Affinage

SMAD6

SMAD family member 6 · UniProt O43541

Length
496 aa
Mass
53.5 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMAD6 is an inhibitory SMAD that serves as a negative-feedback brake on BMP/TGF-β superfamily signaling, acting at the receptor, in the cytoplasm, and within the nucleus (PMID:9335505, PMID:9436979). At the membrane it forms stable associations with type I receptors to block R-Smad phosphorylation, with selectivity for ALK-3/6 over ALK-1/2 dictated by residues in the receptor kinase N-lobe (PMID:9335505, PMID:17493940), and it additionally acts as a 'Smad4 decoy' by binding receptor-phosphorylated Smad1 to prevent productive Smad1–Smad4 complex formation (PMID:9436979). In the nucleus SMAD6 functions as a transcriptional corepressor: it complexes with the homeodomain factor Hoxc-8 to block Smad1-driven transcription (PMID:10722652) and recruits the corepressor CtBP through a PLDLS motif in its linker to repress BMP-induced Id1 (PMID:14645520). SMAD6 also extends beyond canonical Smad signaling to suppress non-canonical and inflammatory cascades, binding TAK1 to block BMP2-induced p38 activation (PMID:10748100), recruiting the deubiquitinase A20 to TRAF6 to abolish K63-linked ubiquitination (PMID:24096742), and binding Pellino-1 to disrupt the IRAK1–Pellino-1–TRAF6 complex and dampen NF-κB activation downstream of IL-1R/TLR (PMID:16951688). A recurring mechanism is SMAD6-dependent recruitment of the E3 ligases Smurf1/2 to direct ubiquitin-proteasome degradation of bound partners, including Runx2, Tbx6, MyD88, and PIAS3 (PMID:16299379, PMID:19561075, PMID:21897371, PMID:29950561). SMAD6 activity is itself tuned by post-translational modification — PRMT1-mediated arginine methylation potentiates its anti-inflammatory MyD88-degrading function (PMID:29420098), UBE2O-mediated monoubiquitination at K174 impairs receptor binding (PMID:23455153), and Arkadia-mediated ubiquitination targets SMAD6 for degradation to relieve BMP inhibition (PMID:25762727). In vivo, Smad6 is essential for cardiovascular development and homeostasis (PMID:10655064), for limiting BMP signaling during endochondral ossification (PMID:21681813), and for endothelial flow responses downstream of Notch1 (PMID:33779885).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1997 High

    Established SMAD6 as a negative regulator of TGF-β superfamily signaling acting at the receptor level, answering how the pathway is intrinsically restrained.

    Evidence Co-IP and phosphorylation assays in mammalian cells showing receptor association and blocked R-Smad phosphorylation

    PMID:9335505

    Open questions at the time
    • Receptor selectivity (ALK subtypes) not yet defined
    • Mechanism of decoy versus receptor block not distinguished
  2. 1998 High

    Defined a distinct cytoplasmic mechanism—competition with Smad4 for phospho-Smad1—showing SMAD6 inhibits downstream of receptor phosphorylation, not only at the receptor.

    Evidence Binding/Co-IP assays in Xenopus embryos and mammalian cells with functional reporters

    PMID:9436979

    Open questions at the time
    • Structural basis of the Smad1–Smad6 complex unresolved
    • Relative contribution of decoy versus receptor mechanisms in vivo unclear
  3. 1998 Medium

    Showed SMAD6 expression is induced by the very ligands it antagonizes, framing it as a negative-feedback component of BMP/TGF-β signaling.

    Evidence Northern blot and RT-PCR after TGF-β, activin, BMP-2/7 and EGF stimulation in multiple cell lines

    PMID:9514869 PMID:9712726

    Open questions at the time
    • Transcription factors mediating induction not yet identified
    • Single-lab transcriptional readouts
  4. 2000 High

    Identified the cis and trans elements driving feedback induction, mapping a BMP-Smad1/5-Smad6 circuit and a nuclear corepressor role.

    Evidence Promoter mutagenesis/EMSA defining the PBE; yeast two-hybrid, Co-IP and EMSA linking SMAD6 to Hoxc-8

    PMID:10692396 PMID:10722652

    Open questions at the time
    • Genome-wide SMAD6 target gene set not defined
    • How nuclear and receptor functions are partitioned unclear
  5. 2000 High

    Extended SMAD6 inhibition to a non-canonical branch (TAK1-p38) and established an essential in vivo cardiovascular role.

    Evidence TAK1 Co-IP with dominant-negative kinase and apoptosis assays; Smad6 knockout mice with cardiovascular phenotypes

    PMID:10655064 PMID:10748100

    Open questions at the time
    • Molecular basis of SMAD6-TAK1 inhibition not defined
    • Cell-type-specific contributions to cardiovascular phenotype not dissected
  6. 2003 High

    Pinpointed the corepressor recruitment mechanism for nuclear repression via the PLDLS-CtBP interaction.

