Affinage

SMAD6

SMAD family member 6 · UniProt O43541

Length
496 aa
Mass
53.5 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMAD6 is an inhibitory SMAD that serves as a central negative regulator of BMP/TGF-β superfamily signaling and inflammatory pathways through multiple cytoplasmic and nuclear mechanisms. In the cytoplasm, SMAD6 binds preferentially to BMP type I receptors ALK-3/6 to block R-SMAD phosphorylation, acts as a SMAD4 decoy by forming inactive complexes with phosphorylated SMAD1, inhibits non-canonical TAK1-p38 signaling by binding TAK1 and recruiting deubiquitinase A20 to TRAF6, and scaffolds Smurf1/Smurf2 E3 ligases to target substrates including Runx2, Tbx6, MyD88, PIAS3, and ALK2 for proteasomal degradation (PMID:9335505, PMID:9436979, PMID:10748100, PMID:24096742, PMID:16299379, PMID:21897371, PMID:29950561). In the nucleus, SMAD6 recruits corepressors CtBP and HDAC3 to repress BMP target genes and glucocorticoid receptor targets, acts as a corepressor with Hox and Dlx transcription factors, and inhibits Wnt/β-catenin signaling by promoting CtBP interaction with the β-catenin/TCF complex (PMID:14645520, PMID:16249187, PMID:10722652, PMID:21730158). SMAD6 itself is regulated post-translationally by UBE2O-mediated monoubiquitination at Lys174, PRMT1 methylation at Arg74, PrKX phosphorylation, Arkadia-mediated degradation, and JNK1-dependent modulation of receptor binding, while its transcription is driven by BMP-activated SMAD1/5-SMAD4 through a GC-rich promoter element and by Runx2 through a bone-specific OSE2-a element, establishing tissue-specific negative feedback loops essential for cardiovascular, skeletal, vascular, and hematopoietic development (PMID:23455153, PMID:17118358, PMID:16491121, PMID:25762727, PMID:10692396, PMID:17215250, PMID:10655064, PMID:21681813, PMID:30098998).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Identification of SMAD6 as an inhibitory SMAD that stably associates with TGF-β/BMP type I receptors and blocks R-SMAD phosphorylation established the existence of intracellular antagonists within the SMAD signaling cascade.

    Evidence Co-immunoprecipitation and phosphorylation assays in transfected mammalian cells

    PMID:9335505

    Open questions at the time
    • Receptor subtype specificity not yet defined
    • Nuclear versus cytoplasmic site of action unclear
    • Post-translational regulation of SMAD6 unknown
  2. 1998 High

    Demonstration that SMAD6 acts as a SMAD4 decoy — competing with SMAD4 for binding to phosphorylated SMAD1 to form an inactive complex — revealed a second inhibitory mechanism independent of receptor blockade and explained SMAD6's preference for BMP over TGF-β signaling.

    Evidence Co-immunoprecipitation in mammalian cells and functional assays in Xenopus embryos

    PMID:9436979

    Open questions at the time
    • Whether SMAD6 employs both mechanisms simultaneously in physiological contexts not resolved
    • Structural basis of SMAD1-SMAD6 versus SMAD1-SMAD4 competition unknown
  3. 2000 High

    Four simultaneous discoveries in 2000 defined the physiological importance and mechanistic breadth of SMAD6: knockout mice revealed essential cardiovascular roles; SMAD6 was shown to block non-canonical BMP-TAK1-p38 signaling by binding TAK1; nuclear corepressor function was established through interaction with Hoxc-8; and BMP-responsive promoter elements were identified, closing the negative feedback loop.

