Affinage

SMAD2

SMAD family member 2 · UniProt Q15796

Round 2 corrected
Length
467 aa
Mass
52.3 kDa
Annotated
2026-04-28
130 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMAD2 is a receptor-activated transcription factor that serves as a central intracellular transducer of TGFβ, Activin, and Nodal signaling, governing mesoderm induction, gastrulation, growth arrest, epithelial-to-mesenchymal transition, fibrosis, and tumor suppression. Upon ligand stimulation, the type I receptor ALK5 phosphorylates SMAD2 at C-terminal serines—a step facilitated by SARA-mediated recruitment—triggering dissociation from SARA, heteromeric complex formation with SMAD4, and nuclear translocation where SMAD2 cooperates with DNA-binding partners (FOXH1, HEB) and coactivators/corepressors (p300/CBP acetylation at Lys19, HDAC4, SKI, LSD1) to activate or repress target genes; a short Δexon3 splice isoform retains direct DNA-binding capacity essential for Nodal target gene activation and embryonic viability (PMID:8980228, PMID:9865696, PMID:8893010, PMID:15630024, PMID:17074756, PMID:31582430). SMAD2 activity is further modulated by linker-region phosphorylation by ERK, CDK8/9, Araf, and CDK2 (controlling nuclear accumulation, transcriptional potency, and proteasomal turnover), by SIRT2-mediated deacetylation promoting SMURF2-dependent ubiquitination, and by PPM1A-mediated dephosphorylation, while Hippo pathway effectors TAZ/YAP dictate subcellular partitioning of active SMAD2/3 complexes in a cell-density-dependent manner (PMID:10197981, PMID:19914168, PMID:23591895, PMID:37777567, PMID:36752205, PMID:21145499). Beyond canonical transcription, SMAD2/3 participates in post-transcriptional regulation by associating with the DROSHA/p68 microprocessor to promote primary miRNA processing (PMID:18548003).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1996 High

    Identification of SMAD2 as a direct substrate of the TGFβ type I receptor kinase established the first link between receptor activation and a defined intracellular effector: C-terminal serine phosphorylation was shown to be necessary for nuclear accumulation and transcriptional signaling, and loss-of-function mutations in colorectal cancers identified SMAD2 as a tumor suppressor.

    Evidence In vitro kinase assay with mutagenesis, dominant-negative analysis, LOH in colorectal carcinomas, Xenopus mesoderm induction assay

    PMID:8752209 PMID:8756346 PMID:8980228

    Open questions at the time
    • Exact stoichiometry of receptor–SMAD2 interaction unknown
    • Mechanism of receptor substrate specificity (SMAD2 vs SMAD1) not defined
  2. 1996 High

    Discovery that SMAD4 (DPC4) forms a ligand-regulated heteromeric complex with SMAD2 resolved how receptor-phosphorylated SMAD2 transmits signals to the nucleus, establishing the paradigm of R-SMAD/co-SMAD complex formation.

    Evidence Reciprocal co-immunoprecipitation, Xenopus embryo rescue, transcriptional reporter assays

    PMID:8893010

    Open questions at the time
    • Trimeric stoichiometry not yet determined
    • How SMAD4 is selectively recruited post-phosphorylation unclear
  3. 1997 High

    Identification of FAST-1 as a DNA-binding partner within the activin-responsive factor (ARF) showed that SMAD2 reaches target genes via transcription-factor adapters, since full-length SMAD2 itself was believed unable to bind DNA directly.

    Evidence Co-IP, yeast two-hybrid, transcriptional assays with deletion mutants; synergistic PAI-1 promoter activation with SMAD3 and SMAD4

    PMID:9288972 PMID:9311995

    Open questions at the time
    • Full repertoire of SMAD2 DNA-binding partners unknown
    • Whether SMAD2 can ever bind DNA directly remained debated
  4. 1998 High

    Two major regulatory inputs converging on SMAD2 were defined: SARA was shown to recruit SMAD2 to the receptor (resolving how pathway specificity is achieved at endosomes), and ERK/MAPK was shown to phosphorylate the linker region to cause cytoplasmic retention, establishing a mechanism for Ras-mediated antagonism of TGFβ signaling.