    Evidence Site-directed PLDLS mutagenesis with Co-IP and Id1 reporter assays

    PMID:14645520

    Open questions at the time
    • Range of promoters subject to CtBP-dependent repression unknown
    • Whether CtBP recruitment cooperates with R-Smad binding unclear
  7. 2005 Medium

    Revealed SMAD6 as an adaptor that targets transcription factors (Runx2) and nuclear receptors (GR) for Smurf1-mediated degradation or corepressor-mediated silencing, broadening its effector repertoire.

    Evidence Co-IP, degradation/ubiquitination assays for Runx2; domain mapping, HDAC3 recruitment and in vivo adenoviral assays for GR; OAZ-driven Smad6 induction by ChIP

    PMID:16249187 PMID:16299379 PMID:16373339

    Open questions at the time
    • Specificity determinants for substrate selection unclear
    • Single-lab Co-IP and degradation evidence
  8. 2006 Medium

    Established SMAD6 as an anti-inflammatory node linking TGF-β/BMP signaling to IL-1R/TLR-NF-κB suppression and identified covalent modification of SMAD6 itself.

    Evidence Pellino-1 Co-IP/domain mapping with NF-κB reporters; PrKX in vitro kinase assay; PRMT1 in vitro methylation with MS; Dlx3 Co-IP/EMSA

    PMID:16491121 PMID:16687405 PMID:16951688 PMID:17118358

    Open questions at the time
    • Functional consequence of R74 methylation not established at this stage
    • Interplay of modifications not resolved
  9. 2007 Medium

    Defined receptor selectivity at residue resolution, explaining why SMAD6 preferentially restrains ALK-3/6 signaling.

    Evidence Mutagenesis of ALK-3 kinase-domain residues with reporter and binding assays

    PMID:17493940

    Open questions at the time
    • Structural complex of SMAD6 with receptor not solved
    • Single-lab mapping
  10. 2009 Medium

    Generalized the Smurf1-recruitment mechanism to additional developmental transcription factors (Tbx6), reinforcing SMAD6 as a degradation adaptor.

    Evidence Co-IP, domain mapping, ubiquitin-proteasome degradation and reporter assays with siRNA validation

    PMID:19561075

    Open questions at the time
    • In vivo relevance to Myf-5 regulation untested
    • Single-lab evidence
  11. 2011 High

    Resolved distinct biochemical mechanisms for inflammatory suppression—A20 recruitment to TRAF6 and Smurf1/2-mediated MyD88 degradation—and confirmed essential in vivo roles in skeletal and neural development.

    Evidence Ubiquitination/Co-IP assays for A20-TRAF6 and MyD88; Smad6 knockout growth-plate histology; in ovo chick knockdown for spinal cord; Runx1-driven enhancer ChIP; JNK1 receptor-binding assays

    PMID:21542012 PMID:21576367 PMID:21681813 PMID:21730158 PMID:21897371 PMID:24096742

    Open questions at the time
    • Coordination between SMAD6's many parallel mechanisms in a single cell unclear
    • Wnt/β-catenin inhibition mechanism only partly mapped
  12. 2013 High

    Showed SMAD6 activity is gated by monoubiquitination, providing a switch that relieves receptor inhibition.

    Evidence Proteomic screen, in vitro ubiquitination with K174/C885 mutagenesis, and BMP7-adipogenesis assays

    PMID:23455153

    Open questions at the time
    • Deubiquitinase reversing K174 modification unknown
    • Physiological triggers of UBE2O activity undefined
  13. 2015 Medium

    Identified Arkadia-mediated degradation as a route to inactivate SMAD6 and positively tune BMP signaling.

    Evidence Ubiquitination/degradation assays with Arkadia C937A mutant and knockout MEFs

    PMID:25762727

    Open questions at the time
    • Signals controlling Arkadia targeting of SMAD6 unknown
    • Single-lab evidence
  14. 2018 Medium

    Extended SMAD6 functions into oncogenic STAT3 signaling and refined the methylation mechanism as functionally consequential for inflammation.

    Evidence PIAS3 Co-IP/domain mapping and ubiquitination in glioma cells; PRMT1 methylation-site mutagenesis with periodontitis model

    PMID:29420098 PMID:29950561

    Open questions at the time
    • Context determining pro- versus anti-tumor roles unclear
    • Single-lab functional assays
  15. 2021 Medium

    Placed SMAD6 within an endothelial mechanotransduction axis, linking it to flow-mediated barrier and alignment responses downstream of Notch1.