    Evidence Smad6 KO mice with cardiac valve/outflow tract defects; Co-IP of SMAD6-TAK1 with kinase-dead rescue; yeast two-hybrid and EMSA for SMAD6-Hoxc-8 DNA binding; promoter deletion and EMSA for SMAD1/5-SMAD4 binding to GCCGnCGC element

    PMID:10655064 PMID:10692396 PMID:10722652 PMID:10748100

    Open questions at the time
    • TAK1 binding mechanism and whether it involves TAB1 or is direct not fully resolved
    • Relative contribution of receptor-level versus nuclear inhibition in vivo unclear
    • Feedback loop dynamics not quantified
  4. 2003 High

    Identification of CtBP as a SMAD6-recruited corepressor via a PLDLS motif in the linker region established the molecular basis of SMAD6's transcriptional repressor activity at BMP target genes such as Id1.

    Evidence Co-IP and mutagenesis of PLDLS motif with BMP-responsive reporter assays

    PMID:14645520

    Open questions at the time
    • Genome-wide targets of SMAD6-CtBP repression not defined
    • Whether CtBP and HDAC3 corepressor activities are independent or cooperative unclear
  5. 2005 High

    Discovery that SMAD6 scaffolds the Smurf1 E3 ligase to Runx2 for ubiquitin-proteasomal degradation, and independently recruits HDAC3 to suppress glucocorticoid receptor transcription, revealed SMAD6 as a versatile adaptor for both protein degradation and chromatin modification beyond canonical SMAD pathways.

    Evidence Reciprocal Co-IP of SMAD6-Runx2-Smurf1 with proteasome inhibitor controls; Co-IP of SMAD6-GR-HDAC3 with chromatin acetylation assays and in vivo adenoviral delivery

    PMID:16249187 PMID:16299379

    Open questions at the time
    • Full repertoire of SMAD6-Smurf substrates not catalogued
    • Whether SMAD6-HDAC3 interaction is direct or bridged unknown
  6. 2006 High

    Multiple 2006 studies expanded SMAD6's regulatory network: post-translational modifications by PrKX (serine phosphorylation) and PRMT1 (Arg74 methylation) were mapped; anti-inflammatory function through disruption of the IRAK1-Pellino-1-TRAF6 complex was demonstrated; Notch-driven SMAD6 expression was shown to set BMP responsiveness; and nuclear interactions with Dlx3/4 homeodomain factors in trophoblasts were established.

    Evidence In vitro kinase and methylation assays with mass spectrometry and mutagenesis; Co-IP of SMAD6-Pellino-1 with NF-κB reporter and siRNA; SMAD6 interaction with Dlx3 by Co-IP, EMSA, and siRNA

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

    Open questions at the time
    • Functional consequence of Arg74 methylation on SMAD6 activity not fully characterized in this year
    • Cross-talk between phosphorylation and methylation modifications unknown
    • Whether Pellino-1 binding and Smurf scaffolding are mutually exclusive unclear
  7. 2007 High

    Receptor subtype specificity of SMAD6 was resolved: SMAD6 preferentially inhibits ALK-3/6 over ALK-1/2, with specific kinase domain residues (Arg-238, Phe-264, Thr-265, Ala-269) determining sensitivity; additionally, Runx2-dependent bone-specific Smad6 transcription through an OSE2-a promoter element was identified.

    Evidence Mutagenesis of ALK-3 kinase domain residues with Co-IP and reporter assays; promoter deletion, EMSA, and ChIP for OSE2-a element

    PMID:17215250 PMID:17493940

    Open questions at the time
    • Structural basis of SMAD6-ALK3 kinase domain interaction not determined
    • Whether ALK-1/2 escape from SMAD6 inhibition is physiologically important in specific tissues unknown
  8. 2009 High

    Extension of the SMAD6-Smurf scaffolding paradigm to Tbx6 degradation showed SMAD6's MH2 domain bridges Smurf1 to diverse transcription factor substrates, establishing a generalizable adaptor mechanism.