    Evidence Direct pulldown/co-IP with SARA mislocalization mutants; in vitro ERK kinase assay with linker mutagenesis and nuclear fractionation

    PMID:10197981 PMID:9865696

    Open questions at the time
    • Whether other FYVE-domain proteins share SARA's function not tested
    • Full map of linker phosphorylation sites and their individual contributions incomplete
  5. 2002 High

    Identification of ERK1-mediated phosphorylation at Thr8 revealed a stabilizing rather than inhibitory role for certain MAPK-SMAD2 modifications, showing that ERK can both positively and negatively regulate SMAD2 depending on the phosphorylation site.

    Evidence In vitro kinase assay with constitutively active MEK1, Thr8 mutagenesis, protein stability and SMAD4 co-IP assays

    PMID:12193595

    Open questions at the time
    • Relative contribution of stabilizing vs. inhibitory ERK sites under physiological conditions not resolved
    • Calmodulin–ERK cross-talk confirmed only in vitro
  6. 2004 High

    Compound knockout of Smad2 and Smad3 in the mouse epiblast demonstrated their cooperative and dose-dependent requirement for mesoderm formation and gastrulation, showing that neither SMAD alone suffices for early embryogenesis.

    Evidence Conditional and compound knockout mouse genetics with allelic series and phenotypic analysis

    PMID:15084457

    Open questions at the time
    • Specific gene targets of SMAD2 vs SMAD3 in the epiblast not delineated
    • Whether SMAD2Δexon3 isoform contributes to dose sensitivity unknown at this stage
  7. 2005 High

    Knock-in replacement of full-length Smad2 with the Δexon3 isoform rescued embryonic lethality and adult viability, establishing that the DNA-binding-competent short isoform is functionally sufficient and that the exon 3 insert specifically prevents direct DNA engagement in the full-length protein.

    Evidence Knock-in mouse engineering, ES cell chimera, definitive endoderm analysis, viability/fertility tests

    PMID:15630024

    Open questions at the time
    • Whether the two isoforms are co-expressed and fulfill distinct roles in adult tissues not established
    • Structural basis for exon 3-mediated inhibition of DNA binding not yet determined
  8. 2006 High

    Discovery that p300/CBP acetylates SMAD2 at Lys19 in a TGFβ-dependent manner, inducing a conformational change that exposes the DNA-binding domain of the short isoform, added a new activating post-translational modification layer to SMAD2 regulation.

    Evidence In vitro acetylation assay, acetyl-Lys19 antibody, ChIP, site-specific mutagenesis, reporter assay

    PMID:17074756

    Open questions at the time
    • In vivo significance of Lys19 acetylation not tested genetically
    • Whether deacetylases reverse this modification at this site not determined
  9. 2008 High

    SMAD2/3 was found to participate in post-transcriptional gene regulation by associating with the DROSHA/p68 microprocessor complex to promote pri-miRNA processing, revealing a non-transcriptional, SMAD4-independent arm of TGFβ signaling.

    Evidence RNA immunoprecipitation, co-IP of SMAD–p68–DROSHA complex, miRNA processing assay in vascular smooth muscle cells

    PMID:18548003

    Open questions at the time
    • Full spectrum of SMAD-regulated miRNAs unknown
    • Whether SMAD2 vs SMAD3 has distinct roles in miRNA processing not resolved
  10. 2009 High

    CDK8/CDK9 were identified as nuclear kinases that phosphorylate the SMAD2/3 linker after transcriptional complex formation, coupling peak transcriptional activity to subsequent ubiquitin-mediated proteasomal degradation—a 'use-and-dispose' mechanism ensuring signal termination.

    Evidence In vitro kinase assay, phospho-site mutagenesis, ubiquitination and turnover assays, reporter gene assay

    PMID:19914168

    Open questions at the time
    • Identity of the specific E3 ligases recruited by CDK-phosphorylated linker not fully defined
    • Whether this cycle operates identically for SMAD2 and SMAD3 not resolved
  11. 2009 High

    TAZ/YAP were established as obligate co-factors for nuclear SMAD2/3 accumulation and transcriptional activity, linking cell density and Hippo signaling to TGFβ output; subsequent work showed that cytoplasmic TAZ/YAP sequesters SMAD2/3 at high cell density.

