{"gene":"SMAD7","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":1998,"finding":"Smad7 mRNA is rapidly and directly induced by TGF-β1, activin, and BMP-7, and antisense Smad7 increases TGF-β1 effects, establishing Smad7 as a negative feedback regulator of TGF-β/BMP signaling.","method":"Antisense RNA expression, mRNA induction assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — antisense RNA functional rescue and transcriptional induction shown in cell lines, single lab with two complementary methods","pmids":["9712726"],"is_preprint":false},{"year":1998,"finding":"Xenopus Smad7 inhibits both activin and BMP pathways by associating with type I receptors and acts as a neural inducer in embryos by blocking BMP-4 signaling, with dosage-dependent effects on mesoderm specification.","method":"Animal cap explant assays, in vivo microinjection, embryological gain-of-function","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in Xenopus embryos, consistent with mammalian mechanism","pmids":["9640328"],"is_preprint":false},{"year":1998,"finding":"Xenopus Smad7 blocks ALK-4-mediated mesoderm induction in a graded fashion and directly activates neural markers in ectodermal explants independent of mesoderm.","method":"Xenopus animal cap explants, ectopic Smad7 expression, marker gene analysis","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays in Xenopus model system, ortholog with conserved mechanism","pmids":["9705232"],"is_preprint":false},{"year":2002,"finding":"Smad7 interacts with the transcriptional coactivator p300, leading to acetylation of Smad7 on two N-terminal lysine residues; acetylation stabilizes Smad7 by preventing ubiquitination of the same lysines by the E3 ligase Smurf1, revealing a competition between acetylation and ubiquitination for Smad7 stability.","method":"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis of lysine residues, ubiquitination assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical assays with mutagenesis, multiple orthogonal methods (Co-IP, acetylation, ubiquitination), single rigorous study","pmids":["12408818"],"is_preprint":false},{"year":2002,"finding":"YAP65 (YAP1) physically interacts with Smad7 via the Smad7 PY motif and additional domains, augments Smad7 association with activated TβRI, and potentiates Smad7 inhibitory activity against TGF-β/Smad3/4-dependent gene transactivation.","method":"Yeast two-hybrid screen, co-immunoprecipitation of co-expressed tagged proteins in COS-7 cells, deletion mutagenesis, reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, deletion mutagenesis and reporter assay, single lab","pmids":["12118366"],"is_preprint":false},{"year":2004,"finding":"Smad7 acts as an adaptor protein recruiting GADD34 (a regulatory subunit of PP1 holoenzyme) and thereby the catalytic subunit PP1c to TβRI, resulting in dephosphorylation of TβRI and providing a negative feedback mechanism; SARA enhances recruitment by controlling PP1c subcellular localization.","method":"Co-immunoprecipitation, RNA interference knockdown, in vitro phosphatase assay with PP1 inhibitor","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP, RNAi epistasis, in vitro dephosphorylation, and SARA localization control, multiple orthogonal methods in one study","pmids":["14718519"],"is_preprint":false},{"year":2004,"finding":"Ski represses basal Smad7 promoter activity in a SBE-dependent manner; Ski and Smad4 bind together to the endogenous Smad7 promoter; RNAi knockdown of Ski elevates endogenous Smad7 mRNA levels.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), SBE mutagenesis, RNAi knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — ChIP on endogenous promoter, mutagenesis of SBE, RNAi functional validation, multiple orthogonal methods","pmids":["15128733"],"is_preprint":false},{"year":2006,"finding":"Smad7 independently of its anti-Smad signaling role binds β-catenin and recruits E3 ligase Smurf2 to the Smad7/β-catenin complex, promoting β-catenin degradation and suppression of Wnt/β-catenin signaling, thereby shifting skin differentiation from hair follicles toward sebaceous glands.","method":"Co-immunoprecipitation, transgenic mouse model (Smad7 overexpression and Smurf2 co-expression), Smad7 siRNA knockdown, Wnt reporter assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of endogenous proteins, double transgenic and KD models, functional readout in vivo, multiple orthogonal methods","pmids":["16950122"],"is_preprint":false},{"year":2006,"finding":"Smad7 promotes skeletal muscle differentiation by directly interacting with MyoD and enhancing MyoD transcriptional activity; MyoD binds and transactivates the Smad7 proximal promoter, creating a positive feedback loop; siRNA knockdown of endogenous Smad7 inhibits C2C12 differentiation.","method":"Co-immunoprecipitation, siRNA knockdown, MyoD promoter transactivation assay, myogenesis phenotypic assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, RNAi loss-of-function, promoter transactivation, multiple orthogonal methods","pmids":["16880533"],"is_preprint":false},{"year":2006,"finding":"Smad7 and protein phosphatase 1α (PP1α) are specifically induced by TGF-β/ALK1 in endothelial cells; Smad7 and PP1α interact, PP1α interacts with ALK1, and this interaction is potentiated by Smad7; ectopic Smad7 or PP1α inhibits TGF-β/ALK1-induced Smad1/5 phosphorylation, while siRNA knockdown of either enhances it.","method":"Co-immunoprecipitation, siRNA knockdown, ectopic expression, kinase/phosphatase assays, PP1 inhibitor treatment","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNAi, pharmacological inhibition, single lab","pmids":["16571110"],"is_preprint":false},{"year":2009,"finding":"Smad7 has a nuclear coactivator function independent of TGF-β receptor binding: a nuclear-localized Smad7 (NLS chimera) does not suppress Smad3 activation but retains the ability to enhance myogenic gene activation by interacting with MyoD and antagonizing repressive MEK effects on MyoD.","method":"Nuclear localization signal (NLS) fusion construct, reporter assays, co-immunoprecipitation, myogenic conversion assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — engineered NLS chimera dissects nuclear vs receptor functions, Co-IP, reporter and myogenic conversion assays, multiple orthogonal methods","pmids":["19995910"],"is_preprint":false},{"year":2009,"finding":"SMAD7 is a potent suppressor of hepcidin expression; SMAD7 overexpression abolishes hepcidin activation by BMPs and TGF-β; a distinct SMAD regulatory motif (GTCAAGAC) in the hepcidin promoter mediates SMAD7-dependent hepcidin suppression, distinct from the hemojuvelin/BMP-responsive elements.","method":"High-throughput siRNA screen, overexpression in primary hepatocytes, promoter mutational analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen validated by overexpression and promoter mutagenesis, single lab","pmids":["20040761"],"is_preprint":false},{"year":2017,"finding":"OTUD1 directly deubiquitinates SMAD7 by cleaving Lysine 33-linked poly-ubiquitin chains on SMAD7 Lysine 220, preventing SMAD7 degradation; deubiquitination exposes the SMAD7 PY motif, enabling SMURF2 binding and subsequent TβRI turnover at the cell surface.","method":"Co-immunoprecipitation, deubiquitination assay, mutagenesis of ubiquitin linkage sites (K33, K220), loss-of-function screen in mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical deubiquitination assay, linkage-specific mutagenesis, Co-IP, in vivo metastasis model, multiple orthogonal methods","pmids":["29235476"],"is_preprint":false},{"year":2017,"finding":"USP26 deubiquitinates and stabilizes SMAD7; TGF-β induces USP26 expression; knockdown of USP26 degrades SMAD7, stabilizes TGF-β receptor, and enhances p-SMAD2 levels.","method":"USP26 