{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ARHGAP36 is an atypical Rho GTPase‐activating protein whose multifaceted functions span normal development and tumorigenesis. In several studies, ARHGAP36 has been shown to act as a positive regulator of the Hedgehog signaling pathway by inhibiting protein kinase A (PKA) activity. It does so using a dual mechanism: one involving a pseudosubstrate motif that directly blocks PKAC activity and another that promotes rapid, ubiquitin‐mediated lysosomal degradation of PKAC, thereby favoring activation of full‐length Gli transcription factors and their accumulation in the primary cilium."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, ARHGAP36 is implicated in a regulatory axis involving Patched1 and Inversin that governs the ciliary translocation of Smoothened, further coupling Hedgehog pathway activation to spatial dynamics within the cell."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " During neural development, its expression—directly induced by specific motor neuron transcription factors and stabilized by AKT signaling—supports the differentiation and diversification of motor neurons, underscoring a critical developmental role."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n ARHGAP36 expression is also up-regulated in several cancers. For instance, in medulloblastomas that have acquired resistance to Smoothened inhibitors, its overexpression has been linked to enhanced Gli-dependent transcription, while in papillary thyroid carcinoma and breast cancer, elevated ARHGAP36 levels promote malignant cell proliferation, migration, and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, genetic studies have identified increased ARHGAP36 expression in pheochromocytomas"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "and revealed de novo or X-linked variants in ARHGAP36 in patients with neural tube defects, suggesting that dysregulation of ARHGAP36 may contribute to neurodevelopmental abnormalities."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, structure–function analyses have dissected critical residues within its GAP-like domain and defined roles for its N- and C-terminal regions in regulating autoinhibition and subcellular localization, providing insights that could guide therapeutic targeting in ARHGAP36-dysregulated diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Paul G Rack, Jun Ni, Alexander Y Payumo, et al. 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