    Evidence Co-IP, ChIP, siRNA, nuclear fractionation in hESCs; Crumbs/phospho-TAZ/YAP assays and mouse embryo immunostaining

    PMID:18568018 PMID:21145499

    Open questions at the time
    • How SMAD2/3 physically associates with phosphorylated TAZ/YAP in the cytoplasm not structurally resolved
    • Relative contribution of TAZ vs YAP to SMAD2 regulation tissue-specifically unknown
  12. 2013 High

    Araf kinase was shown to directly phosphorylate the SMAD2 linker at S253 independently of MEK/ERK, accelerating SMAD2 degradation and attenuating Nodal signaling during zebrafish dorsoventral patterning, thereby adding a Ras-pathway-independent linker kinase.

    Evidence Direct in vitro kinase assay, phospho-site mutagenesis, co-IP, zebrafish morpholino knockdown with dorsalization phenotype

    PMID:23591895

    Open questions at the time
    • Whether Araf-SMAD2 interaction is regulated by growth factor stimulation not fully defined
    • PAK4-mediated SMAD2 phosphorylation at Ser465 confirmed only in overexpression system
  13. 2018 High

    Crystal structures of the SMAD2 and SMAD3 MH2 domains bound to cofactors SKI and FOXH1, respectively, revealed how multiple hydrophobic surface patches mediate competitive or cooperative cofactor binding, providing a structural basis for the context-dependent transcriptional output of SMAD signaling.

    Evidence X-ray crystallography, structure-guided mutagenesis, binding assays

    PMID:29588413

    Open questions at the time
    • Full-length SMAD2 structure with all domains not determined
    • Structural basis for SMAD2-specific cofactor preferences vs SMAD3 not complete
  14. 2019 High

    Structural and ChIP-seq studies resolved a long-standing question by showing that the exon 3-encoded E3 insert does not absolutely prevent DNA binding but constrains conformation; FOXH1 pre-occupies target sites with SMAD3, and upon Nodal signaling SMAD2–SMAD4 complexes join these sites, clarifying how the two R-SMADs cooperate at mesendoderm gene promoters.

    Evidence X-ray crystallography, biochemical DNA-binding assays, ChIP-seq in mouse mesendoderm precursors

    PMID:31582430

    Open questions at the time
    • Whether SMAD2Δexon3 and full-length SMAD2 compete or cooperate at shared loci not established genome-wide
    • Contribution of other pioneer factors beyond FOXH1 unknown
  15. 2020 High

    SMAD2/3 was shown to orchestrate a temporal sequence of chromatin events during EMT: phospho-SMAD2/3 recruits LSD1 to trigger a nuclear oxidative wave within 30–90 min of TGFβ treatment, priming EMT gene promoters; after SMAD2/3 levels decline, LSD1 partners with SNAI1/NCoR1/HDAC3 to consolidate gene repression.

    Evidence ChIP with phospho-SMAD2/3 antibodies, sequential ChIP, mass spectrometry of DNA oxidation, confocal microscopy

    PMID:32697292

    Open questions at the time
    • Whether the oxidative wave is SMAD2-specific or shared with SMAD3 not dissected
    • Generality beyond EMT gene promoters not tested
  16. 2022 High

    Mitochondrial dysfunction was found to activate SMAD2 via MAPK-mediated phosphorylation at a mitochondrial location, causing retinal arteriovenous malformations; genetic deletion of SMAD2 or ALK5 blockade rescued vascular malformations across three independent mitochondrial-gene-knockout models, establishing SMAD2 as a pathological effector downstream of mitochondrial stress.

    Evidence Three endothelial-specific conditional KO mouse models, SMAD2 KO rescue, ALK5 inhibitor rescue, scRNA-seq, MAPK phosphorylation assays

    PMID:36496409

    Open questions at the time
    • How SMAD2 is phosphorylated at mitochondria and whether this represents a distinct pool not mechanistically resolved
    • Whether mitochondrial SMAD2 activation occurs in non-vascular tissues unknown
  17. 2023 High

    Two negative regulators of SMAD2 activity were validated in vivo: SIRT2 deacetylates SMAD2 at Lys451 to promote SMURF2-mediated ubiquitination and degradation (renal tubule-specific SIRT2 deletion worsens fibrosis), while PPM1A dephosphorylates phospho-SMAD2 and its knockout protects against cartilage degeneration by maintaining p-SMAD2 levels.

