{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRRAS2, also known as TC21, is a small GTPase that plays a fundamental role in normal lymphocyte biology by constitutively interacting with T cell and B cell antigen receptors. This interaction directly links these receptors to phosphatidylinositol‑3‑kinase (PI3K)–mediated survival signaling, thereby promoting homeostatic proliferation and cell survival in immune cells. Moreover, structural studies have revealed that RRAS2 engages downstream effectors through critical recognition “hotspots” that are conserved despite sequence variability, ensuring precise communication with signaling cascades."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its function in immune cell maintenance, RRAS2 has emerged as a key player in developmental disorders. Germline mutations in RRAS2 have been identified in individuals with Noonan syndrome and related RASopathies, where changes affecting conserved residues around the nucleotide binding pocket lead to hyperactivation of the MAPK pathway and alterations in cytoskeletal organization. These pathogenic variants underscore the critical role of RRAS2 in modulating developmental signaling and highlight its contribution to the phenotypic variability observed in such syndromes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRRAS2 is also intimately involved in tumorigenesis across a wide spectrum of human cancers. On the one hand, oncogenic overexpression or activating mutations of RRAS2 promote cell transformation, enhance proliferation, and enable invasion and metastasis by engaging several downstream pathways including PI3K, MAPK, and mTOR. For instance, in breast cancer, ovarian cancer, and osteosarcoma, RRAS2 drives primary tumor growth and metastatic spread, while in hepatocellular carcinoma and certain central nervous system tumors its overexpression correlates with enhanced motility and early neoplastic changes. Dysregulated RRAS2 function also contributes to therapy resistance, as evidenced by its modulation of hormone receptor signaling and tamoxifen responsiveness in breast cancer. In addition, regulatory mechanisms involving guanine nucleotide exchange factors and microRNAs—as seen with RasGRF‐mediated activation, inhibition by Cdc42, and miR‑23b–induced suppression in cutaneous squamous cell carcinoma—further fine-tune RRAS2’s activity. Intriguingly, alterations in its untranslated regions not only serve as prognostic markers in chronic lymphocytic leukemia but also indicate that even in the presence of mutations in classical RAS genes, RRAS2 exerts nonredundant, context‑dependent oncogenic functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Pilar Delgado, Beatriz Cubelos, Enrique Calleja, et al. 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