knockdown, overexpression, co-immunoprecipitation, p-SMAD2 level measurement","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal regulation shown by KD and OE, Co-IP, single lab","pmids":["28381482"],"is_preprint":false},{"year":2017,"finding":"Smad7 activates STAT3 signaling to maintain mouse ESC pluripotency independently of TGF-β receptors but dependently on LIF co-receptor gp130; Smad7 directly binds the intracellular domain of gp130 and disrupts SHP2-gp130 or SOCS3-gp130 complexes, amplifying STAT3 activation.","method":"Co-immunoprecipitation, domain binding assays, ESC self-renewal and iPSC reprogramming assays, genetic rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of Smad7-gp130, disruption of SHP2/SOCS3 complexes, multiple functional readouts (ESC self-renewal, reprogramming), single lab with multiple orthogonal methods","pmids":["28874583"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the MH2 domain of mouse Smad7 at 1.9 Å resolution reveals a unique three-finger-like structure (residues 331-361, 379-387, and the L3 loop) stabilized by a hydrogen-bond network; this surface is distinct from the basic groove shared with Smad6 and R-Smads, providing a structural basis for Smad7's broader inhibitory activity against all seven TGF-β family type I receptors.","method":"X-ray crystallography (1.9 Å resolution), structural comparison","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — high-resolution crystal structure with structural analysis of functional surfaces, single study but Tier 1 method","pmids":["33166654"],"is_preprint":false},{"year":2020,"finding":"Smad7 interacts with ErbB2 in a TGF-β-independent manner and restrains ErbB1/ErbB2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins, and CD44; Smad7 also deactivates Smad2/3 and non-Smad TGF-β pathways without affecting TGF-β receptor activity in cardiac myofibroblasts.","method":"Co-immunoprecipitation (Smad7-ErbB2), myofibroblast-specific conditional Smad7 knockout, unbiased transcriptomics and proteomics, mouse model of non-reperfused infarction","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, conditional KO with in vivo phenotype, unbiased transcriptomics and proteomics, multiple orthogonal methods","pmids":["34905511"],"is_preprint":false},{"year":2021,"finding":"PRMT5 methylates Smad7 on Arg-57 (symmetric dimethylation), enhancing Smad7 binding to the IL-6 co-receptor gp130, thereby ensuring robust STAT3 activation; Smad7 depletion blocks PRMT5-mediated STAT3 activation.","method":"Co-immunoprecipitation, in vitro methylation assay, arginine mutagenesis (Arg-57), PRMT5 depletion/inhibition, STAT3 activation readout","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro methylation assay, site-specific mutagenesis (R57), Co-IP, functional rescue, multiple orthogonal methods","pmids":["34026434"],"is_preprint":false},{"year":2020,"finding":"Mesenchymal MACF1 directly interacts with SMAD7 and facilitates SMAD7 nuclear translocation to initiate downstream osteogenic pathways; conditional Macf1 knockout in mesenchymal stem cells decreases osteogenic differentiation.","method":"Co-immunoprecipitation (MACF1-SMAD7), conditional gene knockout, nuclear translocation assay, osteogenic differentiation assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, conditional KO, nuclear localization assay, single lab","pmids":["32143362"],"is_preprint":false},{"year":2022,"finding":"TAZ interacts with Smad7 and β-catenin in myoblasts and represses myogenic differentiation; TAZ becomes hyperphosphorylated at Ser89 during differentiation, leading to cytoplasmic sequestration; TAZ exhibits liquid-liquid phase separation properties in the nucleus.","method":"Co-immunoprecipitation (TAZ-Smad7, TAZ-β-catenin), ectopic TAZ expression, TAZ depletion, live-cell imaging (LLPS), Ser89 phosphorylation analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, loss- and gain-of-function, live imaging, single lab","pmids":["34859820"],"is_preprint":false},{"year":2017,"finding":"HDAC5 interacts with MEF2A to suppress MEF2A binding to the Smad7 promoter, repressing Smad7 promoter activity and thereby maintaining TGF-β1-induced Smad2/3 phosphorylation; Smad7 knockdown rescues the reduction in Smad2/3 phosphorylation caused by HDAC5 deficiency.","method":"Luciferase reporter assay, ChIP-qPCR, siRNA knockdown of HDAC5 and Smad7, in vivo hypertrophic scar model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, reporter assay, epistatic knockdown rescue, single lab","pmids":["36263180"],"is_preprint":false},{"year":2019,"finding":"HERC3 promotes ubiquitination-mediated degradation of SMAD7 in an autolysosome-dependent manner; HERC3 overexpression increases p-SMAD2/3 and activates the TGF-β pathway, inducing EMT in glioblastoma cells.","method":"Isobaric proteomics (iTRAQ), Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, intracranial xenograft","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification, Co-IP, ubiquitination assay, in vivo model, single lab","pmids":["30862693"],"is_preprint":false},{"year":2019,"finding":"TIEG1 directly binds a GC-box/Sp1 site (nucleotides -1392 to -1382) in the Smad7 promoter to repress Smad7 transcription; TIEG1 knockdown increases Smad7 promoter activity and protein expression, while overexpression decreases them; TIEG1-mediated Smad7 suppression promotes TGF-β1-driven Smad2 phosphorylation.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown and overexpression","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP on endogenous promoter, functional reporter assay, KD and OE, single lab","pmids":["28108300"],"is_preprint":false},{"year":2024,"finding":"In cardiac fibroblasts, Smad7 loss accentuates secretion of MMP2, and Smad7 overexpression reduces MMP2 levels; Smad7 suppresses macrophage activation through paracrine effects mediated by fibroblast-derived matricellular proteins (CD5L, SPARC, CTGF, ECM1, TGFBI); myofibroblast-specific Smad7 KO increases mortality, fibrosis, and dysfunction after pressure overload.","method":"Myofibroblast-specific conditional Smad7 KO (transverse aortic constriction model), secretomic analysis, collagen lattice contraction assay, MMP2 activity assay, macrophage co-culture","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with in vivo phenotype, secretomics, multiple functional assays, multiple orthogonal methods","pmids":["38899461"],"is_preprint":false},{"year":2023,"finding":"Overexpressed Smad7 physically binds to IκBα and inhibits its ubiquitination, thereby preventing NF-κB signaling activation in microglia.","method":"Co-immunoprecipitation (Smad7-IκBα), ubiquitination assay, Cx3cr1-Smad7 AAV overexpression model, neuroinflammation phenotypic readout","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo AAV model, single lab","pmids":["36739479"],"is_preprint":false},{"year":2014,"finding":"SMAD7 promotes beta-cell proliferation by increasing CyclinD1 and CyclinD2 and inducing nuclear exclusion of p27; M2 macrophage-derived TGF-β1 and EGF cooperate to induce SMAD7 upregulation and inhibit SMAD2 nuclear translocation in beta cells.","method":"Beta-cell-specific Smad7 mutant mice (PDL model), SMAD7 forced expression in beta cells in vivo, blockade of macrophage infiltration, CyclinD1/D2 and p27 protein analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional mutant mice, in vivo forced expression, mechanistic molecular readouts, single lab","pmids":["24639504"],"is_preprint":false},{"year":2009,"finding":"Smad7 overexpression blocks Smad2 phosphorylation induced by bleomycin in mouse lungs and prevents lung fibrosis (suppression of type I procollagen mRNA and hydroxyproline content), while Smad6 overexpression does not.","method":"Adenoviral gene transfer of Smad7 (vs Smad6) in mouse bleomycin lung fibrosis