    Evidence In vitro deacetylation and ubiquitination assays, Lys451 mutagenesis, tubular-specific KO/OE mice; PPM1A–pSMAD2 co-IP, PPM1A KO mouse, pharmacological inhibitor rescue

    PMID:36752205 PMID:37777567

    Open questions at the time
    • Whether SIRT2-mediated Lys451 deacetylation and p300-mediated Lys19 acetylation are independently regulated or coordinated unknown
    • Full acetylation/deacetylation landscape of SMAD2 not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full-length SMAD2 structure integrating MH1-linker-MH2 domain conformational states; the genome-wide division of labor between SMAD2 isoforms and SMAD3 across tissues; whether the mitochondrially-activated SMAD2 pool represents a structurally or functionally distinct species; and the complete map of linker-region phosphorylation-dependent E3 ligase recruitment specificity.
  • No full-length SMAD2 structure available
  • Genome-wide isoform-specific target gene assignments lacking
  • Mitochondrial SMAD2 activation mechanism unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 8 GO:0005829 cytosol 4 GO:0005886 plasma membrane 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-8953854 Metabolism of RNA 1
Partners
FOXH1SARASKISMAD3SMAD4SMURF2TAZYAP1
Complex memberships
DROSHA/p68/SMAD2/3 microprocessor complexSMAD2/FOXH1/SMAD4 (ARF)SMAD2/SMAD4 heterotrimer