    Evidence Notch1-SMAD6-PCDH12 epistasis with flow alignment, barrier and gene-expression assays

    PMID:33779885

    Open questions at the time
    • Direct biochemical link between SMAD6 and PCDH12 not defined
    • Single-lab epistasis

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SMAD6's many parallel activities—receptor inhibition, decoy function, transcriptional corepression, degradation-adaptor roles, and inflammatory suppression—are integrated and prioritized within a single cell, and the structural basis of its key interactions, remain unresolved.
  • No structural model of SMAD6-receptor or SMAD6-Smad1 complexes in the corpus
  • Hierarchy among cytoplasmic versus nuclear functions undefined
  • Disease-causing human mutations not addressed in the timeline

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CTBPMYD88PELLINO-1RUNX2SMAD1SMURF1TAK1TRAF6

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 SMAD6 forms stable associations with TGF-β superfamily type I receptors and interferes with phosphorylation of Smad2 and subsequent heteromerization with Smad4; it also inhibits BMP type IB receptor-induced phosphorylation of Smad1, acting as a negative regulator of TGF-β superfamily signaling. Co-immunoprecipitation, phosphorylation assays, overexpression in mammalian cells Nature High 9335505
1998 SMAD6 specifically competes with Smad4 for binding to receptor-phosphorylated Smad1, yielding an apparently inactive Smad1-Smad6 complex, thereby acting as a 'Smad4 decoy' to selectively antagonize BMP/Smad1 signaling without inhibiting receptor-mediated phosphorylation of Smad1. Binding assays in Xenopus embryos and mammalian cells, co-immunoprecipitation, overexpression/loss-of-function Genes & Development High 9436979
1998 SMAD6 mRNA is rapidly and directly induced by TGF-β1, activin, and BMP-7, as well as by EGF, establishing that expression of inhibitory Smads is regulated by multiple stimuli including TGF-β family members whose signaling they antagonize. Northern blot, RT-PCR, antisense RNA expression experiments in cultured cells Biochemical and Biophysical Research Communications Medium 9712726
1998 Smad6 mRNA expression is dramatically and selectively induced by BMP-2 and BMP-7 (OP-1) in various cell types, forming a negative feedback loop to regulate BMP signaling activity. Northern blot, RT-PCR in multiple cell types treated with BMPs Biochemical and Biophysical Research Communications Medium 9514869
2000 Smad6 interacts with the homeodomain transcription factor Hoxc-8 as a transcriptional corepressor in the nucleus; the Smad6-Hoxc-8 complex binds DNA and inhibits Smad1 interaction with Hoxc-8 and Smad1-induced transcription, establishing a nuclear function for Smad6 in BMP signaling inhibition. Yeast two-hybrid, co-immunoprecipitation, gel-shift (EMSA) assays, transcriptional reporter assays The Journal of Biological Chemistry High 10722652
2000 Smad6 expression is regulated by BMP-activated Smad1/5 via direct binding of Smad1/5 and Smad4 to a GC-rich BMP-responsive element (PBE) in the proximal Smad6 promoter, identifying the BMP-Smad1/5-Smad6 axis as a negative feedback circuit. Promoter deletion analysis, luciferase reporter assays, DNA-binding assays (gel shift), cotransfection experiments The Journal of Biological Chemistry High 10692396
2000 Smad6 negatively regulates the BMP2-induced TAK1-p38 kinase apoptotic pathway in addition to the Smad pathway; Smad6 directly binds TAK1 and blocks BMP2-induced TAK1 activation and p38 phosphorylation, conferring resistance to BMP2-induced apoptosis. Overexpression in MH60 hybridoma cells, kinase-negative dominant-negative assays, co-immunoprecipitation, kinase activation assays The Journal of Biological Chemistry Medium 10748100
2000 Targeted deletion of Smad6 (Madh6) in mice causes cardiac valve hyperplasia, outflow tract septation defects, aortic ossification, and elevated blood pressure, establishing an essential in vivo role for Smad6 in cardiovascular development and homeostasis. Targeted gene disruption in mice (knockout), LacZ reporter insertion, histological and physiological analysis Nature Genetics High 10655064
2003 Smad6 represses BMP-induced Id1 transcription by recruiting the transcriptional corepressor CtBP via a PLDLS consensus motif in the Smad6 linker region; mutation of the PLDLS motif abolishes CtBP binding and Smad6 repressor activity. Luciferase reporter assays, co-immunoprecipitation, site-directed mutagenesis of PLDLS motif Molecular and Cellular Biology High 14645520
2005 Smad6 directly interacts with Runx2 and mediates Smurf1-induced ubiquitin-proteasome-dependent degradation of Runx2, providing an indirect mechanism for Smurf1-induced Runx2 degradation beyond the PY motif interaction. Co-immunoprecipitation, ubiquitin-proteasome degradation assays, overexpression in mammalian cells The Journal of Biological Chemistry Medium 16299379