model, Smad2 phosphorylation analysis, hydroxyproline content measurement","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene transfer with direct molecular (p-Smad2) and functional (fibrosis) readouts, comparative Smad6 control","pmids":["10393693"],"is_preprint":false},{"year":2008,"finding":"Smad7 mutant mice with deletion of the MH2 domain develop cardiovascular defects (ventricular septal defect, non-compaction, outflow tract malformation) with elevated Smad2/3 phosphorylation in atrioventricular cushion and increased apoptosis in that region.","method":"Targeted deletion of MH2 domain in mice, cardiac histology, Smad2/3 phosphorylation analysis, apoptosis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined molecular and phenotypic readouts, single lab","pmids":["18952608"],"is_preprint":false},{"year":2018,"finding":"Hepatocyte-specific Smad7 knockout mice show decreased serum and tissue iron, increased hepcidin and phospho-Smad1/5/8, and mild iron-deficiency anemia due to reduced intestinal ferroportin, demonstrating Smad7 as a key negative regulator of iron homeostasis via BMP-Smad signaling.","method":"Hepatocyte-specific Smad7 knockout mice, serum iron/hepcidin measurements, phospho-Smad1/5/8 analysis, RNA-seq, in vitro overexpression of compensatory genes","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined molecular (p-Smad1/5/8, hepcidin) and systemic (iron, hemoglobin) phenotypes, RNA-seq, multiple orthogonal readouts","pmids":["29575577"],"is_preprint":false}],"current_model":"SMAD7 is an inhibitory Smad that functions as a central negative feedback regulator of TGF-β/BMP signaling: it is transcriptionally induced by TGF-β (and other stimuli), binds activated type I receptors to block R-Smad phosphorylation, recruits GADD34-PP1c to dephosphorylate TβRI, and recruits SMURF1/2 E3 ligases to promote receptor ubiquitination and degradation; its own stability is governed by competition between p300-mediated acetylation (stabilizing) and SMURF1-mediated ubiquitination (destabilizing) at overlapping N-terminal lysines, with deubiquitinases OTUD1 and USP26 further stabilizing SMAD7; beyond TGF-β, SMAD7 has TGF-β-independent nuclear functions including co-activation of MyoD to promote myogenesis, direct binding to gp130 to amplify LIF/STAT3 signaling (potentiated by PRMT5-mediated Arg-57 methylation), interaction with β-catenin/SMURF2 to suppress Wnt signaling, interaction with ErbB2 to restrain ErbB1/2 fibrogenic signaling, binding to IκBα to inhibit NF-κB, and facilitation of SMAD7 nuclear translocation by MACF1 to drive osteogenesis; its transcription is repressed by Ski/Smad4 at the SBE and by HDAC5/MEF2A and TIEG1 at the promoter, and epigenetically silenced by DNA methylation via DNMT1 or PHF14/DNMT3B."},"narrative":{"mechanistic_narrative":"SMAD7 is an inhibitory Smad that serves as the central negative-feedback brake on TGF-β/BMP-family signaling: it is rapidly and directly induced by TGF-β1, activin, and BMP-7, and blocking it amplifies TGF-β responses [PMID:9712726]. Mechanistically, SMAD7 associates with activated type I receptors to terminate signaling through two complementary routes — it acts as an adaptor that recruits the GADD34–PP1c holoenzyme (with SARA controlling PP1c localization) to dephosphorylate TβRI [PMID:14718519], and it recruits the E3 ligase SMURF2 to drive receptor turnover, an interaction gated by deubiquitination of SMAD7 at K220 by OTUD1, which exposes its PY motif [PMID:29235476]. A crystal structure of the SMAD7 MH2 domain reveals a unique three-finger surface that rationalizes its broad inhibitory reach across TGF-β-family type I receptors [PMID:33166654]. SMAD7 abundance is itself a regulatory node: p300-mediated acetylation and SMURF1-mediated ubiquitination compete at the same N-terminal lysines to set protein stability [PMID:12408818], with OTUD1 and USP26 stabilizing the protein [PMID:29235476, PMID:28381482] and HERC3 promoting its autolysosomal degradation [PMID:30862693]. Its transcription is set by repressors including Ski/Smad4 at the SBE [PMID:15128733], HDAC5/MEF2A [PMID:36263180], and TIEG1 [PMID:28108300] at the promoter. Beyond receptor antagonism, SMAD7 has TGF-β-independent activities: a nuclear coactivator function that potentiates MyoD-driven myogenesis [PMID:16880533, PMID:19995910], direct binding to gp130 that amplifies LIF/STAT3 signaling to sustain pluripotency (potentiated by PRMT5 methylation of Arg-57) [PMID:28874583, PMID:34026434], recruitment of SMURF2 to β-catenin to suppress Wnt signaling [PMID:16950122], binding to ErbB2 to restrain fibrogenic signaling [PMID:34905511], and binding to IκBα to inhibit NF-κB [PMID:36739479]. Functionally these activities converge on suppression of fibrosis [PMID:38899461, PMID:10393693], regulation of iron homeostasis through BMP–Smad control of hepcidin [PMID:29575577, PMID:20040761], cardiac development [PMID:18952608], and tissue differentiation programs [PMID:16950122, PMID:16880533].","teleology":[{"year":1998,"claim":"Established SMAD7 as a TGF-β/BMP-induced negative feedback regulator rather than a signal transducer, defining the inhibitory-Smad concept.","evidence":"mRNA induction assays and antisense knockdown in cell lines; Xenopus animal cap and microinjection assays showing receptor association and neural induction","pmids":["9712726","9640328","9705232"],"confidence":"Medium","gaps":["Did not resolve the biochemical mechanism of receptor inhibition","Stoichiometry and binding mode at type I receptors undefined"]},{"year":2002,"claim":"Defined how SMAD7 protein levels are set, showing acetylation and ubiquitination compete at shared N-terminal lysines to control stability.","evidence":"Co-IP, in vitro acetylation, lysine mutagenesis, and ubiquitination assays identifying p300 and SMURF1","pmids":["12408818"],"confidence":"High","gaps":["Did not establish upstream signals controlling the acetylation/ubiquitination switch","Physiological stoichiometry of acetylation in vivo unaddressed"]},{"year":2004,"claim":"Resolved the catalytic mechanism of receptor shutdown, showing SMAD7 is an adaptor delivering a phosphatase to TβRI.","evidence":"Co-IP, RNAi epistasis, in vitro phosphatase assays with PP1 inhibitor, and SARA localization control","pmids":["14718519"],"confidence":"High","gaps":["Relative contribution of dephosphorylation versus receptor degradation not quantified","Whether GADD34-PP1c recruitment operates on all type I receptors unknown"]},{"year":2004,"claim":"Identified transcriptional repression of SMAD7 as a tuning mechanism, with Ski/Smad4 acting at the SBE.","evidence":"Luciferase reporters, ChIP on the endogenous promoter, SBE mutagenesis, and Ski RNAi","pmids":["15128733"],"confidence":"High","gaps":["Did not map combinatorial control with other promoter factors","Cell-type specificity of Ski repression unaddressed"]},{"year":2006,"claim":"Revealed TGF-β-independent nuclear and cytoplasmic functions, dissociating SMAD7 from pure receptor antagonism.","evidence":"Co-IP, siRNA, promoter transactivation, and transgenic/knockout mouse models for MyoD-driven myogenesis and β-catenin/SMURF2-mediated Wnt suppression","pmids":["16880533","16950122"],"confidence":"High","gaps":["Whether nuclear functions require partial receptor pathway input not fully separated","Structural basis for MyoD and β-catenin binding undefined"]},{"year":2009,"claim":"Genetically separated the nuclear coactivator activity from receptor inhibition using a forced-nuclear SMAD7 chimera.","evidence":"NLS-fusion construct, reporter and myogenic conversion assays, Co-IP showing MyoD coactivation without Smad3 suppression","pmids":["19995910"],"confidence":"High","gaps":["Endogenous balance between nuclear and cytoplasmic pools not quantified","Mechanism