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MADR2 (SMAD2) is directly phosphorylated by the TGFβ type I receptor complex on C-terminal serines; this phosphorylation requires activation of receptor I by receptor II and is necessary for nuclear accumulation and initiation of signaling. Mutation of the phosphorylation sites generates a dominant-negative MADR2 that stably associates with receptors and fails to accumulate in the nucleus. Co-immunoprecipitation, in vitro kinase assay, dominant-negative mutagenesis, transcriptional reporter assay Cell High 8980228
1996 MADR2 (SMAD2) is specifically regulated by TGFβ but not BMPs, maps to chromosome 18q21, and missense mutations found in colorectal carcinomas are functionally inactivating, establishing SMAD2 as a tumor suppressor that participates in TGFβ signaling. Mutational analysis, functional biochemical assays, loss-of-heterozygosity analysis Cell High 8752209
1996 SMAD2 (Madr2) induces dorsal mesoderm from Xenopus ectoderm in an activin-dependent manner; activin promotes nuclear concentration of Madr2, whereas a C-terminal fragment of Madr2 is constitutively nuclear, indicating a repressive N-terminal domain that anchors the protein in the cytoplasm until ligand stimulation. Xenopus ectoderm functional assay, lacZ fusion localization, overexpression Genes & development High 8756346
1996 DPC4 (SMAD4) associates with SMAD2 in response to activin or TGFβ and is essential for SMAD2 function in mesoderm induction and antimitogenic/transcriptional responses; SMAD2 and SMAD4 form a regulated heteromeric complex downstream of receptor activation. Co-immunoprecipitation, Xenopus embryo functional rescue, transcriptional reporter assay Nature High 8893010
1997 SMAD4 (Smad4/FAST-1) is present in the activin-responsive factor (ARF) together with Smad2 and the DNA-binding partner FAST-1; ligand-stimulated co-immunoprecipitation showed FAST-1 interacts directly with Smad2 via its C-terminal domain, and Smad4 stabilizes the Smad2–FAST-1 complex as an active DNA-binding factor. Co-immunoprecipitation, yeast two-hybrid, transcriptional assay with deletion mutants Nature High 9288972
1997 Smad2 and Smad3 interact with the kinase-deficient TGFβ type I receptor after its phosphorylation by TβRII; TGFβ1 induces phosphorylation and nuclear translocation of Smad2 and Smad3; Smad2, Smad3, and Smad4 form heteromeric complexes in a TβR-activation-dependent manner and show synergistic transcriptional activation of the PAI-1 promoter. Co-immunoprecipitation in COS cells, phosphorylation assays in Mv1Lu cells, nuclear fractionation, transcriptional reporter assay, dominant-negative Smad3 The EMBO journal High 9311995
1998 TGFβ and oncogenic Ras/Erk MAP kinase signals converge on Smad2 and Smad3: ERK phosphorylates Smad2/3 at specific linker-region sites (separate from receptor phosphorylation sites), causing cytoplasmic retention and inhibiting TGFβ-induced nuclear accumulation and transcription; mutation of these MAP kinase sites yields Ras-resistant Smad3. In vitro kinase assay, phospho-site mutagenesis, nuclear fractionation, transcriptional reporter assay Genes & development High 10197981
1998 SARA (Smad anchor for receptor activation), a FYVE-domain protein, directly interacts with Smad2 and Smad3, recruits Smad2 to the TGFβ receptor by controlling its subcellular localization, and is required for TGFβ-dependent transcriptional responses; phosphorylation of Smad2 induces its dissociation from SARA with concomitant Smad2/Smad4 complex formation and nuclear translocation. Direct protein interaction (pulldown, co-IP), subcellular localization (imaging), SARA mislocalization mutants, transcriptional reporter assay Cell High 9865696
1998 HGF and EGF, acting through receptor tyrosine kinases via MEK1/Erk, can induce phosphorylation and nuclear translocation of Smad2 and activate SMAD-dependent reporter gene expression; a Smad2 mutation that blocks TGFβ signaling also blocks HGF signaling, demonstrating that Smad2 acts as a common effector of both TGFβ/activin receptor and RTK pathways. Phosphorylation assay, nuclear fractionation, dominant-negative mutagenesis, reporter gene assay, MEK1 dominant-active/inhibitor experiments Genes & development High 9620846
1998 Calmodulin directly binds to two conserved regions in Smad2 and inhibits Smad2 function; calmodulin binding to Smads inhibits subsequent Erk2-dependent phosphorylation of Smad2, and conversely, prior Erk phosphorylation inhibits calmodulin binding, revealing a cross-talk between Ca2+/calmodulin, RTK, and TGFβ pathways. Direct binding assay, Xenopus embryo functional assay, phosphorylation assays, structure-function mutagenesis The Journal of biological chemistry Medium 11007779
1999 The MH1 domain of Smad2 has inhibitory effects on nuclear localization in response to ALK7 signaling; a chimeric Smad3-2 (MH1 of Smad3, MH2 of Smad2) was activated and translocated to the nucleus by constitutively active ALK7, whereas Smad2 itself was not, demonstrating a domain-specific requirement for Smad2 activation by this receptor. Chimeric protein construction, nuclear translocation assay, PAI-1 promoter reporter assay Biochemical and biophysical research communications Medium 9920806