2005 Smad6 interacts with the N-terminal domain of the glucocorticoid receptor (GR) through its MH2 domain, suppresses GR-mediated transcriptional activity by recruiting histone deacetylase 3 (HDAC3) to DNA-bound GR, and antagonizes histone H3/H4 acetylation; adenovirus-mediated Smad6 overexpression inhibits glucocorticoid action in rat liver in vivo. Co-immunoprecipitation, transcriptional reporter assays, adenoviral overexpression in vivo, domain mapping The Journal of Biological Chemistry Medium 16249187
2006 Smad6 directly binds to Pellino-1 (an adaptor of IRAK1) via its MH2 domain, thereby disrupting the IRAK1-Pellino-1-TRAF6 signaling complex, preventing IκBα degradation and NF-κB nuclear translocation, and mediating TGF-β/BMP-induced anti-inflammatory effects on IL-1R/TLR signaling. Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assays, domain mapping Nature Immunology High 16951688
2006 PRMT1 (protein arginine N-methyltransferase 1) methylates Smad6 at arginine 74 in its N-terminal domain; Smad6 (but not Smad4 or R-Smads) is a substrate of PRMT1-mediated dimethylation. In vitro methylation assay, mass spectrometry identification of methylation site, co-immunoprecipitation, mutagenesis (Smad6R74A) FEBS Letters Medium 17118358
2006 Smad6 is phosphorylated by protein kinase X (PrKX) at a serine residue; PrKX and Smad6 co-localize to the nucleus during macrophage differentiation, and both proteins are required for PMA-induced HL-60 cell attachment, spreading, and differentiation. Yeast two-hybrid, co-immunoprecipitation, in vitro phosphorylation assay, mutagenesis of phosphorylation site, chromatin immunoprecipitation, siRNA knockdown Oncogene Medium 16491121
2007 Smad6 preferentially inhibits BMP signaling through ALK-3/6 receptors over ALK-1/2 receptors; specific amino acid residues in the N-terminal lobe of the ALK-3 kinase domain (Arg-238, Phe-264, Thr-265, Ala-269) are responsible for Smad6 sensitivity, and Smad6 interaction with type I receptors is a critical step in its inhibitory function. Reporter assays, mutagenesis of ALK-3 residues, binding/co-immunoprecipitation studies The Journal of Biological Chemistry Medium 17493940
2009 Smad6 interacts with T-box transcription factor Tbx6 via its MH2 domain (interacting with residues 90-180 of Tbx6) and recruits Smurf1 to facilitate ubiquitin-proteasome-dependent degradation of Tbx6, reducing Tbx6-mediated Myf-5 gene activation. Co-immunoprecipitation, ubiquitin-proteasome degradation assays, domain mapping, siRNA knockdown, luciferase reporter The Journal of Biological Chemistry Medium 19561075
2011 Smad6 inhibits the non-canonical TGF-β1 TRAF6-TAK1-p38 MAPK/JNK pathway by recruiting the A20 deubiquitinase to TRAF6, abolishing K63-linked polyubiquitination of TRAF6 and preventing downstream TAK1 and p38/JNK phosphorylation. Co-immunoprecipitation, ubiquitination assays, siRNA knockdown in cell lines and animal models, phosphorylation assays Nature Communications High 24096742
2011 TGF-β1-induced Smad6 (but not Smad7) recruits Smurf1 and Smurf2 E3 ubiquitin ligases to mediate K48-linked polyubiquitination and proteasomal degradation of MyD88, thereby suppressing TLR4 and TLR2 (MyD88-dependent) pro-inflammatory signaling but not MyD88-independent TLR3 signaling. Co-immunoprecipitation, siRNA knockdown, ubiquitination assays, NF-κB nuclear translocation assay Nature Communications High 21897371
2011 Loss of Smad6 in mice causes defects in endochondral bone formation, including delayed hypertrophic differentiation at midgestation and expanded hypertrophic zone at late gestation, attributed to increased BMP responsiveness in Smad6-deficient chondrocytes; Smad6 is essential to limit BMP signaling during cartilage development. Smad6 knockout mice, histological analysis of growth plates, BMP responsiveness assays in chondrocytes Journal of Bone and Mineral Research High 21681813
2011 Smad6 promotes neuronal differentiation in the intermediate zone of the dorsal spinal cord by inhibiting both the BMP pathway and the Wnt/β-catenin pathway; the inhibition of Wnt/β-catenin by Smad6 is independent of BMP inhibition and is mediated through the N-terminal domain and linker region of Smad6, which enhances interaction of CtBP with the β-catenin/TCF complex. In ovo knockdown (chick), reporter assays, domain mapping, co-immunoprecipitation PNAS Medium 21730158
2013 UBE2O (E2-230K) functions as an E2-E3 hybrid ubiquitin-conjugating enzyme that monoubiquitinates SMAD6 at lysine 174 (requiring Cys-885 of UBE2O); monoubiquitination of SMAD6 at this site impairs SMAD6 binding to the BMP type I receptor, thereby potentiating BMP7 signaling; UBE2O and SMAD6 cooperate in regulation of BMP7-induced adipogenesis. Proteomic interaction screen, in vitro ubiquitination assay, site-directed mutagenesis (K174, C885), binding assays, adipogenesis functional assay The EMBO Journal High 23455153