    Evidence Co-IP with domain mapping, ubiquitination and degradation assays, siRNA knockdown, and Myf-5 reporter readout

    PMID:19561075

    Open questions at the time
    • Whether SMAD6-Smurf targets other T-box family members not tested
    • In vivo significance for somitogenesis not demonstrated
  9. 2011 High

    A cluster of 2011 studies defined SMAD6's roles in innate immunity, Wnt inhibition, skeletal development, and hematopoietic feedback: SMAD6 recruits Smurf1/2 for K48-linked ubiquitination and degradation of MyD88; SMAD6 inhibits Wnt/β-catenin signaling by enhancing CtBP-β-catenin/TCF interaction during neural differentiation; Smad6 KO mice exhibit vertebral and growth plate defects from excess BMP signaling; JNK1 reduces SMAD6-receptor binding to enhance BMP responsiveness; and Runx1 drives Smad6 expression to create a self-limiting hematopoietic feedback loop.

    Evidence Co-IP with ubiquitin linkage assays and NF-κB reporters; in ovo knockdown in chick with domain deletion analysis; Smad6 KO mouse skeletal phenotyping with chondrocyte BMP assays; JNK gain/loss-of-function with receptor Co-IP; ChIP in AGM region with Runx1 KO embryos

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

    Open questions at the time
    • Whether SMAD6-mediated Wnt inhibition operates beyond neural and hepatic contexts not established
    • Mechanism by which JNK1 displaces SMAD6 from receptors not molecularly defined
    • Relative contributions of Smurf1 versus Smurf2 to MyD88 degradation not resolved
  10. 2013 High

    Two key regulatory mechanisms were uncovered: SMAD6 recruits deubiquitinase A20 to remove K63-polyubiquitin from TRAF6, blocking non-canonical TGF-β1-TAK1 signaling; and UBE2O monoubiquitinates SMAD6 at Lys174, impairing receptor binding and thereby relieving SMAD6's inhibition of BMP7 signaling to promote adipogenesis.

    Evidence Co-IP of A20-SMAD6-TRAF6 with K63 deubiquitination assays and in vivo validation; in vitro ubiquitination reconstitution with Lys174 mutagenesis, receptor binding assays, and adipogenesis readout

    PMID:23455153 PMID:24096742

    Open questions at the time
    • Whether A20 recruitment and Smurf scaffolding occur on the same or different SMAD6 pools unknown
    • Other monoubiquitination sites on SMAD6 not surveyed
    • Tissue-specific regulation of UBE2O-SMAD6 axis not explored
  11. 2015 High

    Arkadia (RNF111) was identified as an E3 ligase that ubiquitinates and degrades SMAD6 via the proteasome, providing a mechanism for relieving SMAD6-imposed BMP inhibition during osteoblast differentiation.

    Evidence Ubiquitylation assay with catalytic mutant C937A, proteasome inhibitor treatment, Arkadia KO MEFs, BMP reporter assays

    PMID:25762727

    Open questions at the time
    • Whether Arkadia targets SMAD6 in non-bone contexts unknown
    • Lysine residues on SMAD6 targeted by Arkadia not mapped
  12. 2017 High

    AMPK activation was shown to upregulate both SMAD6 and Smurf1 and enhance their interaction, leading to degradation of the BMP type I receptor ALK2, including the disease-associated ALK2-R206H FOP mutant — revealing a pharmacologically targetable SMAD6-dependent receptor turnover pathway.

    Evidence Co-IP and siRNA epistasis for SMAD6-Smurf1-ALK2, proteasome inhibitor validation, FOP patient-derived iPSCs

    PMID:28847510

    Open questions at the time
    • Whether SMAD6-Smurf1 targets other type I receptors beyond ALK2 via AMPK not tested
    • In vivo therapeutic efficacy not demonstrated
  13. 2018 High

    Three 2018 studies revealed new dimensions of SMAD6 function: PRMT1-mediated methylation enables SMAD6 to recruit and degrade MyD88, limiting inflammation and bone loss; nuclear SMAD6 scaffolds Smurf1 to degrade the STAT3 inhibitor PIAS3, promoting glioma growth; and SMAD6 loss causes vascular hemorrhage through increased VE-cadherin endocytosis and disrupted adherens junctions.