of nuclear import in physiological settings unaddressed"]},{"year":2017,"claim":"Identified deubiquitinases that stabilize SMAD7 and linked deubiquitination to its receptor-degrading function.","evidence":"Linkage-specific ubiquitination assays, K33/K220 mutagenesis, Co-IP, and reciprocal knockdown for OTUD1 and USP26","pmids":["29235476","28381482"],"confidence":"High","gaps":["Tissue contexts where each DUB dominates not delineated","Cross-talk between OTUD1/USP26 and HERC3-driven degradation unresolved"]},{"year":2017,"claim":"Established SMAD7 as a direct amplifier of LIF/STAT3 signaling through gp130 binding, independent of TGF-β receptors.","evidence":"Co-IP, domain binding, disruption of SHP2/SOCS3-gp130 complexes, and ESC self-renewal/reprogramming assays","pmids":["28874583"],"confidence":"High","gaps":["Whether gp130 binding occurs in non-stem-cell contexts not tested here","Quantitative competition with SHP2/SOCS3 not measured"]},{"year":2020,"claim":"Provided a structural rationale for SMAD7's broad inhibitory activity via a unique MH2-domain surface.","evidence":"1.9 Å X-ray crystal structure of the mouse Smad7 MH2 domain with structural comparison to Smad6/R-Smads","pmids":["33166654"],"confidence":"High","gaps":["No co-structure with a type I receptor","Functional residues not validated by mutagenesis in this study"]},{"year":2021,"claim":"Showed a post-translational modification (PRMT5 Arg-57 methylation) tunes SMAD7's gp130/STAT3 amplifier function.","evidence":"In vitro methylation, R57 mutagenesis, Co-IP, PRMT5 depletion, and STAT3 activation readouts","pmids":["34026434"],"confidence":"High","gaps":["Interplay between Arg-57 methylation and lysine acetylation/ubiquitination unknown","Whether methylation affects receptor-inhibitory functions untested"]},{"year":2020,"claim":"Linked SMAD7 to fibrogenic ErbB signaling restraint, broadening its anti-fibrotic mechanism beyond Smad inhibition.","evidence":"Co-IP, myofibroblast-specific conditional KO with infarct model, unbiased transcriptomics and proteomics showing ErbB2 binding","pmids":["34905511"],"confidence":"High","gaps":["Direct structural interface with ErbB2 not defined","Relative weight of ErbB versus Smad effects in fibrosis not partitioned"]},{"year":2024,"claim":"Demonstrated that SMAD7 in myofibroblasts restrains fibrosis and inflammation through paracrine matricellular signaling in vivo.","evidence":"Myofibroblast-specific conditional KO (TAC model), secretomics, MMP2 activity and macrophage co-culture assays","pmids":["38899461"],"confidence":"High","gaps":["Direct molecular control of secreted factors by SMAD7 not mapped","Whether paracrine effect depends on receptor inhibition or other functions unclear"]},{"year":2018,"claim":"Established a systemic physiological role: hepatic SMAD7 negatively regulates iron homeostasis by restraining BMP-Smad-driven hepcidin.","evidence":"Hepatocyte-specific KO with iron/hepcidin measurements, phospho-Smad1/5/8 analysis, RNA-seq; prior hepcidin promoter mutagenesis","pmids":["29575577","20040761"],"confidence":"High","gaps":["The promoter motif mediating SMAD7-dependent hepcidin suppression not mechanistically connected to receptor inhibition","Tissue-autonomous versus systemic contributions partly unresolved"]},{"year":null,"claim":"How SMAD7's competing post-translational modifications, multiple non-canonical partners, and tissue-specific transcriptional control are integrated to select among its receptor-inhibitory versus coactivator functions in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking modification state to functional output","No co-structure of SMAD7 bound to a type I receptor or to its non-canonical partners","Quantitative partitioning between nuclear and receptor-proximal pools in vivo lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,12,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,12,24,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,24]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,12,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,8,27]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,12,13,21]}],"complexes":[],"partners":["SMURF2","PP1C","GADD34","P300","OTUD1","MYOD","GP130","ERBB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15105","full_name":"SMAD family member 7","aliases":["Mothers against decapentaplegic homolog 7","MAD homolog 7","Mothers against DPP homolog 7","Mothers against decapentaplegic homolog 8","MAD homolog 8","Mothers against DPP homolog 8"],"length_aa":426,"mass_kda":46.4,"function":"Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access (PubMed:21791611). Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O15105/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SMAD7","classification":"Not Classified","n_dependent_lines":59,"n_total_lines":1208,"dependency_fraction":0.048841059602649006},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SMAD7","total_profiled":1310},"omim":[{"mim_id":"616272","title":"MICRO RNA 520G; MIR520G","url":"https://www.omim.org/entry/616272"},{"mim_id":"612229","title":"COLORECTAL CANCER, SUSCEPTIBILITY TO, 3; CRCS3","url":"https://www.omim.org/entry/612229"},{"mim_id":"610667","title":"UBIQUITIN CARBOXYL-TERMINAL HYDROLASE L5; 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23426374","citation_count":24,"is_preprint":false},{"pmid":"27717618","id":"PMC_27717618","title":"miR-21 promotes collagen production in keloid via Smad7.","date":"2016","source":"Burns : journal of the International Society for Burn Injuries","url":"https://pubmed.ncbi.nlm.nih.gov/27717618","citation_count":24,"is_preprint":false},{"pmid":"28300830","id":"PMC_28300830","title":"Smad7 knockdown activates protein kinase RNA-associated eIF2α pathway leading to colon cancer cell death.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28300830","citation_count":23,"is_preprint":false},{"pmid":"37416778","id":"PMC_37416778","title":"FOXO3 regulates Smad3 and Smad7 through SPON1 circular RNA to inhibit idiopathic pulmonary fibrosis.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37416778","citation_count":22,"is_preprint":false},{"pmid":"35982887","id":"PMC_35982887","title":"Nitroxoline suppresses metastasis in bladder cancer via EGR1/circNDRG1/miR-520h/smad7/EMT signaling pathway.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35982887","citation_count":22,"is_preprint":false},{"pmid":"23155305","id":"PMC_23155305","title":"Role of Smad7 in inflammatory bowel diseases.","date":"2012","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/23155305","citation_count":22,"is_preprint":false},{"pmid":"25883225","id":"PMC_25883225","title":"Smad7 protects against chronic aristolochic acid nephropathy in mice.