2015 Arkadia E3 ubiquitin ligase induces ubiquitylation and proteasome-dependent degradation of Smad6 (as well as Smad7 and c-Ski/SnoN), thereby positively regulating BMP signaling; Arkadia lacking E3 ligase activity (C937A mutant) fails to degrade Smad6. Ubiquitination assays, proteasome inhibitor treatments, Arkadia knockout MEFs, mutagenesis of Arkadia active site, transcriptional reporter assays Journal of Biochemistry Medium 25762727
2018 Nuclear Smad6 interacts directly with PIAS3 via its MH2 domain (and PIAS3 Ring domain), recruits Smurf1 via the PY motif to promote PIAS3 ubiquitination and degradation, thereby reducing PIAS3-mediated STAT3 inhibition and promoting glioma cell growth. Co-immunoprecipitation, domain mapping (MH2, PY motif mutations), ubiquitination assays, functional glioma cell assays Nature Communications Medium 29950561
2018 PRMT1-induced arginine methylation of Smad6 enables Smad6 to recruit MyD88 and promote its degradation, thereby inhibiting TLR-NF-κB signaling and periodontal inflammation; disruption of Smad6 methylation exacerbates inflammation and bone loss in experimental periodontitis. PRMT1-Smad6 signaling assays, methylation-site mutagenesis, MyD88 degradation assays, siRNA knockdown, experimental periodontitis animal model Journal of Dental Research Medium 29420098
2021 SMAD6 functions downstream of Notch1 signaling and upstream of the vascular protocadherin PCDH12 to transduce endothelial cell flow-mediated responses; SMAD6 depletion causes defective barrier function, upregulation of proliferation-associated genes, downregulation of junction-associated genes, and impaired flow-mediated endothelial cell alignment. Notch1 pathway manipulation combined with SMAD6 knockdown/rescue, flow alignment assays, gene expression analysis, barrier function assays Angiogenesis Medium 33779885
2005 OAZ (transcriptional activator and Smad1/4 cofactor) forms a complex with Smad1/4 upon BMP4 stimulation and activates the Smad6 gene; removal of endogenous OAZ prevents BMP4-induced Smad6 induction and extends Smad1 phosphorylation, while forced OAZ expression in cells that lack it accelerates Smad6 induction and attenuates BMP responses. OAZ knockout/knockdown and overexpression, chromatin immunoprecipitation, reporter assays, phospho-Smad1 assays The Journal of Biological Chemistry Medium 16373339
2006 Smad6 interacts with Dlx3 homeobox transcription factor (via the homeodomain-containing region residues 80-163 of Dlx3) in the nucleus of trophoblasts; Smad6 inhibits Dlx3 binding to target gene promoters (Esx1) and represses Dlx3-dependent transcription, as confirmed by siRNA knockdown of endogenous Smad6. Co-immunoprecipitation, immunocytochemistry, in vitro protein interaction mapping, EMSA, luciferase reporter, siRNA knockdown The Journal of Biological Chemistry Medium 16687405
2011 Runx1 (together with Fli1, Gata2, and Scl) directly regulates Smad6 expression via a novel upstream enhancer in the aorta-gonad-mesonephros region, establishing a functional rheostat where Runx1 controls its own activity by driving expression of Smad6, which targets Runx1 to the proteasome. ChIP, luciferase reporter (enhancer assay), Runx1 null embryo analysis, proteasomal inhibitor experiments Molecular and Cellular Biology Medium 21576367
2017 AMPK activation upregulates Smad6 and Smurf1 and enhances their interaction, leading to proteasome-dependent degradation of ALK2; knockdown of Smad6 or Smurf1 prevents metformin-induced reduction of ALK2 levels, placing the Smad6-Smurf1 complex as a mediator of AMPK-induced ALK2 degradation. AMPK activators/inhibitors, siRNA knockdown of Smad6/Smurf1, co-immunoprecipitation, proteasome inhibitor assays, iPS cell osteogenic differentiation Biochimica et Biophysica Acta: Molecular Cell Research Medium 28847510
2010 Smad6 and Smad7 bind simultaneously to discrete non-overlapping regions of Pellino-1 via distinct portions of their MH2 domains, and combined knockdown of both Smad6 and Smad7 further reduces TGF-β1 anti-inflammatory activity compared to single knockdown. Co-immunoprecipitation, domain mapping, double siRNA knockdown, NF-κB reporter assays Biochemical and Biophysical Research Communications Medium 20171181
2011 JNK1 (but not JNK2) activation decreases binding of inhibitory Smad6 to BMPR-I and reciprocally increases Smad1 binding to BMPR-I, thereby increasing cellular responsiveness to BMP-2 and promoting osteoblast differentiation. JNK gain-of-function and loss-of-function, receptor binding assays, phospho-Smad1 assays, osteoblast differentiation (mineralized nodule formation) Journal of Bone and Mineral Research Medium 21542012