    Evidence In vitro methylation with in vivo periodontitis model; Co-IP and domain mapping of SMAD6-PIAS3-Smurf1 with glioma cell growth assays; conditional/global SMAD6 KO mice with retinal vessel imaging and VE-cadherin endocytosis assay

    PMID:29420098 PMID:29950561 PMID:30098998

    Open questions at the time
    • Whether SMAD6-PIAS3 axis operates in tumors beyond glioma not tested
    • Direct mechanism linking SMAD6 loss to VE-cadherin endocytosis not molecularly defined
    • Methylation-dependent substrate selection by SMAD6 not systematically addressed
  14. 2021 High

    SMAD6 was placed in a Notch1→SMAD6→PCDH12 signaling axis in endothelial cells that controls flow-mediated responses, barrier function, and junctional gene expression, extending SMAD6's vascular roles beyond BMP inhibition.

    Evidence siRNA knockdown and genetic rescue in endothelial cells under flow, epistasis with Notch1 pathway manipulation, gene expression profiling

    PMID:33779885

    Open questions at the time
    • Whether SMAD6's role in flow sensing requires its BMP-inhibitory or scaffolding activities unknown
    • Mechanism by which SMAD6 regulates PCDH12 expression not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis of SMAD6's selective interaction with ALK-3/6, how multiple post-translational modifications (ubiquitination, methylation, phosphorylation) are integrated to regulate SMAD6 activity in specific cellular contexts, and whether SMAD6's diverse scaffolding, corepressor, and decoy functions are partitioned by subcellular localization or by distinct SMAD6 pools.
  • No crystal structure of SMAD6 in complex with any receptor or partner
  • Systematic identification of all SMAD6-Smurf substrates lacking
  • Integration of multiple PTMs on a single SMAD6 molecule not studied

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 5 GO:0140110 transcription regulator activity 4
Localization
GO:0005634 nucleus 6 GO:0005829 cytosol 6
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-392499 Metabolism of proteins 6 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3
Partners
CTBP1MAP3K7SMAD1SMURF1SMURF2TNFAIP3TRAF6UBE2O

