{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZFYVE9, also known as Smad Anchor for Receptor Activation (SARA), is a FYVE domain‐containing adaptor protein that primarily localizes to early endosomes by binding phosphatidylinositol 3‐phosphate. Its intrinsically flexible, largely disordered Smad‐binding domain enables it to recruit non‑phosphorylated Smad2/3 to activated TGF‑β receptors, thereby facilitating their phosphorylation and proper downstream signal transduction. In addition, related FYVE proteins—such as endofin, which preferentially modulates BMP–Smad signaling—underscore the versatility and context‐dependent functions of this protein family. Intriguingly, beyond its canonical role in TGF‑β signaling, ZFYVE9 has been implicated in specialized membrane trafficking events, such as orchestrating vesicular delivery during photoreceptor outer segment disc formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLocalizing to endosomes not only positions ZFYVE9 for Smad recruitment but also integrates it into the regulation of receptor trafficking and signal modulation. For example, its interactions with endocytic regulators—including PI3K subunits and the small GTPase Rab5—are critical for the internalization of TGF‑β receptors and formation of productive SARA–Smad complexes. Alterations in ZFYVE9 expression, whether through proteasome‐dependent degradation mediated by Smurf2/Smad7 complexes or via PI3K pathway perturbation, have been linked to impaired Smad2 activation. These changes are especially consequential in cellular models where high glucose or similar stressors provoke epithelial–mesenchymal transition (EMT) and extracellular matrix reorganization. Furthermore, binding partners such as ERBIN have been shown to interact with ZFYVE9, shifting the balance of Smad-dependent transcription and fine-tuning cellular responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its central roles in receptor trafficking and Smad activation, ZFYVE9 is implicated in diverse physiological and pathological contexts. In the retina, it contributes to the precise vesicular targeting of rhodopsin required for outer segment disc biogenesis, whereas in the central nervous system elevated ZFYVE9 expression and consequent Smad3 activation have been associated with temporal lobe epilepsy. Moreover, structural studies reveal that its disordered Smad-binding region mediates interactions via hydrophobic patches on the MH2 domains of Smads, providing a flexible mechanism for recognition of diverse targets. Notably, conflicting findings in certain B-cell lymphomas have suggested that ZFYVE9 may be dispensable for TGF‑β signaling under specific conditions. Finally, it is important to recognize that the acronym “SARA” is also used to denote the Scale for Assessment and Rating of Ataxia—a clinical instrument entirely distinct from the ZFYVE9 adaptor protein."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ekaterini Panopoulou, David J Gillooly, Jeffrey L Wrana, et al. 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