{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRAB5C has emerged as a pivotal regulator of endocytic trafficking in several cancers. In breast cancer, EGFR activation promotes RAB5C activity that facilitates integrin recycling and cell invasion by linking the Arf6–AMAP1 pathway with integrin‐recycling machinery."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, selective involvement of RAB5C in growth factor–induced Rac1 activation has been shown to drive membrane ruffling and cell motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In precursor‑B acute lymphoblastic leukemia, targeting of RAB5C by miR‑509 inhibited cell growth, underscoring its role in promoting proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Similarly, RAB5C functions in the proper trafficking of therapeutic phosphorothioate antisense oligonucleotides (PS‑ASOs), enabling their productive uptake and endosomal escape."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In rectal adenocarcinoma, RAB5C modulates EGFR internalization and subsequent nuclear relocalization that impacts DNA repair machinery and radiotherapy resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In papillary thyroid carcinoma, downregulation of RAB5C via miR‑145 suppresses cell proliferation and invasion, and in breast cancer HuR‐mediated stabilization of RAB5C mRNA supports tumor cell survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in tumorigenesis, RAB5C orchestrates several aspects of receptor trafficking and intracellular signaling. Physical interaction studies have identified novel binding partners of RAB5C, suggesting its integration in complex protein networks."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " RAB5C is also implicated in maintaining insulin receptor homeostasis within endosomal compartments, contributing to a type 2 diabetes–associated network."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In cellular models exploring antisense oligonucleotide uptake, an siRNA screen pinpointed RAB5C as an essential mediator of productive ASO trafficking."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Furthermore, studies of focal adhesion kinase (FAK) indicate that FAK‐dependent activation of Rab5—including its RAB5C isoform—is critical for orchestrating integrin trafficking and cell migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In endothelial cells, the activator RIN2 and RAB5C preserve VEGF receptor 2 levels by preventing lysosomal degradation, which is fundamental for angiogenic sprouting."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In addition, modulation of RAB5C by the TBC1D16 protein has been shown to suppress prototype foamy virus replication"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and emerging evidence suggests that RAB5C may contribute to chemoresistance in colorectal cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRAB5C also plays roles in non‐oncogenic contexts. Germline heterozygous RAB5C variants have been linked to neurodevelopmental disorders characterized by macrocephaly and intellectual disability, reflecting the importance of precise endocytic regulation in brain development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Finally, in respiratory epithelial cells, activated RAB5C promotes autophagy via interactions with Beclin1 and subsequent LC3‐II upregulation, thereby enhancing replication of both enveloped and non‑enveloped respiratory viruses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yasuhito Onodera, Jin-Min Nam, Ari Hashimoto, et al. 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