Evidence

Reading pass · 32 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, interferes with phosphorylation of Smad2 by the TGF-β type I receptor, blocks subsequent Smad2-Smad4 heteromerization, and inhibits phosphorylation of Smad1 induced by the BMP type IB receptor, acting as an inhibitory Smad. Co-immunoprecipitation, phosphorylation assays, transfection-based signaling assays Nature High 9335505
1998 Smad6 specifically competes with Smad4 for binding to receptor-activated (phosphorylated) Smad1, yielding an apparently inactive Smad1-Smad6 complex, thereby acting as a Smad4 decoy to selectively antagonize BMP/Smad1 signaling without interfering with receptor-mediated phosphorylation of Smad1. Co-immunoprecipitation, Xenopus embryo overexpression assays, mammalian cell transfection, transcriptional reporter assays Genes & Development High 9436979
2007 Smad6 selectively inhibits BMP signaling from the ALK-3/6 subgroup of BMP type I receptors in preference to the ALK-1/2 subgroup; specific amino acid residues (Arg-238, Phe-264, Thr-265, Ala-269) in the N-terminal lobe of the ALK-3 kinase domain determine Smad6 sensitivity, and direct interaction with type I receptors is a critical step in Smad6 function. Transcriptional reporter assays, mutagenesis of receptor residues, co-immunoprecipitation Journal of Biological Chemistry High 17493940
2000 Smad6 interacts with the homeobox transcription factor Hoxc-8 as a transcriptional corepressor in the nucleus; the Smad6-Hoxc-8 heterodimer binds DNA (including Hoxa-9 sites) and inhibits Smad1 interaction with Hoxc-8 and Smad1-induced transcriptional activity, providing a nuclear mechanism of BMP signal inhibition. Yeast two-hybrid, co-immunoprecipitation, gel-shift (EMSA) assays, luciferase reporter assays Journal of Biological Chemistry High 10722652
2000 Smad6 knockout mice display cardiac valve hyperplasia, outflow tract septation defects, aortic ossification, and elevated blood pressure, demonstrating an essential in vivo role for Smad6 in cardiovascular development and homeostasis through modulation of TGF-β superfamily signaling. Targeted gene disruption (knockout mouse), LacZ reporter knock-in for expression mapping, histological and physiological analyses Nature Genetics High 10655064
2000 BMP2-induced apoptosis is mediated through activation of TAK1 and subsequent p38 phosphorylation; Smad6 blocks this pathway by directly binding to TAK1, preventing TAK1 activation and p38 phosphorylation, demonstrating a non-Smad inhibitory mechanism. Kinase-negative TAK1 expression, co-immunoprecipitation of Smad6-TAK1, apoptosis assays, Western blot for p38 phosphorylation Journal of Biological Chemistry High 10748100
2000 The mouse Smad6 promoter contains a proximal BMP-responsive element (PBE) with a GC-rich GCCGnCGC-like motif that is directly bound by BMP-activated Smad1/5 and Smad4, driving Smad6 transcription as a negative feedback loop. Promoter deletion analysis, luciferase reporter assays, gel-shift (EMSA) for direct DNA binding by Smad1/5 and Smad4 Journal of Biological Chemistry High 10692396
2003 Smad6 recruits transcriptional corepressor CtBP via a consensus PLDLS motif in its linker region to repress BMP-induced Id1 transcription; mutation of the PLDLS motif abolishes CtBP binding and the repressor activity of Smad6. Co-immunoprecipitation, mutagenesis of the PLDLS motif, luciferase reporter assays Molecular and Cellular Biology High 14645520
2005 Smad6 interacts with Runx2 (but not Smad7) and mediates Smurf1-induced ubiquitin-proteasome-dependent degradation of Runx2, serving as a scaffold between Smurf1 and Runx2 in a Smad6-dependent manner. Co-immunoprecipitation, ubiquitin-proteasome degradation assays with proteasome inhibitors, deletion mutant analysis Journal of Biological Chemistry High 16299379
2005 Smad6 interacts with the N-terminal domain of the glucocorticoid receptor (GR) through its MH2 domain and suppresses GR-mediated transcriptional activity by recruiting histone deacetylase 3 (HDAC3) to DNA-bound GR, antagonizing histone H3/H4 acetylation induced by p160 coactivators. Co-immunoprecipitation, adenovirus-mediated overexpression in vivo (rat liver), chromatin acetylation assays, luciferase reporter assays Journal of Biological Chemistry High 16249187
2006 Smad6 binds to Pellino-1 (an adaptor protein of IRAK1) via its MH2 domain, abrogating IRAK1-Pellino-1-TRAF6 complex formation after IL-1β stimulation, thereby preventing IκBα degradation, NF-κB nuclear translocation, and pro-inflammatory gene expression as part of TGF-β/BMP anti-inflammatory signaling. Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assays, gene expression analysis Nature Immunology High 16951688
