the transmembrane protein CD81 to regulate tetraspanin signaling, interacts with ion exchangers (such as NCX isoforms) to affect calcium homeostasis, and binds to neuronal navigator 2 (NAV2) to facilitate neurite outgrowth and neuronal migration. Moreover, the existence of a splicing variant of 14-3-3ε suggests additional layers of regulation, while its expression in meningiomas and participation in chondrocyte signaling via CD13 implicate it in both central nervous system development and osteoarthritis pathogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Cheng-Han Lee, Adrian Mariño-Enriquez, Wenbin Ou, et al. 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