2002 ERK1 phosphorylates Smad2 at Thr8 (a site overlapping the calmodulin-binding region), increasing Smad2 protein stability (half-life) and complex formation with Smad4, leading to enhanced Smad2 transcriptional activity; calmodulin inhibits ERK1-mediated Smad2 phosphorylation and negatively regulates Smad2 levels. In vitro kinase assay with constitutively active MEK1, phospho-site mutagenesis (Thr8 and ERK sites), protein stability assay, Smad4 co-immunoprecipitation, transcriptional reporter assay, ERK phosphatase (HVH2) co-transfection The Journal of biological chemistry High 12193595
2004 Combinatorial loss of Smad2 and Smad3 in the mouse epiblast results in complete failure of mesoderm formation and gastrulation; selective removal of Smad3 with only one wild-type copy of Smad2 impairs anterior axial mesendoderm, demonstrating dose-dependent and cooperative roles in early embryogenesis. Conditional and compound knockout mouse genetics, embryo phenotypic analysis Development (Cambridge, England) High 15084457
2005 The short splice isoform of Smad2 lacking exon 3 (Smad2Δexon3) retains DNA-binding activity (unlike full-length Smad2) and can functionally substitute for full-length Smad2 in anterior-posterior axis specification, definitive endoderm formation, and adult viability; full-length Smad2 cannot activate essential Nodal target genes, whereas Smad2Δexon3 and Smad3 can. Knock-in mouse engineering, embryonic stem cell chimera assay, definitive endoderm fate analysis, viability/fertility assessment Genes & development High 15630024
2006 Smad2 is acetylated by coactivators p300, CBP, and P/CAF in a TGFβ-dependent manner; Lys19 in the MH1 domain is the major acetylation site in both long and short Smad2 isoforms; acetylation of Lys19 induces a conformational change in the MH1 domain of the short isoform that makes its DNA-binding domain accessible, enhancing DNA binding in vitro and association with target promoters in vivo, thereby augmenting transcriptional activity. In vitro acetylation assay, acetyl-Lys19-specific antibody, ChIP, site-specific mutagenesis, transcriptional reporter assay The Journal of biological chemistry High 17074756
2008 SMAD proteins (including Smad2/3) are recruited to primary miRNA transcripts (pri-miR-21) in a complex with the RNA helicase p68, a component of the DROSHA microprocessor complex; this interaction promotes processing of pri-miR-21 to pre-miR-21, a post-transcriptional mechanism that is independent of SMAD4 and regulates vascular smooth muscle cell phenotype. RNA immunoprecipitation, Co-IP of SMAD-p68-DROSHA complex, miRNA processing assay, smooth muscle cell phenotype assay Nature High 18548003
2009 Nuclear CDK8 and CDK9 phosphorylate the linker region of receptor-activated Smad2/3 after their TGFβ-induced transcriptional complex formation; this phosphorylation promotes Smad transcriptional action and subsequently recruits specific ubiquitin ligases for proteasome-mediated turnover of activated Smad proteins, driving a cycle of Smad utilization and disposal. In vitro kinase assay with CDK8/9, phospho-site mutagenesis, ubiquitination assay, reporter gene assay, Smad turnover assay Cell High 19914168
2009 TAZ (transcriptional regulator) binds heteromeric Smad2/3-Smad4 complexes in response to TGFβ stimulation and is recruited to TGFβ response elements; TAZ is required for nuclear accumulation and transcriptional activation by Smad2/3-Smad4 complexes in human embryonic stem cells, controlling self-renewal. Co-IP of Smad2/3-TAZ complexes, ChIP, siRNA knockdown with phenotypic analysis, nuclear fractionation Nature cell biology High 18568018
2009 A mutant-p53/Smad2/3 ternary complex, formed in response to TGFβ+oncogenic Ras, opposes p63 to promote cell migration, invasion, and metastasis; Smads serve as essential scaffolds within this complex, and mutant-p53 uses Smads to antagonize p63 function. Co-immunoprecipitation, epistasis with dominant-negative and siRNA, in vivo metastasis assay Cell High 19345189
2010 TAZ/YAP dictate the subcellular localization of active SMAD2/3 complexes in response to cell density: high-density Hippo-driven cytoplasmic TAZ/YAP sequesters SMAD2/3 complexes, suppressing TGFβ signaling; the Crumbs polarity complex promotes TAZ/YAP phosphorylation to relay cell density information and suppress nuclear SMAD2/3 accumulation. Co-IP, nuclear fractionation, mouse embryo immunostaining, siRNA knockdown, phospho-TAZ/YAP functional assays Developmental cell High 21145499
