{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRIO functions as a multivalent signaling scaffold endowed with two distinct guanine nucleotide exchange factor (GEF) modules that activate Rho family GTPases such as Rac1, RhoG, and RhoA. This catalytic versatility underpins its key role in remodeling the actin cytoskeleton to drive cell migration, invasion, and metastasis. For example, in malignant gliomas, TRIO overexpression enhances invasive growth while its depletion impairs migration, invasion, and proliferation. In metastatic tumor cells, TRIO promotes invadopodia turnover and thereby facilitates the dynamic remodeling required for invasion. Moreover, by transducing signals from heterotrimeric G protein‐coupled receptors, TRIO couples extracellular stimuli to Rho GTPase activation and helps coordinate endothelial docking structures that support leukocyte transmigration. Gene amplification and the generation of oncogenic splice variants further associate TRIO with aggressive phenotypes in cancers such as urinary bladder, cervical, hepatocellular, and osteosarcoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, TRIO is a pivotal mediator of neuronal development—regulating processes such as neuronal migration, axon guidance, dendritic arborization, and synaptogenesis—through its precise control of Rac1‐dependent actin remodeling. Pathogenic mutations (often clustered within its GEF1 domain or adjacent spectrin repeats) can lead to either hyperactive or hypoactive Rac1 signaling, resulting in aberrant glutamatergic synapse formation and contributing to neurodevelopmental disorders that range from intellectual disability to autism spectrum disorder and bipolar disease. In addition, TRIO engages with cytoskeletal partners such as Navigator 1 and components of the presynaptic active zone to localize its GEF activity at neurite tips, thereby promoting proper neurite outgrowth and synaptic function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in tumor progression and neurodevelopment, TRIO integrates multiple extracellular signals via its dual GEF modules and accessory domains to achieve precise spatiotemporal regulation of Rho GTPase activity in diverse cellular contexts. Structural and biochemical investigations reveal that intramolecular interactions—particularly between its Dbl homology/pleckstrin homology (DH/PH) cassettes and spectrin repeats—modulate its catalytic output, thereby fine‐tuning processes such as lamellipodia dynamics, cytokinesis, and receptor transactivation events. These mechanistic insights underscore TRIO’s function as a central hub linking receptor or G protein signaling to cytoskeletal reorganization and cell polarity in both physiological and pathological settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "34"}, {"type": "fg_f", "ref": "28"}, {"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Bodour Salhia, Nhan L Tran, Amanda Chan, et al. 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