{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC3A2, also known as CD98hc or 4F2hc, plays a central role as a membrane‐anchored regulatory protein that partners with integrins to amplify outside–in signaling. By physically associating with β1 integrins, SLC3A2 modulates key cellular processes such as cell spreading, adhesion, migration, survival, and T‐cell clonal expansion—processes that underlie both normal adaptive immunity and oncogenic transformation. Its overexpression is linked to aberrant integrin‐dependent activation of intracellular effectors including phosphatidylinositol 3‐kinase/Akt, focal adhesion kinase and Rac, thus promoting anchorage-independent growth and tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in integrin modulation, SLC3A2 is indispensable as the heavy chain subunit of heteromeric amino acid transporters. Its non‐covalent and disulfide‐bonded association with light chain partners (such as LAT1, LAT2 and others) is critical for the surface expression, stability, and function of these transporters. Structural studies using cryo–electron microscopy and biochemical analyses have revealed that SLC3A2 not only helps localize transporters to the plasma membrane but also contributes to the transmembrane flux of large neutral amino acids, thereby regulating nutrient uptake, metabolic reprogramming, and even glucose transporter (GLUT1) stabilization. These functions are crucial for sustaining cell growth and proliferation, particularly in cancer cells where altered nutrient metabolism supports rapid tumor expansion and survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these biochemical roles, SLC3A2 is implicated in several developmental and tumor‐related contexts. In various cancers ranging from breast and colorectal to lung and osteosarcoma, its aberrant expression correlates with increased cell proliferation, migration, and poor clinical outcomes. Moreover, SLC3A2 serves as a key regulator in processes such as trophoblast fusion for placental development and as a fusion partner in oncogenic rearrangements (e.g. SLC3A2–NRG1) that drive aggressive tumor phenotypes. Its involvement in modulating epithelial–mesenchymal transition, cell invasion, and even interactions with other membrane proteins such as CD147 further highlight its multifunctional nature in regulating tumor progression and metastasis, as well as its potential as a prognostic marker and therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of neurodevelopment, SLC3A2 is also differentially expressed in the fetal brain and placental tissues, suggesting that beyond its roles in nutrient transport and adhesion, it may influence cellular differentiation and developmental outcomes. Aberrant SLC3A2 expression in these settings has been linked to altered thyroid hormone distribution and amino acid homeostasis, with potential implications for neurodevelopmental disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chloe C Feral, Naoyuki Nishiya, Csilla A Fenczik, et al. 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