{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTSC2 is a critical tumor suppressor that functions as part of the TSC1–TSC2 complex to regulate cell growth by acting as a negative modulator of mechanistic target of rapamycin (mTOR) signaling. By serving as a GTPase-activating protein toward Rheb, TSC2 limits mTOR complex 1 (mTORC1) activity and thereby controls the phosphorylation of key downstream effectors such as p70 S6 kinase and 4E‐binding protein 1—central regulators of protein synthesis and cell growth. Its partnership with TSC1 not only ensures proper complex formation but also facilitates additional regulatory functions, including a contributory role in mTOR complex 2–mediated Akt activation. In this way, TSC2 integrates signals from growth factors, nutrients, and cellular energy status to maintain homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe activity of TSC2 is tightly controlled by multiple post‐translational modifications that respond to diverse extracellular and intracellular cues. Phosphorylation events mediated by kinases such as Akt, Erk, and stress‐activated kinases (including those in the p38–MK2 and LKB1–AMPK pathways) modulate TSC2’s GAP activity, stability, and subcellular localization—including recruitment to lysosomes under amino acid deprivation. Such modifications also promote binding to regulatory proteins like 14–3–3, which can further attenuate TSC2 function under growth‐stimulating conditions, while ROS and other stress signals engage ATM-dependent pathways that couple TSC2 activation to autophagy. These finely tuned regulatory mechanisms ensure that mTOR signaling is suppressed during stress, nutrient scarcity, or other adverse metabolic conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, aberrations in TSC2—ranging from inactivating mutations to altered regulation by upstream signals—are central to the pathogenesis of tuberous sclerosis complex and have been linked to a broad spectrum of disorders including benign hamartomas, neurological malformations, and certain neoplasms. Detailed genotype–phenotype studies reveal that TSC2 mutations tend to associate with more severe disease manifestations than TSC1 alterations, with mosaic mutations and distinct subcellular misregulation contributing to pathology in organs as diverse as the brain, kidney, and even in epithelial tumors such as oral squamous cell carcinoma. Moreover, emerging evidence implicates dysregulated TSC2–mTOR signaling in the orchestration of immune responses, endoplasmic reticulum stress, and neuronal polarity, thereby underscoring its multifaceted role in both normal development and disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ken Inoki, Yong Li, Tianquan Zhu, et al. 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