{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSMURF1 is a HECT‐domain E3 ubiquitin ligase that plays a central role in controlling cytoskeletal dynamics and cell motility. It is recruited to cellular protrusions by polarity complexes and mediates localized degradation of RhoA, thereby regulating actin cytoskeleton reorganization and tumor cell migration. In addition, through its interaction with inhibitory Smad7, SMURF1 modulates the turnover of TGF‑β receptors and influences directional cell movement and polarity. These activities have been documented in diverse cellular contexts—from the regulation of lamellipodia formation in transformed cells to the modulation of migratory behavior during pathological conditions—supporting SMURF1’s pivotal function in governing cellular motility and invasive potential."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of TGF‑β/BMP and osteogenic signaling, SMURF1 orchestrates receptor turnover and transcription factor degradation to finely tune cellular responsiveness and differentiation. By mediating ubiquitination and proteasomal degradation of critical effectors such as Runx2, and by promoting the nuclear export of inhibitory Smad7, SMURF1 acts as a negative regulator of the BMP–Smad–Runx2 cascade. Moreover, its activity can be modulated by upstream factors including Cdh1 and specific miRNAs, thus impacting osteoblast function, autophagosome maturation via substrates like UVRAG, and overall BMP signaling sensitivity in both normal bone formation and fibrotic conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cell polarity and differentiation, SMURF1 contributes to diverse aspects of disease pathogenesis, particularly in cancer and stress responses. In several malignancies—including pancreatic, gastric, lung, ovarian, and colon cancers—SMURF1 is frequently amplified or upregulated, where it accelerates tumor progression by promoting the degradation of substrates that negatively regulate cell growth, adhesion, and immune responses. For example, SMURF1 targets proteins involved in antiviral signaling (such as STAT1 and MAVS), modulates endoplasmic reticulum homeostasis by degrading WFS1, and influences axon growth and vascular integrity through interactions with factors like CCM2 and ARHGAP26. Its activity is further regulated by interacting partners such as FKBP12, USP9X, Ndfip1, and transcription factors like USF2, while being targeted by several microRNAs (e.g. miR‑1254) and kinases (e.g. p70S6K) that affect its stability and substrate specificity. 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