{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ARHGAP21 is a multifunctional Rho GTPase‐activating protein that plays a central role in regulating cytoskeletal dynamics, membrane trafficking, cell adhesion, and migration. Structural studies have revealed that ARHGAP21 modulates the activity of small GTPases—including Cdc42, RhoA, and RhoC—by interacting with distinct domains and being recruited to the Golgi apparatus via ARF1, thereby influencing actin dynamics and Golgi architecture."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, ARHGAP21 forms complexes with signaling proteins such as β‐arrestin1 to fine‐tune RhoA activation in response to stimuli like angiotensin II, which in turn modulates stress fiber formation and cell contractility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cancer cells, ARHGAP21 has been implicated in controlling proliferation, migration, and the epithelial‐to‐mesenchymal transition through its regulation of Cdc42 activity and its interplay with cytoskeletal components. For instance, studies in prostate, glioblastoma, and colon carcinoma models demonstrate that ARHGAP21 affects cell adhesion and invasion via its influence on focal adhesion kinase signaling and α‐tubulin modification."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": " Furthermore, recent work has identified a role for ARHGAP21—as well as its functionally related homolog ARHGAP23—as key effectors in lateral signaling processes that coordinate multi‐axial protrusive activity during cancer cell migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in cell motility and cancer, ARHGAP21 is involved in the regulation of metabolic processes. Experimental models have shown that reduced ARHGAP21 expression enhances hepatic insulin signaling while altering lipid synthesis and export, and whole‐body haploinsufficiency of ARHGAP21 is associated with altered food intake and energy expenditure, suggesting a role in central energy homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Additionally, regulatory mechanisms such as SUMOylation appear to modulate ARHGAP21’s activity and may further influence its role in cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n MicroRNA-mediated regulation of ARHGAP21 has also been highlighted in the context of viral infection; for example, miR-199a targets ARHGAP21 to modulate the secondary envelopment of herpes simplex virus-1, underscoring its importance in intracellular vesicular trafficking."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Finally, comprehensive reviews emphasize that ARHGAP21’s diverse roles in cell adhesion, migration, Golgi regulation, and even insulin secretion make it a promising therapeutic target across multiple disease states."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Julie Ménétrey, Mylène Perderiset, Jérome Cicolari, et al. 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