2013 Araf kinase directly binds to and phosphorylates Smad2 in the linker region (with S253 being indispensable) in a Mek/Erk-independent manner, thereby accelerating degradation of activated Smad2 and attenuating Smad2 signaling; knockdown of araf in zebrafish increases activated Smad2 with decreased linker phosphorylation and leads to dorsalized embryos with excess mesendoderm. Direct in vitro kinase assay (Araf phosphorylates Smad2), phospho-site mutagenesis, co-immunoprecipitation, zebrafish knockdown with developmental phenotype, protein degradation assay Nature communications High 23591895
2013 PAK4 interacts with Smad2/3 (independently of PAK4 kinase activity) to block TGFβ1-induced C-terminal phosphorylation of Smad2 (Ser465/467); separately, PAK4 kinase activity phosphorylates Smad2 at Ser465, targeting Smad2 for degradation via the ubiquitin-proteasome pathway under HGF stimulation. Co-immunoprecipitation, phospho-specific antibodies, kinase assay, ubiquitin-proteasome inhibitor experiment, kinase-dead PAK4 mutant Oncogene High 23934187
2015 HEB helix-loop-helix protein associates with SMAD2/3 at Nodal-responsive elements (independently of PRC2) and with PRC2 at developmental promoters; HEB depletion causes premature differentiation after Activin exposure, demonstrating that HEB links Nodal/SMAD2/3 signaling to derepression of poised developmental promoters in embryonic stem cells. ChIP-seq, co-immunoprecipitation, siRNA knockdown with differentiation assay Nature communications Medium 25775035
2015 Endoglin impedes Smad2 transcriptional repressor activity at the BECN1 (beclin1) promoter; Smad2, but not Smad3, acts as a repressor of beclin1 expression in endothelial cells, and Smad2 knockdown increases beclin1 levels and autophagy, establishing Smad2 as a transcriptional repressor upstream of the BECN1 promoter. siRNA knockdown, promoter-reporter assay, ChIP, autophagy functional assay The Journal of biological chemistry Medium 25931117
2016 Smad2 and Smad3 inhibit Ihh expression in growth plate chondrocytes by binding to distinct Smad-binding elements (SBEs) in the Ihh promoter and recruiting different repressive complexes: Smad2 associates with HDAC4 at the Ihh promoter (TGFβ induces Smad2-HDAC4 association), while Smad3 recruits SnoN and Ski; cartilage-specific deletion of Smad2 in mice results in expanded columnar and hypertrophic zones with increased Ihh expression. Cartilage-specific knockout mouse, ChIP, Smad2-HDAC4 co-IP, Ihh promoter mutagenesis of SBEs, qRT-PCR PLoS genetics High 27741240
2017 Smad3, but not Smad2, is preferentially nuclear and sequestered from membrane signaling at baseline; Smad3's ability to oligomerize with Smad4 upon agonist stimulation is impaired by its unique linker region; Smad2 is the more sensitive TGFβ transducer and plays a crucial role in epiblast development, whereas nuclear Smad3 promotes early neural development in a signaling-independent manner. Nuclear fractionation, Smad4 co-IP upon stimulation, mouse embryo epiblast analysis, linker-region domain swap experiments Scientific reports Medium 26905010
2017 CCT6A (chaperonin containing TCP1 subunit 6A) directly binds SMAD2 and suppresses SMAD2 function in non-small cell lung carcinoma cells; suppression of SMAD2 (with SMAD3 intact) switches TGFβ-induced transcriptional responses toward a prometastatic state, and selective inhibition of CCT6A or SMAD3 suppresses TGFβ-mediated metastasis. Co-immunoprecipitation (direct binding of CCT6A to SMAD2), siRNA knockdown, animal metastasis model, transcriptional profiling The Journal of clinical investigation High 28375158
2017 Fibroblast-specific deletion of Smad3, but not Smad2, markedly reduces pressure overload-induced cardiac fibrosis in vivo; combined deletion of Smad2 and Smad3 from cardiac fibroblasts attenuates cellular expansion and fibrosis-mediating gene expression, demonstrating that TGFβ-Smad2/3 signaling in activated tissue-resident cardiac fibroblasts is the principal mediator of the cardiac fibrotic response. Fibroblast- and myofibroblast-specific inducible Cre conditional knockout mice, pressure overload model, histological and gene expression analysis The Journal of clinical investigation High 28891814
2018 Crystal structures of SMAD3-MH2 in complex with FOXH1 and SMAD2-MH2 in complex with the corepressor SKI reveal that multiple hydrophobic patches on the MH2 domain surfaces of SMAD2 and SMAD3 serve as docking sites for different subsets of cofactors, which bind cooperatively or competitively to determine TGFβ signaling output. X-ray crystallography, structure-guided mutagenesis, binding assays Science signaling High 29588413
2019 Structural and biochemical studies show that binding of SMAD2 to DNA depends on the conformation of the E3 insert (exon 3-encoded), previously thought to render SMAD2 unable to bind DNA; FOXH1 recruits SMAD3 to target sites independently of TGFβ, while SMAD2 remains cytoplasmic at baseline and, upon Nodal signaling, binds SMAD4 and joins SMAD3:FOXH1 complexes at mesendoderm differentiation gene promoters. X-ray crystallography, biochemical DNA-binding assays, ChIP-seq, mouse mesendoderm precursor analysis Genes & development High 31582430