2006 Smad6 is phosphorylated at a serine residue by protein kinase X (PrKX); during macrophage differentiation of HL-60 cells, Smad6 co-localizes with PrKX in the nucleus and shows increased serine phosphorylation, correlating with increased Smad6 binding to osteopontin, Id2, and Hex gene promoters. Yeast two-hybrid, co-immunoprecipitation, in vitro phosphorylation assay, mutagenesis, EMSA, chromatin immunoprecipitation (ChIP), siRNA knockdown Oncogene High 16491121
2006 PRMT1 methylates Smad6 (and Smad7) but not R-Smads or Smad4; PRMT1 interacts with the N-terminal domain of Smad6 and dimethylates Arg74 in mouse Smad6 as identified by mass spectrometry. In vitro methylation assay, mass spectrometry, co-immunoprecipitation, mutagenesis (Smad6-R74A) FEBS Letters High 17118358
2009 Smad6 directly interacts with Tbx6 through its MH2 domain (binding residues 90-180 of Tbx6) and recruits Smurf1 to facilitate ubiquitin-proteasome-dependent degradation of Tbx6, thereby reducing Tbx6-mediated Myf-5 gene activation. Co-immunoprecipitation, domain mapping, ubiquitination/degradation assays, siRNA knockdown, reporter assays Journal of Biological Chemistry High 19561075
2011 TGF-β1-induced Smad6 (but not Smad7) recruits Smurf1 and Smurf2 E3 ubiquitin ligases to mediate K48-linked polyubiquitination and proteasomal degradation of the TLR adaptor MyD88, thereby inhibiting MyD88-dependent pro-inflammatory NF-κB signaling. Co-immunoprecipitation, ubiquitin linkage assays, siRNA knockdown, NF-κB reporter assays, gene expression analysis Nature Communications High 21897371
2011 Smad6 promotes neuronal differentiation in the intermediate zone of the chick dorsal spinal cord by inhibiting both BMP signaling and the Wnt/β-catenin pathway; the inhibition of Wnt/β-catenin is independent of BMP inhibition and is mediated through the N-terminal domain and linker region of Smad6, which enhances CtBP interaction with the β-catenin/TCF complex. In ovo knockdown experiments (chick), reporter assays, co-immunoprecipitation, domain deletion analysis PNAS High 21730158
2013 Smad6 (but not Smad7) negatively regulates the noncanonical TGF-β1-TRAF6-TAK1-p38 MAPK/JNK pathway by recruiting the deubiquitinase A20 to TRAF6, removing K63-linked polyubiquitin chains from TRAF6 and preventing TAK1 activation. Co-immunoprecipitation, ubiquitin linkage assays, siRNA knockdown in cells and in vivo animal models, MAPK phosphorylation assays Nature Communications High 24096742
2013 UBE2O (E2-230K) functions as an E2-E3 hybrid enzyme that monoubiquitinates SMAD6 at lysine 174; monoubiquitinated SMAD6 has impaired binding to the BMP type I receptor, reducing its inhibitory activity toward BMP7 signaling, and this modification promotes BMP7-induced adipogenesis. Proteomic interaction screen, in vitro ubiquitination assay, mutagenesis (Lys174 and Cys885 of UBE2O), co-immunoprecipitation, BMP signaling reporter assays, adipogenesis assays EMBO Journal High 23455153
2015 Arkadia (an E3 ubiquitin ligase) induces ubiquitylation and proteasome-dependent degradation of Smad6 (in addition to Smad7 and c-Ski/SnoN); wild-type Arkadia but not the catalytically inactive C937A mutant causes Smad6 degradation, thereby enhancing BMP-induced osteoblast differentiation. Ubiquitylation assay, proteasome inhibitor treatment, Arkadia knockdown/KO MEFs, luciferase reporter assays, mutagenesis Journal of Biochemistry High 25762727
2018 Nuclear Smad6 directly interacts with PIAS3 through its MH2 domain, recruits Smurf1 (via Smad6's MH2 domain and PY motif) to promote PIAS3 ubiquitination and degradation, thereby reducing PIAS3-mediated STAT3 inhibition and enhancing STAT3-driven glioma cell growth. Co-immunoprecipitation, domain mapping, ubiquitination assays, siRNA knockdown, cell growth and stem-cell initiation assays Nature Communications High 29950561
2018 PRMT1-induced arginine methylation of Smad6 enables Smad6 to recruit MyD88 and promote its degradation, thereby inhibiting TLR-NF-κB signaling; disruption of Smad6 methylation exacerbates inflammation and bone loss in experimental periodontitis. Co-immunoprecipitation, in vitro methylation assay, siRNA knockdown, NF-κB reporter assays, in vivo periodontitis model Journal of Dental Research High 29420098
2021 SMAD6 functions downstream of ligand-induced Notch1 signaling and upstream of the vascular protocadherin PCDH12 to transduce endothelial cell flow-mediated responses; loss of SMAD6 in endothelial cells causes defective barrier function, upregulation of proliferation-associated genes, downregulation of junction genes, and impaired flow-mediated alignment. siRNA knockdown, endothelial cell flow assays, genetic rescue with full-length SMAD6, gene expression analysis, Notch1 pathway manipulation Angiogenesis High 33779885