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Smad6 inhibits signalling by the TGF-beta superfamily. Nature 875 9335505
1998 Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes & development 580 9436979
2000 A role for smad6 in development and homeostasis of the cardiovascular system. Nature genetics 388 10655064
1998 Induction of inhibitory Smad6 and Smad7 mRNA by TGF-beta family members. Biochemical and biophysical research communications 301 9712726
2000 Smad6 is a Smad1/5-induced smad inhibitor. Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter. The Journal of biological chemistry 231 10692396
2000 BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. The Journal of biological chemistry 203 10748100
1999 Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells. The Journal of biological chemistry 191 10224135
2016 Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles. eLife 163 27606499
2001 Müllerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces SMAD6 expression. Molecular endocrinology (Baltimore, Md.) 144 11376113
1998 Induction of Smad6 mRNA by bone morphogenetic proteins. Biochemical and biophysical research communications 138 9514869
2007 Selective inhibitory effects of Smad6 on bone morphogenetic protein type I receptors. The Journal of biological chemistry 131 17493940
2005 Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. The Journal of biological chemistry 128 16299379
2011 Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling. Nature communications 120 21897371
2000 Smad6 as a transcriptional corepressor. The Journal of biological chemistry 119 10722652
2006 Smad6 negatively regulates interleukin 1-receptor-Toll-like receptor signaling through direct interaction with the adaptor Pellino-1. Nature immunology 114 16951688
2012 Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation. Human mutation 98 22275001
2013 Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6. Nature communications 91 24096742
1999 Smad6 suppresses TGF-beta-induced growth inhibition in COLO-357 pancreatic cancer cells and is overexpressed in pancreatic cancer. Biochemical and biophysical research communications 91 10049697
2016 Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6. Nature communications 86 27834400
2017 Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor. Frontiers in physiology 84 28659821
2013 Fine-tuning BMP7 signalling in adipogenesis by UBE2O/E2-230K-mediated monoubiquitination of SMAD6. The EMBO journal 80 23455153
2003 Smad6 recruits transcription corepressor CtBP to repress bone morphogenetic protein-induced transcription. Molecular and cellular biology 80 14645520
1999 Evidence for a role of Smad6 in chick cardiac development. Developmental biology 72 10525349
2020 Saliva exosomes-derived UBE2O mRNA promotes angiogenesis in cutaneous wounds by targeting SMAD6. Journal of nanobiotechnology 71 32375794
2000 Smad7 and Smad6 differentially modulate transforming growth factor beta -induced inhibition of embryonic lung morphogenesis. The Journal of biological chemistry 68 10801843
2005 Activin receptor-like kinase 2 and Smad6 regulate epithelial-mesenchymal transformation during cardiac valve formation. Developmental biology 67 15766759
1998 Smad6 functions as an intracellular antagonist of some TGF-beta family members during Xenopus embryogenesis. Genes to cells : devoted to molecular & cellular mechanisms 65 9734784
2012 Up-regulation of BMP-2 antagonizes TGF-β1/ROCK-enhanced cardiac fibrotic signalling through activation of Smurf1/Smad6 complex. Journal of cellular and molecular medicine 62 22283839
2011 Smad6 is essential to limit BMP signaling during cartilage development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 58 21681813
2018 Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition. Nature communications 55 29950561
2011 Preferential activation of SMAD1/5/8 on the fibrosa endothelium in calcified human aortic valves--association with low BMP antagonists and SMAD6. PloS one 55 21698246
2008 SMAD6 contributes to patient survival in non-small cell lung cancer and its knockdown reestablishes TGF-beta homeostasis in lung cancer cells. Cancer research 55 19047146
2007 Bone morphogenetic protein 2 activates Smad6 gene transcription through bone-specific transcription factor Runx2. The Journal of biological chemistry 54 17215250
2006 Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring. Journal of plastic, reconstructive & aesthetic surgery : JPRAS 53 16676428
2003 Smad7 but not Smad6 cooperates with oncogenic ras to cause malignant conversion in a mouse model for squamous cell carcinoma. Cancer research 53 14633701
2010 Breast milk-transforming growth factor-β₂ specifically attenuates IL-1β-induced inflammatory responses in the immature human intestine via an SMAD6- and ERK-dependent mechanism. Neonatology 46 20881435
2015 Protective Role of Smad6 in Inflammation-Induced Valvular Cell Calcification. Journal of cellular biochemistry 44 25864564