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25883225","citation_count":22,"is_preprint":false},{"pmid":"32038943","id":"PMC_32038943","title":"MiR-216a accelerates proliferation and fibrogenesis via targeting PTEN and SMAD7 in human cardiac fibroblasts.","date":"2019","source":"Cardiovascular diagnosis and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32038943","citation_count":22,"is_preprint":false},{"pmid":"19847872","id":"PMC_19847872","title":"Non-viral Smad7 gene delivery and attenuation of postoperative peritoneal adhesion in an experimental model.","date":"2009","source":"The British journal of surgery","url":"https://pubmed.ncbi.nlm.nih.gov/19847872","citation_count":21,"is_preprint":false},{"pmid":"37641479","id":"PMC_37641479","title":"Hydronidone ameliorates liver fibrosis by inhibiting activation of hepatic stellate cells via Smad7-mediated degradation of TGFβRI.","date":"2023","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/37641479","citation_count":20,"is_preprint":false},{"pmid":"33166654","id":"PMC_33166654","title":"Structural basis for inhibitory effects of Smad7 on TGF-β family signaling.","date":"2020","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/33166654","citation_count":20,"is_preprint":false},{"pmid":"33920230","id":"PMC_33920230","title":"Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33920230","citation_count":19,"is_preprint":false},{"pmid":"34859820","id":"PMC_34859820","title":"TAZ exhibits phase separation properties and interacts with Smad7 and β-catenin to repress skeletal myogenesis.","date":"2022","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34859820","citation_count":19,"is_preprint":false},{"pmid":"29575577","id":"PMC_29575577","title":"Smad7 deficiency decreases iron and haemoglobin through hepcidin up-regulation by multilayer compensatory mechanisms.","date":"2018","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29575577","citation_count":19,"is_preprint":false},{"pmid":"10906784","id":"PMC_10906784","title":"Expression of the inhibitory Smad7 in early mouse development and upregulation during embryonic vasculogenesis.","date":"2000","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/10906784","citation_count":19,"is_preprint":false},{"pmid":"29610597","id":"PMC_29610597","title":"Immunohistochemical Expression of TGF-Β1, SMAD4, SMAD7, TGFβRII and CD68-Positive TAM Densities in Papillary Thyroid Cancer.","date":"2018","source":"Open access Macedonian journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29610597","citation_count":19,"is_preprint":false},{"pmid":"28983617","id":"PMC_28983617","title":"CREB1 and Smad3 mediate TGF‑β3‑induced Smad7 expression in rat hepatic stellate cells.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28983617","citation_count":18,"is_preprint":false},{"pmid":"36056599","id":"PMC_36056599","title":"CDCA7 promotes TGF-β-induced epithelial-mesenchymal transition via transcriptionally regulating Smad4/Smad7 in ESCC.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/36056599","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50894,"output_tokens":7172,"usd":0.130131,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16296,"output_tokens":4366,"usd":0.095315,"stage2_stop_reason":"end_turn"},"total_usd":0.225446,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Smad7 mRNA is rapidly and directly induced by TGF-β1, activin, and BMP-7, and antisense Smad7 increases TGF-β1 effects, establishing Smad7 as a negative feedback regulator of TGF-β/BMP signaling.\",\n      \"method\": \"Antisense RNA expression, mRNA induction assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — antisense RNA functional rescue and transcriptional induction shown in cell lines, single lab with two complementary methods\",\n      \"pmids\": [\"9712726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Xenopus Smad7 inhibits both activin and BMP pathways by associating with type I receptors and acts as a neural inducer in embryos by blocking BMP-4 signaling, with dosage-dependent effects on mesoderm specification.\",\n      \"method\": \"Animal cap explant assays, in vivo microinjection, embryological gain-of-function\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in Xenopus embryos, consistent with mammalian mechanism\",\n      \"pmids\": [\"9640328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Xenopus Smad7 blocks ALK-4-mediated mesoderm induction in a graded fashion and directly activates neural markers in ectodermal explants independent of mesoderm.\",\n      \"method\": \"Xenopus animal cap explants, ectopic Smad7 expression, marker gene analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays in Xenopus model system, ortholog with conserved mechanism\",\n      \"pmids\": [\"9705232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Smad7 interacts with the transcriptional coactivator p300, leading to acetylation of Smad7 on two N-terminal lysine residues; acetylation stabilizes Smad7 by preventing ubiquitination of the same lysines by the E3 ligase Smurf1, revealing a competition between acetylation and ubiquitination for Smad7 stability.\",\n      \"method\": \"Co-immunoprecipitation, in vitro acetylation assay, mutagenesis of lysine residues, ubiquitination assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical assays with mutagenesis, multiple orthogonal methods (Co-IP, acetylation, ubiquitination), single rigorous study\",\n      \"pmids\": [\"12408818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"YAP65 (YAP1) physically interacts with Smad7 via the Smad7 PY motif and additional domains, augments Smad7 association with activated TβRI, and potentiates Smad7 inhibitory activity against TGF-β/Smad3/4-dependent gene transactivation.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation of co-expressed tagged proteins in COS-7 cells, deletion mutagenesis, reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP, deletion mutagenesis and reporter assay, single lab\",\n      \"pmids\": [\"12118366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Smad7 acts as an adaptor protein recruiting GADD34 (a regulatory subunit of PP1 holoenzyme) and thereby the catalytic subunit PP1c to TβRI, resulting in dephosphorylation of TβRI and providing a negative feedback mechanism; SARA enhances recruitment by controlling PP1c subcellular localization.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference knockdown, in vitro phosphatase assay with PP1 inhibitor\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP, RNAi epistasis, in vitro dephosphorylation, and SARA localization control, multiple orthogonal methods in one study\",\n      \"pmids\": [\"14718519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ski represses basal Smad7 promoter activity in a SBE-dependent manner; Ski and Smad4 bind together to the endogenous Smad7 promoter; RNAi knockdown of Ski elevates endogenous Smad7 mRNA levels.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), SBE mutagenesis, RNAi knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — ChIP on endogenous promoter, mutagenesis of SBE, RNAi functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"15128733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Smad7 independently of its anti-Smad signaling role binds β-catenin and recruits E3 ligase Smurf2 to the Smad7/β-catenin complex, promoting β-catenin degradation and suppression of Wnt/β-catenin signaling, thereby shifting skin differentiation from hair follicles toward sebaceous glands.\",\n      \"method\": \"Co-immunoprecipitation, transgenic mouse model (Smad7 overexpression and Smurf2 co-expression), Smad7 siRNA knockdown, Wnt reporter assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of endogenous proteins, double transgenic and KD models, functional readout in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"16950122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Smad7 promotes skeletal muscle differentiation by directly interacting with MyoD and enhancing MyoD transcriptional activity; MyoD binds and transactivates the Smad7 proximal promoter, creating a positive feedback loop; siRNA knockdown of endogenous Smad7 inhibits C2C12 differentiation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, MyoD promoter transactivation assay, myogenesis phenotypic assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, RNAi loss-of-function, promoter transactivation, multiple orthogonal methods\",\n      \"pmids\": [\"16880533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Smad7 and protein phosphatase 1α (PP1α) are specifically induced by TGF-β/ALK1 in endothelial cells; Smad7 and PP1α interact, PP1α interacts with ALK1, and this interaction is potentiated by Smad7; ectopic Smad7 or PP1α inhibits TGF-β/ALK1-induced Smad1/5 phosphorylation, while siRNA knockdown of either enhances it.