2011 Loss of Smad6 in mice leads to skeletal defects including posterior vertebral transformation, bilateral ossification centers, bifid sternebrae, and an expanded hypertrophic zone in growth plates due to increased BMP responsiveness in Smad6-deficient chondrocytes, establishing Smad6 as an essential intracellular limiter of BMP signaling during endochondral bone formation. Smad6 knockout mouse, histological analysis, BMP responsiveness assays in isolated chondrocytes Journal of Bone and Mineral Research High 21681813
2011 JNK1 activation decreases binding of inhibitory Smad6 to the type I BMP receptor (BMPR-I) and reciprocally increases binding of Smad1 to BMPR-I, thereby increasing cellular responsiveness to BMP-2 and promoting osteoblast differentiation. JNK gain- and loss-of-function, co-immunoprecipitation of Smad6/Smad1 with BMPR-I, osteoblast differentiation and mineralization assays Journal of Bone and Mineral Research Medium 21542012
2011 Runx1 directly regulates Smad6 expression in the aorta-gonad-mesonephros region via a novel upstream enhancer (with Fli1, Gata2, and Scl), establishing a rheostat in which Runx1 drives its own negative control through Smad6-mediated proteasomal targeting of Runx1. ChIP in AGM region, Runx1 KO embryo analysis, proteasome inhibitor experiments, enhancer reporter assays Molecular and Cellular Biology High 21576367
2009 Smad6 inhibits the Wnt/β-catenin pathway in hepatic progenitor cells by promoting CtBP interaction with the β-catenin/TCF complex to inhibit β-catenin-mediated transcriptional activation, suppressing HPC proliferation and self-renewal. Ectopic expression, siRNA knockdown of β-catenin, co-immunoprecipitation, reporter assays, proliferation assays Journal of Cellular Physiology Medium 24446200
2007 BMP-2 activates Smad6 gene transcription via a bone-specific OSE2-a element in the Smad6 promoter through the combined action of Runx2 and BMP-activated Smad1; Smad1 excludes Smurf1 from the OSE2 site, promoting Smad6 transcription, while Smurf1 inhibits it. Promoter deletion/mutation analysis, luciferase reporter assays, EMSA, ChIP assays Journal of Biological Chemistry High 17215250
2006 Smad6 interacts with Dlx3 (via residues 80-163 of Dlx3 including part of the homeodomain) and Dlx4 homeobox transcription factors in the nucleus of trophoblasts, inhibiting Dlx3 binding to specific target gene promoter sites and repressing Dlx3-dependent transcription. Co-immunoprecipitation, immunocytochemistry, in vitro protein interaction with deletion mutants, EMSA, luciferase reporter assays, siRNA knockdown Journal of Biological Chemistry High 16687405
2016 Notch signaling sets endothelial cell BMP responsiveness by regulating SMAD6 expression upstream of BMP target gene transcription; SMAD6 acts as a cell-intrinsic BMP inhibitor downstream of Notch, controlling lateral vessel branching in response to pro-angiogenic BMP2 and BMP6 ligands. Zebrafish in vivo model, endothelial cell in vitro BMP assays, Notch pathway manipulation, SMAD6 overexpression/knockdown Nature Communications High 27834400
2017 AMPK activation upregulates Smad6 and Smurf1 and enhances their interaction, leading to proteasome-dependent degradation of ALK2 (including the FOP-associated ALK2-R206H mutant); knockdown of either Smad6 or Smurf1 prevents metformin-induced ALK2 reduction. Co-immunoprecipitation, siRNA knockdown of Smad6/Smurf1, proteasome inhibitor assays, AMPK gain/loss-of-function, FOP patient-derived iPS cells Biochimica et Biophysica Acta High 28847510
2018 SMAD6 loss in murine development causes vessel hemorrhage associated with increased VE-cadherin endocytosis, disrupted endothelial adherens junctions, increased vessel branching and sprouting in postnatal retinal vessels, placing SMAD6 as essential for vascular junction stabilization. Conditional/global SMAD6 KO mice, retinal vessel imaging, endothelial cell junction analysis, VE-cadherin endocytosis assay, siRNA knockdown in vitro Developmental Biology High 30098998
2001 Smad6 and Smad7 inhibit BMP2-induced neurite outgrowth in PC12 cells by interacting physically with TAK1-binding protein (TAB1), a molecule required for TAK1 activation, thereby blocking the TAK1-p38 kinase pathway. Co-immunoprecipitation of Smad6/7 with TAB1, kinase-negative TAK1 expression, neurite outgrowth assay, p38 phosphorylation assay Genes to Cells Medium 11737269