2005 The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor: potential clinical implications. The Journal of biological chemistry 44 16249187
2001 Developmentally regulated expression of Smad3, Smad4, Smad6, and Smad7 involved in TGF-beta signaling. Mechanisms of development 44 11231077
2020 MicroRNA-374a-5p inhibits neuroinflammation in neonatal hypoxic-ischemic encephalopathy via regulating NLRP3 inflammasome targeted Smad6. Life sciences 43 32304765
2016 Infection of Hepatocytes With HCV Increases Cell Surface Levels of Heparan Sulfate Proteoglycans, Uptake of Cholesterol and Lipoprotein, and Virus Entry by Up-regulating SMAD6 and SMAD7. Gastroenterology 42 27693511
2010 Smad7 and Smad6 bind to discrete regions of Pellino-1 via their MH2 domains to mediate TGF-beta1-induced negative regulation of IL-1R/TLR signaling. Biochemical and biophysical research communications 42 20171181
2001 Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7. Genes to cells : devoted to molecular & cellular mechanisms 42 11737269
2004 CREB Cooperates with BMP-stimulated Smad signaling to enhance transcription of the Smad6 promoter. Journal of cellular physiology 41 14755548
2020 SMAD6 variants in craniosynostosis: genotype and phenotype evaluation. Genetics in medicine : official journal of the American College of Medical Genetics 39 32499606
2018 Smad6 Methylation Represses NFκB Activation and Periodontal Inflammation. Journal of dental research 39 29420098
2016 Smad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft model. Scientific reports 39 27113436
2005 OAZ regulates bone morphogenetic protein signaling through Smad6 activation. The Journal of biological chemistry 39 16373339
2012 Semaphorin 7A contributes to West Nile virus pathogenesis through TGF-β1/Smad6 signaling. Journal of immunology (Baltimore, Md. : 1950) 38 22896629
2003 Smad6 is induced by BMP-2 and modulates chondrocyte differentiation. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 37 12919880
2018 miR‑186, a serum microRNA, induces endothelial cell apoptosis by targeting SMAD6 in Kawasaki disease. International journal of molecular medicine 36 29344637
2012 Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload. Biochimica et biophysica acta 35 22960056
2015 Inhibition of lethal inflammatory responses through the targeting of membrane-associated Toll-like receptor 4 signaling complexes with a Smad6-derived peptide. EMBO molecular medicine 33 25766838
2011 Activation of c-Jun NH(2)-terminal kinase 1 increases cellular responsiveness to BMP-2 and decreases binding of inhibitory Smad6 to the type 1 BMP receptor. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 33 21542012
2003 Adenoviral overexpression of Smad-7 and Smad-6 differentially regulates TGF-beta-mediated chondrocyte proliferation and proteoglycan synthesis. Osteoarthritis and cartilage 32 14609530
2021 SMAD6 transduces endothelial cell flow responses required for blood vessel homeostasis. Angiogenesis 31 33779885
2020 SMAD6 Genotype Predicts Neurodevelopment in Nonsyndromic Craniosynostosis. Plastic and reconstructive surgery 31 31592950
2017 AMPK downregulates ALK2 via increasing the interaction between Smurf1 and Smad6, leading to inhibition of osteogenic differentiation. Biochimica et biophysica acta. Molecular cell research 31 28847510
2018 Hepatic SMARCA4 predicts HCC recurrence and promotes tumour cell proliferation by regulating SMAD6 expression. Cell death & disease 29 29352111
2011 Smad6 promotes neuronal differentiation in the intermediate zone of the dorsal neural tube by inhibition of the Wnt/beta-catenin pathway. Proceedings of the National Academy of Sciences of the United States of America 29 21730158
2020 Mesenchymal Behavior of the Endothelium Promoted by SMAD6 Downregulation Is Associated With Brain Arteriovenous Malformation Microhemorrhage. Stroke 28 32486965
2012 The CREB-Smad6-Runx2 axis contributes to the impaired osteogenesis potential of bone marrow stromal cells in fibrous dysplasia of bone. The Journal of pathology 28 22450860
2020 Foxf2 and Smad6 co-regulation of collagen 5A2 transcription is involved in the pathogenesis of intrauterine adhesion. Journal of cellular and molecular medicine 27 32022446
2019 SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis. Genetics in medicine : official journal of the American College of Medical Genetics 27 31138930
2003 Mutational analysis of TGF-beta type II receptor, Smad2, Smad3, Smad4, Smad6 and Smad7 genes in colorectal cancer. Journal of experimental & clinical cancer research : CR 27 12866583
2020 Circular RNA hsa_circ_0000517 modulates hepatocellular carcinoma advancement via the miR-326/SMAD6 axis. Cancer cell international 26 32774154
2009 Smad6 inhibits the transcriptional activity of Tbx6 by mediating its degradation. The Journal of biological chemistry 26 19561075
2006 Methylation of Smad6 by protein arginine N-methyltransferase 1. FEBS letters 26 17118358