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ectopic expression, kinase/phosphatase assays, PP1 inhibitor treatment\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNAi, pharmacological inhibition, single lab\",\n      \"pmids\": [\"16571110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Smad7 has a nuclear coactivator function independent of TGF-β receptor binding: a nuclear-localized Smad7 (NLS chimera) does not suppress Smad3 activation but retains the ability to enhance myogenic gene activation by interacting with MyoD and antagonizing repressive MEK effects on MyoD.\",\n      \"method\": \"Nuclear localization signal (NLS) fusion construct, reporter assays, co-immunoprecipitation, myogenic conversion assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — engineered NLS chimera dissects nuclear vs receptor functions, Co-IP, reporter and myogenic conversion assays, multiple orthogonal methods\",\n      \"pmids\": [\"19995910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SMAD7 is a potent suppressor of hepcidin expression; SMAD7 overexpression abolishes hepcidin activation by BMPs and TGF-β; a distinct SMAD regulatory motif (GTCAAGAC) in the hepcidin promoter mediates SMAD7-dependent hepcidin suppression, distinct from the hemojuvelin/BMP-responsive elements.\",\n      \"method\": \"High-throughput siRNA screen, overexpression in primary hepatocytes, promoter mutational analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen validated by overexpression and promoter mutagenesis, single lab\",\n      \"pmids\": [\"20040761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OTUD1 directly deubiquitinates SMAD7 by cleaving Lysine 33-linked poly-ubiquitin chains on SMAD7 Lysine 220, preventing SMAD7 degradation; deubiquitination exposes the SMAD7 PY motif, enabling SMURF2 binding and subsequent TβRI turnover at the cell surface.\",\n      \"method\": \"Co-immunoprecipitation, deubiquitination assay, mutagenesis of ubiquitin linkage sites (K33, K220), loss-of-function screen in mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical deubiquitination assay, linkage-specific mutagenesis, Co-IP, in vivo metastasis model, multiple orthogonal methods\",\n      \"pmids\": [\"29235476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP26 deubiquitinates and stabilizes SMAD7; TGF-β induces USP26 expression; knockdown of USP26 degrades SMAD7, stabilizes TGF-β receptor, and enhances p-SMAD2 levels.\",\n      \"method\": \"USP26 knockdown, overexpression, co-immunoprecipitation, p-SMAD2 level measurement\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal regulation shown by KD and OE, Co-IP, single lab\",\n      \"pmids\": [\"28381482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Smad7 activates STAT3 signaling to maintain mouse ESC pluripotency independently of TGF-β receptors but dependently on LIF co-receptor gp130; Smad7 directly binds the intracellular domain of gp130 and disrupts SHP2-gp130 or SOCS3-gp130 complexes, amplifying STAT3 activation.\",\n      \"method\": \"Co-immunoprecipitation, domain binding assays, ESC self-renewal and iPSC reprogramming assays, genetic rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of Smad7-gp130, disruption of SHP2/SOCS3 complexes, multiple functional readouts (ESC self-renewal, reprogramming), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28874583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the MH2 domain of mouse Smad7 at 1.9 Å resolution reveals a unique three-finger-like structure (residues 331-361, 379-387, and the L3 loop) stabilized by a hydrogen-bond network; this surface is distinct from the basic groove shared with Smad6 and R-Smads, providing a structural basis for Smad7's broader inhibitory activity against all seven TGF-β family type I receptors.\",\n      \"method\": \"X-ray crystallography (1.9 Å resolution), structural comparison\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — high-resolution crystal structure with structural analysis of functional surfaces, single study but Tier 1 method\",\n      \"pmids\": [\"33166654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Smad7 interacts with ErbB2 in a TGF-β-independent manner and restrains ErbB1/ErbB2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins, and CD44; Smad7 also deactivates Smad2/3 and non-Smad TGF-β pathways without affecting TGF-β receptor activity in cardiac myofibroblasts.\",\n      \"method\": \"Co-immunoprecipitation (Smad7-ErbB2), myofibroblast-specific conditional Smad7 knockout, unbiased transcriptomics and proteomics, mouse model of non-reperfused infarction\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, conditional KO with in vivo phenotype, unbiased transcriptomics and proteomics, multiple orthogonal methods\",\n      \"pmids\": [\"34905511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT5 methylates Smad7 on Arg-57 (symmetric dimethylation), enhancing Smad7 binding to the IL-6 co-receptor gp130, thereby ensuring robust STAT3 activation; Smad7 depletion blocks PRMT5-mediated STAT3 activation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, arginine mutagenesis (Arg-57), PRMT5 depletion/inhibition, STAT3 activation readout\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro methylation assay, site-specific mutagenesis (R57), Co-IP, functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"34026434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mesenchymal MACF1 directly interacts with SMAD7 and facilitates SMAD7 nuclear translocation to initiate downstream osteogenic pathways; conditional Macf1 knockout in mesenchymal stem cells decreases osteogenic differentiation.\",\n      \"method\": \"Co-immunoprecipitation (MACF1-SMAD7), conditional gene knockout, nuclear translocation assay, osteogenic differentiation assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, conditional KO, nuclear localization assay, single lab\",\n      \"pmids\": [\"32143362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAZ interacts with Smad7 and β-catenin in myoblasts and represses myogenic differentiation; TAZ becomes hyperphosphorylated at Ser89 during differentiation, leading to cytoplasmic sequestration; TAZ exhibits liquid-liquid phase separation properties in the nucleus.\",\n      \"method\": \"Co-immunoprecipitation (TAZ-Smad7, TAZ-β-catenin), ectopic TAZ expression, TAZ depletion, live-cell imaging (LLPS), Ser89 phosphorylation analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, loss- and gain-of-function, live imaging, single lab\",\n      \"pmids\": [\"34859820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC5 interacts with MEF2A to suppress MEF2A binding to the Smad7 promoter, repressing Smad7 promoter activity and thereby maintaining TGF-β1-induced Smad2/3 phosphorylation; Smad7 knockdown rescues the reduction in Smad2/3 phosphorylation caused by HDAC5 deficiency.\",\n      \"method\": \"Luciferase reporter assay, ChIP-qPCR, siRNA knockdown of HDAC5 and Smad7, in vivo hypertrophic scar model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, reporter assay, epistatic knockdown rescue, single lab\",\n      \"pmids\": [\"36263180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HERC3 promotes ubiquitination-mediated degradation of SMAD7 in an autolysosome-dependent manner; HERC3 overexpression increases p-SMAD2/3 and activates the TGF-β pathway, inducing EMT in glioblastoma cells.