2019 WWP2 E3 ubiquitin ligase (N-terminal isoform) interacts with SMAD2 after TGFβ1 stimulation; WWP2 mediates TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2 in primary cardiac fibroblasts, and transgenic mice lacking the N-terminal WWP2 region show reduced myocardial fibrosis. Co-immunoprecipitation, nuclear fractionation, transgenic/KO mouse model, cardiac fibrosis phenotype Nature communications High 31399586
2019 Conditional knockout of Smad2 in renal tubular epithelial cells protects against cisplatin-induced acute kidney injury by reducing p53-mediated apoptosis, RIPK-mediated necroptosis, and p65 NF-κB-driven inflammation; unlike its protective role in fibrosis, Smad2 promotes acute kidney injury by inducing programmed cell death. Renal tubular-specific conditional knockout mouse, cisplatin and ischemia-reperfusion models, in vitro Smad2 KD/OE in HK2 cells, lentiviral in vivo silencing Theranostics High 31754396
2020 Phospho-SMAD2/3, recruited to TGFβ1-responsive promoters together with LSD1 (lysine-specific demethylase 1), triggers an LSD1-mediated nuclear oxidative wave within 30–90 min of TGFβ1 treatment, which primes EMT gene promoters for activation or repression; after 90 min, phospho-SMAD2/3 levels decline and LSD1 is redirected with newly synthesized SNAI1 and NCoR1/HDAC3 to repress TGFβ1-target genes. Confocal microscopy, mass spectrometry (DNA oxidation), ChIP with phospho-SMAD2/3 antibodies, sequential ChIP, promoter analysis Nucleic acids research High 32697292
2020 Mutant FOXL2C134W acquires the ability to bind SMAD4, forming a FOXL2C134W/SMAD4/SMAD2/3 complex that binds a novel hybrid DNA motif (AGHCAHAA) and induces an enhancer-like chromatin state driving EMT and oncogenic gene expression in adult granulosa cell tumors; ablation of SMAD4 or SMAD2/3 strongly reduces FOXL2C134W binding and associated gene expression. ChIP-seq, co-immunoprecipitation, siRNA ablation of SMAD2/3 and SMAD4, ATAC-seq, transcriptomics Cancer research High 32641411
2021 Creatine promotes cancer metastasis via MPS1 (monopolar spindle 1) kinase-activated phosphorylation of Smad2 and Smad3, leading to upregulation of Snail and Slug; MPS1 inhibition or GATM knockdown suppresses metastasis by downregulating Smad2/3 phosphorylation-driven transcription. In vivo orthotopic mouse metastasis models, MPS1 kinase assay/inhibition, GATM knockdown, Snail/Slug reporter assays Cell metabolism High 33811821
2021 Low fluid shear stress activates Smad2/3 phosphorylation through the type I TGFβ receptor ALK5 and transmembrane co-receptor Neuropilin-1 (which increases sensitivity to circulating BMP-9); Smad2/3 nuclear translocation and target gene expression are maximal at low FSS and suppressed at physiological high shear via MEKK3/Klf2-CDK2-dependent linker region phosphorylation; EC-specific deletion of Alk5 blocks inward arterial remodeling upon carotid ligation. Flow chamber assays, EC-specific Alk5 conditional KO mice, carotid ligation model, phospho-Smad2/3 nuclear imaging, CDK2 pharmacological inhibition Proceedings of the National Academy of Sciences of the United States of America High 34504019
2022 Mitochondrial dysfunction (from TFAM, COX10, or TRX2 depletion) induces MAPKs-mediated phosphorylation of SMAD2 at a mitochondrial location and enhances ALK5-SMAD2 signaling, causing retinal arteriovenous malformations; genetic deficiency of SMAD2 or pharmacological ALK5 blockade prevents retinal vascular malformations in all three mutant mouse models. Endothelial-specific conditional KO mice (three different mitochondrial genes), SMAD2 KO rescue, ALK5 inhibitor rescue, single-cell RNA-seq, mechanistic MAPK phosphorylation assays Nature communications High 36496409
2023 SIRT2 deacetylase directly interacts with SMAD2 and deacetylates it at Lys451, promoting SMAD2 ubiquitination and degradation via SMURF2 (SMAD-specific E3 ubiquitin ligase 2), thereby reducing SMAD2 phosphorylation and nuclear localization; renal tubule-specific SIRT2 deletion aggravates fibrosis while overexpression ameliorates it. Co-immunoprecipitation, in vitro deacetylation assay, ubiquitination assay, site-specific mutagenesis (Lys451), tubular-specific KO/OE mouse models Cell death & disease High 37777567
2023 PPM1A (protein phosphatase magnesium-dependent 1A) directly interacts with and dephosphorylates phospho-SMAD2, and PPM1A KO in mice substantially protects against cartilage degeneration by maintaining higher p-SMAD2 levels in chondrocytes; intra-articular injection of PPM1A inhibitors recapitulated the protective effect, confirming PPM1A as a phosphatase that negatively regulates TGFβ/SMAD2 signaling in cartilage. Co-immunoprecipitation (PPM1A-pSMAD2 interaction), PPM1A KO mouse (DMM model), phosphatase inhibitor pharmacology, rescue with ALK5/SMAD2 pathway inhibitor JCI insight High 36752205

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 TGF-beta signal transduction. Annual review of biochemistry 3810 9759503
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
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