2021 Hsa-miR-186-5p regulates TGFβ signaling pathway through expression suppression of SMAD6 and SMAD7 genes in colorectal cancer. Biological chemistry 25 33938174
2011 Lipopolysaccharide inhibits transforming growth factor-beta1-stimulated Smad6 expression by inducing phosphorylation of the linker region of Smad3 through a TLR4-IRAK1-ERK1/2 pathway. FEBS letters 25 21295571
2018 Developmental SMAD6 loss leads to blood vessel hemorrhage and disrupted endothelial cell junctions. Developmental biology 24 30098998
2022 SMAD6-deficiency in human genetic disorders. NPJ genomic medicine 22 36414630
2006 Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation. Oncogene 22 16491121
2006 Crk-associated substrate lymphocyte type regulates transforming growth factor-beta signaling by inhibiting Smad6 and Smad7. Oncogene 22 16909115
2020 Investigation of Genetic Polymorphisms in BMP2, BMP4, SMAD6, and RUNX2 and Persistent Apical Periodontitis. Journal of endodontics 21 33245975
2007 Molecular Interaction Between Smurfl WW2 Domain and PPXY Motifs of Smadl, Smad5, and Smad6-Modeling and Analysis. Journal of biomolecular structure & dynamics 21 22670624
2005 Bone morphogenetic protein activities are enhanced by 3',5'-cyclic adenosine monophosphate through suppression of Smad6 expression in osteoprogenitor cells. Bone 21 16203197
2000 Localization of Smad6 and Smad7 in the rat kidney and their regulated expression in the anti-Thy-1 nephritis. Molecular cell biology research communications : MCBRC 21 11170839
2012 Inhibition of erythropoiesis by Smad6 in human cord blood hematopoietic stem cells. Biochemical and biophysical research communications 20 22705548
2022 MiR-20a: a mechanosensitive microRNA that regulates fluid shear stress-mediated osteogenic differentiation via the BMP2 signaling pathway by targeting BAMBI and SMAD6. Annals of translational medicine 19 35845505
2020 HNF1B inhibits cell proliferation via repression of SMAD6 expression in prostate cancer. Journal of cellular and molecular medicine 18 33174391
2019 miR-134 inhibits chondrogenic differentiation of bone marrow mesenchymal stem cells by targetting SMAD6. Bioscience reports 18 30135141
2011 A Runx1-Smad6 rheostat controls Runx1 activity during embryonic hematopoiesis. Molecular and cellular biology 18 21576367
2007 Molecular interaction between Smurf1 WW2 domain and PPXY motifs of Smad1, Smad5, and Smad6--modeling and analysis. Journal of biomolecular structure & dynamics 18 17676934
2018 Co-occurrence of frameshift mutations in SMAD6 and TCF12 in a child with complex craniosynostosis. Human genome variation 17 30038786
2004 Expressions of inhibitory Smads, Smad6 and Smad7, are differentially regulated by TPA in human lung fibroblast cells. Biochemical and biophysical research communications 17 15033458
2020 SMAD6, positively regulated by the DNM3OS-miR-134-5p axis, confers promoting effects to cell proliferation, migration and EMT process in retinoblastoma. Cancer cell international 16 31992960
2019 MicroRNA-186 improves fracture healing through activating the bone morphogenetic protein signalling pathway by inhibiting SMAD6 in a mouse model of femoral fracture: An animal study. Bone & joint research 16 31832175
2018 MicroRNA‑92a overexpression promotes the osteogenic differentiation of bone mesenchymal stem cells by impeding Smad6‑mediated runt‑related transcription factor 2 degradation. Molecular medicine reports 16 29620201
2014 Smad6 suppresses the growth and self-renewal of hepatic progenitor cells. Journal of cellular physiology 16 24446200
2001 Mutational analysis of the Smad6 and Smad7 genes in hepatocellular carcinoma. International journal of molecular medicine 16 11408948
2019 A novel SMAD6 variant in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm. Molecular genetics & genomic medicine 15 30848080
2015 Arkadia enhances BMP signalling through ubiquitylation and degradation of Smad6. Journal of biochemistry 15 25762727
2021 A high level of lncFGD5-AS1 inhibits epithelial-to-Mesenchymal transition by regulating the miR-196a-5p/SMAD6/BMP axis in gastric Cancer. BMC cancer 14 33892661
2019 Biallelic variants in SMAD6 are associated with a complex cardiovascular phenotype. Human genetics 14 30963242
2009 Hoxc8 represses BMP-induced expression of Smad6. Molecules and cells 14 20016939
2006 Smad6 represses Dlx3 transcriptional activity through inhibition of DNA binding. The Journal of biological chemistry 14 16687405
2005 Adrenomedullin impairs the profibrotic effects of transforming growth factor-beta1 through recruiting Smad6 protein in human renal tubular cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 14 15665522
2000 Mutation analysis of the Smad6 and Smad7 gene in human ovarian cancers. International journal of oncology 14 11078792
2021 A genotype and phenotype analysis of SMAD6 mutant patients with radioulnar synostosis. Molecular genetics & genomic medicine 13 34953066

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