\",\n      \"method\": \"Isobaric proteomics (iTRAQ), Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, intracranial xenograft\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification, Co-IP, ubiquitination assay, in vivo model, single lab\",\n      \"pmids\": [\"30862693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TIEG1 directly binds a GC-box/Sp1 site (nucleotides -1392 to -1382) in the Smad7 promoter to repress Smad7 transcription; TIEG1 knockdown increases Smad7 promoter activity and protein expression, while overexpression decreases them; TIEG1-mediated Smad7 suppression promotes TGF-β1-driven Smad2 phosphorylation.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown and overexpression\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP on endogenous promoter, functional reporter assay, KD and OE, single lab\",\n      \"pmids\": [\"28108300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In cardiac fibroblasts, Smad7 loss accentuates secretion of MMP2, and Smad7 overexpression reduces MMP2 levels; Smad7 suppresses macrophage activation through paracrine effects mediated by fibroblast-derived matricellular proteins (CD5L, SPARC, CTGF, ECM1, TGFBI); myofibroblast-specific Smad7 KO increases mortality, fibrosis, and dysfunction after pressure overload.\",\n      \"method\": \"Myofibroblast-specific conditional Smad7 KO (transverse aortic constriction model), secretomic analysis, collagen lattice contraction assay, MMP2 activity assay, macrophage co-culture\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with in vivo phenotype, secretomics, multiple functional assays, multiple orthogonal methods\",\n      \"pmids\": [\"38899461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Overexpressed Smad7 physically binds to IκBα and inhibits its ubiquitination, thereby preventing NF-κB signaling activation in microglia.\",\n      \"method\": \"Co-immunoprecipitation (Smad7-IκBα), ubiquitination assay, Cx3cr1-Smad7 AAV overexpression model, neuroinflammation phenotypic readout\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, in vivo AAV model, single lab\",\n      \"pmids\": [\"36739479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SMAD7 promotes beta-cell proliferation by increasing CyclinD1 and CyclinD2 and inducing nuclear exclusion of p27; M2 macrophage-derived TGF-β1 and EGF cooperate to induce SMAD7 upregulation and inhibit SMAD2 nuclear translocation in beta cells.\",\n      \"method\": \"Beta-cell-specific Smad7 mutant mice (PDL model), SMAD7 forced expression in beta cells in vivo, blockade of macrophage infiltration, CyclinD1/D2 and p27 protein analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional mutant mice, in vivo forced expression, mechanistic molecular readouts, single lab\",\n      \"pmids\": [\"24639504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Smad7 overexpression blocks Smad2 phosphorylation induced by bleomycin in mouse lungs and prevents lung fibrosis (suppression of type I procollagen mRNA and hydroxyproline content), while Smad6 overexpression does not.\",\n      \"method\": \"Adenoviral gene transfer of Smad7 (vs Smad6) in mouse bleomycin lung fibrosis model, Smad2 phosphorylation analysis, hydroxyproline content measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene transfer with direct molecular (p-Smad2) and functional (fibrosis) readouts, comparative Smad6 control\",\n      \"pmids\": [\"10393693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Smad7 mutant mice with deletion of the MH2 domain develop cardiovascular defects (ventricular septal defect, non-compaction, outflow tract malformation) with elevated Smad2/3 phosphorylation in atrioventricular cushion and increased apoptosis in that region.\",\n      \"method\": \"Targeted deletion of MH2 domain in mice, cardiac histology, Smad2/3 phosphorylation analysis, apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined molecular and phenotypic readouts, single lab\",\n      \"pmids\": [\"18952608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Hepatocyte-specific Smad7 knockout mice show decreased serum and tissue iron, increased hepcidin and phospho-Smad1/5/8, and mild iron-deficiency anemia due to reduced intestinal ferroportin, demonstrating Smad7 as a key negative regulator of iron homeostasis via BMP-Smad signaling.\",\n      \"method\": \"Hepatocyte-specific Smad7 knockout mice, serum iron/hepcidin measurements, phospho-Smad1/5/8 analysis, RNA-seq, in vitro overexpression of compensatory genes\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined molecular (p-Smad1/5/8, hepcidin) and systemic (iron, hemoglobin) phenotypes, RNA-seq, multiple orthogonal readouts\",\n      \"pmids\": [\"29575577\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMAD7 is an inhibitory Smad that functions as a central negative feedback regulator of TGF-β/BMP signaling: it is transcriptionally induced by TGF-β (and other stimuli), binds activated type I receptors to block R-Smad phosphorylation, recruits GADD34-PP1c to dephosphorylate TβRI, and recruits SMURF1/2 E3 ligases to promote receptor ubiquitination and degradation; its own stability is governed by competition between p300-mediated acetylation (stabilizing) and SMURF1-mediated ubiquitination (destabilizing) at overlapping N-terminal lysines, with deubiquitinases OTUD1 and USP26 further stabilizing SMAD7; beyond TGF-β, SMAD7 has TGF-β-independent nuclear functions including co-activation of MyoD to promote myogenesis, direct binding to gp130 to amplify LIF/STAT3 signaling (potentiated by PRMT5-mediated Arg-57 methylation), interaction with β-catenin/SMURF2 to suppress Wnt signaling, interaction with ErbB2 to restrain ErbB1/2 fibrogenic signaling, binding to IκBα to inhibit NF-κB, and facilitation of SMAD7 nuclear translocation by MACF1 to drive osteogenesis; its transcription is repressed by Ski/Smad4 at the SBE and by HDAC5/MEF2A and TIEG1 at the promoter, and epigenetically silenced by DNA methylation via DNMT1 or PHF14/DNMT3B.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMAD7 is an inhibitory Smad that serves as the central negative-feedback brake on TGF-β/BMP-family signaling: it is rapidly and directly induced by TGF-β1, activin, and BMP-7, and blocking it amplifies TGF-β responses [#0]. Mechanistically, SMAD7 associates with activated type I receptors to terminate signaling through two complementary routes — it acts as an adaptor that recruits the GADD34–PP1c holoenzyme (with SARA controlling PP1c localization) to dephosphorylate TβRI [#5], and it recruits the E3 ligase SMURF2 to drive receptor turnover, an interaction gated by deubiquitination of SMAD7 at K220 by OTUD1, which exposes its PY motif [#12]. A crystal structure of the SMAD7 MH2 domain reveals a unique three-finger surface that rationalizes its broad inhibitory reach across TGF-β-family type I receptors [#15]. SMAD7 abundance is itself a regulatory node: p300-mediated acetylation and SMURF1-mediated ubiquitination compete at the same N-terminal lysines to set protein stability [#3], with OTUD1 and USP26 stabilizing the protein [#12, #13] and HERC3 promoting its autolysosomal degradation [#21]. Its transcription is set by repressors including Ski/Smad4 at the SBE [#6], HDAC5/MEF2A [#20], and TIEG1 [#22] at the promoter. Beyond receptor antagonism, SMAD7 has TGF-β-independent activities: a nuclear coactivator function that potentiates MyoD-driven myogenesis [#8, #10], direct binding to gp130 that amplifies LIF/STAT3 signaling to sustain pluripotency (potentiated by PRMT5 methylation of Arg-57) [#14, #17], recruitment of SMURF2 to β-catenin to suppress Wnt signaling [#7], binding to ErbB2 to restrain fibrogenic signaling [#16], and binding to IκBα to inhibit NF-κB [#24]. Functionally these activities converge on suppression of fibrosis [#23, #26], regulation of iron homeostasis through BMP–Smad control of hepcidin [#28, #11], cardiac development [#27], and tissue differentiation programs [#7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established SMAD7 as a TGF-β/BMP-induced negative feedback regulator rather than a signal transducer, defining the inhibitory-Smad concept.