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 874 9335505
1998 Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes & development 579 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 300 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 230 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 202 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 162 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 130 17493940
2005 Smad6 interacts with Runx2 and mediates Smad ubiquitin regulatory factor 1-induced Runx2 degradation. The Journal of biological chemistry 127 16299379
2011 Smad6-specific recruitment of Smurf E3 ligases mediates TGF-β1-induced degradation of MyD88 in TLR4 signalling. Nature communications 119 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 113 16951688
2012 Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation. Human mutation 97 22275001
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
2013 Smad6 inhibits non-canonical TGF-β1 signalling by recruiting the deubiquitinase A20 to TRAF6. Nature communications 90 24096742
2016 Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6. Nature communications 85 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 79 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 61 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
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
2018 Nuclear Smad6 promotes gliomagenesis by negatively regulating PIAS3-mediated STAT3 inhibition. Nature communications 54 29950561
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 54 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
1997 Cloning and characterization of a novel member of the human Mad gene family (MADH6). Genomics 46 9205116
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 42 32304765
2001 Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7. Genes to cells : devoted to molecular & cellular mechanisms 42 11737269
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 41 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 41 20171181
2004 CREB Cooperates with BMP-stimulated Smad signaling to enhance transcription of the Smad6 promoter. Journal of cellular physiology 41 14755548
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
2020 SMAD6 variants in craniosynostosis: genotype and phenotype evaluation. Genetics in medicine : official journal of the American College of Medical Genetics 37 32499606
2018 Smad6 Methylation Represses NFκB Activation and Periodontal Inflammation. Journal of dental research 37 29420098
2012 Semaphorin 7A contributes to West Nile virus pathogenesis through TGF-β1/Smad6 signaling. Journal of immunology (Baltimore, Md. : 1950) 37 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 34 29344637
2012 Smad6 and Smad7 are co-regulated with hepcidin in mouse models of iron overload. Biochimica et biophysica acta 34 22960056
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
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 32 25766838
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 30 28847510
2018 Hepatic SMARCA4 predicts HCC recurrence and promotes tumour cell proliferation by regulating SMAD6 expression. Cell death & disease 29 29352111
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
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 28 21730158
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 Mesenchymal Behavior of the Endothelium Promoted by SMAD6 Downregulation Is Associated With Brain Arteriovenous Malformation Microhemorrhage. Stroke 26 32486965
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
2018 Developmental SMAD6 loss leads to blood vessel hemorrhage and disrupted endothelial cell junctions. Developmental biology 24 30098998
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 24 21295571
2022 SMAD6-deficiency in human genetic disorders. NPJ genomic medicine 22 36414630
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
2006 Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation. Oncogene 21 16491121
2006 Crk-associated substrate lymphocyte type regulates transforming growth factor-beta signaling by inhibiting Smad6 and Smad7. Oncogene 21 16909115
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 18 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