\",\n      \"evidence\": \"mRNA induction assays and antisense knockdown in cell lines; Xenopus animal cap and microinjection assays showing receptor association and neural induction\",\n      \"pmids\": [\"9712726\", \"9640328\", \"9705232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve the biochemical mechanism of receptor inhibition\", \"Stoichiometry and binding mode at type I receptors undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined how SMAD7 protein levels are set, showing acetylation and ubiquitination compete at shared N-terminal lysines to control stability.\",\n      \"evidence\": \"Co-IP, in vitro acetylation, lysine mutagenesis, and ubiquitination assays identifying p300 and SMURF1\",\n      \"pmids\": [\"12408818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish upstream signals controlling the acetylation/ubiquitination switch\", \"Physiological stoichiometry of acetylation in vivo unaddressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the catalytic mechanism of receptor shutdown, showing SMAD7 is an adaptor delivering a phosphatase to TβRI.\",\n      \"evidence\": \"Co-IP, RNAi epistasis, in vitro phosphatase assays with PP1 inhibitor, and SARA localization control\",\n      \"pmids\": [\"14718519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of dephosphorylation versus receptor degradation not quantified\", \"Whether GADD34-PP1c recruitment operates on all type I receptors unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified transcriptional repression of SMAD7 as a tuning mechanism, with Ski/Smad4 acting at the SBE.\",\n      \"evidence\": \"Luciferase reporters, ChIP on the endogenous promoter, SBE mutagenesis, and Ski RNAi\",\n      \"pmids\": [\"15128733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map combinatorial control with other promoter factors\", \"Cell-type specificity of Ski repression unaddressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed TGF-β-independent nuclear and cytoplasmic functions, dissociating SMAD7 from pure receptor antagonism.\",\n      \"evidence\": \"Co-IP, siRNA, promoter transactivation, and transgenic/knockout mouse models for MyoD-driven myogenesis and β-catenin/SMURF2-mediated Wnt suppression\",\n      \"pmids\": [\"16880533\", \"16950122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nuclear functions require partial receptor pathway input not fully separated\", \"Structural basis for MyoD and β-catenin binding undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetically separated the nuclear coactivator activity from receptor inhibition using a forced-nuclear SMAD7 chimera.\",\n      \"evidence\": \"NLS-fusion construct, reporter and myogenic conversion assays, Co-IP showing MyoD coactivation without Smad3 suppression\",\n      \"pmids\": [\"19995910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous balance between nuclear and cytoplasmic pools not quantified\", \"Mechanism of nuclear import in physiological settings unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified deubiquitinases that stabilize SMAD7 and linked deubiquitination to its receptor-degrading function.\",\n      \"evidence\": \"Linkage-specific ubiquitination assays, K33/K220 mutagenesis, Co-IP, and reciprocal knockdown for OTUD1 and USP26\",\n      \"pmids\": [\"29235476\", \"28381482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue contexts where each DUB dominates not delineated\", \"Cross-talk between OTUD1/USP26 and HERC3-driven degradation unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established SMAD7 as a direct amplifier of LIF/STAT3 signaling through gp130 binding, independent of TGF-β receptors.\",\n      \"evidence\": \"Co-IP, domain binding, disruption of SHP2/SOCS3-gp130 complexes, and ESC self-renewal/reprogramming assays\",\n      \"pmids\": [\"28874583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether gp130 binding occurs in non-stem-cell contexts not tested here\", \"Quantitative competition with SHP2/SOCS3 not measured\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided a structural rationale for SMAD7's broad inhibitory activity via a unique MH2-domain surface.\",\n      \"evidence\": \"1.9 Å X-ray crystal structure of the mouse Smad7 MH2 domain with structural comparison to Smad6/R-Smads\",\n      \"pmids\": [\"33166654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure with a type I receptor\", \"Functional residues not validated by mutagenesis in this study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed a post-translational modification (PRMT5 Arg-57 methylation) tunes SMAD7's gp130/STAT3 amplifier function.\",\n      \"evidence\": \"In vitro methylation, R57 mutagenesis, Co-IP, PRMT5 depletion, and STAT3 activation readouts\",\n      \"pmids\": [\"34026434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between Arg-57 methylation and lysine acetylation/ubiquitination unknown\", \"Whether methylation affects receptor-inhibitory functions untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked SMAD7 to fibrogenic ErbB signaling restraint, broadening its anti-fibrotic mechanism beyond Smad inhibition.\",\n      \"evidence\": \"Co-IP, myofibroblast-specific conditional KO with infarct model, unbiased transcriptomics and proteomics showing ErbB2 binding\",\n      \"pmids\": [\"34905511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural interface with ErbB2 not defined\", \"Relative weight of ErbB versus Smad effects in fibrosis not partitioned\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that SMAD7 in myofibroblasts restrains fibrosis and inflammation through paracrine matricellular signaling in vivo.\",\n      \"evidence\": \"Myofibroblast-specific conditional KO (TAC model), secretomics, MMP2 activity and macrophage co-culture assays\",\n      \"pmids\": [\"38899461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular control of secreted factors by SMAD7 not mapped\", \"Whether paracrine effect depends on receptor inhibition or other functions unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established a systemic physiological role: hepatic SMAD7 negatively regulates iron homeostasis by restraining BMP-Smad-driven hepcidin.\",\n      \"evidence\": \"Hepatocyte-specific KO with iron/hepcidin measurements, phospho-Smad1/5/8 analysis, RNA-seq; prior hepcidin promoter mutagenesis\",\n      \"pmids\": [\"29575577\", \"20040761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The promoter motif mediating SMAD7-dependent hepcidin suppression not mechanistically connected to receptor inhibition\", \"Tissue-autonomous versus systemic contributions partly unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SMAD7's competing post-translational modifications, multiple non-canonical partners, and tissue-specific transcriptional control are integrated to select among its receptor-inhibitory versus coactivator functions in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking modification state to functional output\", \"No co-structure of SMAD7 bound to a type I receptor or to its non-canonical partners\", \"Quantitative partitioning between nuclear and receptor-proximal pools in vivo lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 12, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 12, 24, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 24]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 12, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 8, 27]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 12, 13, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SMURF2\", \"PP1c\", \"GADD34\", \"p300\", \"OTUD1\", \"MyoD\", \"gp130\", \"ErbB2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}