Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass database
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Structural basis of Smad2 recognition by the Smad anchor for receptor activation.
Smad proteins function as co-modulators for MEF2 transcriptional regulatory proteins.
Ski-interacting protein interacts with Smad proteins to augment transforming growth factor-beta-dependent transcription.
The adaptor molecule Disabled-2 links the transforming growth factor beta receptors to the Smad pathway.
Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.
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Phosphorylated SMAD2 MH2 forms a homotrimer through phosphoserine recognition.
"The crystal structure of a phosphorylated Smad2, at 1.8 A resolution, reveals the formation of a homotrimer mediated by the C-terminal phosphoserine (pSer) residues."
Cellular response to hypoxia involves signaling via Smad proteins.
The transforming activity of Ski and SnoN is dependent on their ability to repress the activity of Smad proteins.
Differential regulation of TGF-beta signaling through Smad2, Smad3 and Smad4.
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SMAD2, SMAD3 and SMAD4 have distinct cell-dependent effects on TGF-beta-responsive gene expression.
"we identified TGF-beta-dependent genes that are differentially regulated by Smad2 and Smad3 under regular growth conditions on a genome-wide scale."
c-Ski inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements.
Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells.
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Nodal signals through ALK7 and SMAD2/3 in human trophoblast cells.
"Nodal, acting through ALK7 and Smad2/3, inhibits proliferation and induces apoptosis in human trophoblast cells."
Functional proteomics mapping of a human signaling pathway.
Disorder in a target for the smad2 mad homology 2 domain and its implications for binding and specificity.
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The SMAD2 MH2 domain recognizes disordered SARA binding sequences.
"Our results are consistent with a series of hydrophobic patches on the MH2 that are able to recognize disordered regions of proteins."
Structural basis of heteromeric smad protein assembly in TGF-beta signaling.
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Structures establish heterotrimers containing two phosphorylated R-SMAD subunits and one SMAD4.
"Both complexes are heterotrimers, comprising two phosphorylated R-Smad subunits and one Smad4 subunit, a finding that was corroborated by isothermal titration calorimetry and mutational studies."
The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines.
Cloning and functional characterization of a new Ski homolog, Fussel-18, specifically expressed in neuronal tissues.
Smad transcription factors.
PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.
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PPM1A binds and dephosphorylates activated SMAD2/3, promoting their nuclear export.
"PPM1A dephosphorylates and promotes nuclear export of TGFbeta-activated Smad2/3."
Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion.
Potentiation of Smad-mediated transcriptional activation by the RNA-binding protein RBPMS.
The left-right axis is regulated by the interplay of Coco, Xnr1 and derrière in Xenopus embryos.
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The study concerns Xenopus left-right patterning; its abstract does not resolve the annotated SMAD2 manipulation.
"Formation of the left-right axis involves a symmetry-breaking signal originating in the node or its equivalents, which increases TGF-beta signaling on the left side of the embryo and ultimately leads to asymmetric patterning of the viscera."
Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling.
Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation.
Cholesterol suppresses cellular TGF-beta responsiveness: implications in atherogenesis.
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Cholesterol attenuates TGF-beta responsiveness by changing receptor partitioning and downstream SMAD signaling.
"cholesterol treatment suppresses or attenuates TGF-beta responsiveness in all cell types studied as determined by measuring TGF-beta-induced Smad2 phosphorylation and nuclear translocation, TGF-beta-induced PAI-1 expression, TGF-beta-induced luciferase reporter gene expression and TGF-beta-induced growth inhibition."
IKKalpha is a critical coregulator of a Smad4-independent TGFbeta-Smad2/3 signaling pathway that controls keratinocyte differentiation.
Identification of PCTA, a TGIF antagonist that promotes PML function in TGF-beta signalling.
SMAD proteins control DROSHA-mediated microRNA maturation.
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TGF-beta recruits SMAD2 to pri-miR-21 in the R-SMAD/DROSHA processing pathway.
"whereas TGF-β increased binding to pri-miR-21 by SMAD2 and SMAD3, but not by SMAD1, indicating that the association between R-SMADs and pri-miR-21 is specifically regulated by ligand stimulation"
TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal.
Identification of novel Smad2 and Smad3 associated proteins in response to TGF-beta1.
HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition.
An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-beta signalling.
Holding their own: the noncanonical roles of Smad proteins.
Ski co-repressor complexes maintain the basal repressed state of the TGF-beta target gene, SMAD7, via HDAC3 and PRMT5.
SKI and MEL1 cooperate to inhibit transforming growth factor-beta signal in gastric cancer cells.
Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins.
FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination.
Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling.
A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis.
Bone morphogenetic protein (BMP) and activin type II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells.
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BMP9 induces SMAD2-dependent inflammatory transcription and SMAD4-dependent target-gene responses in human endothelial cells.
"The IL-8 and E-selectin transcriptional responses were shown to be Smad2-dependent, a novel finding."
MTMR4 attenuates transforming growth factor beta (TGFbeta) signaling by dephosphorylating R-Smads in endosomes.
TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling.
A comprehensive resource of interacting protein regions for refining human transcription factor networks.
An atlas of combinatorial transcriptional regulation in mouse and man.
TIF1gamma controls erythroid cell fate by regulating transcription elongation.
Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificity.
The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway.
Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT.
Homeodomain protein DLX4 counteracts key transcriptional control mechanisms of the TGF-β cytostatic program and blocks the antiproliferative effect of TGF-β.
Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells.
ZNF580, a novel C2H2 zinc-finger transcription factor, interacts with the TGF-β signal molecule Smad2.
A Pin1/mutant p53 axis promotes aggressiveness in breast cancer.
HEB and E2A function as SMAD/FOXH1 cofactors.
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SMAD2/3/4 and FOXH1 occupy regulatory DNA in human embryonic stem cells and derived endoderm.
"We identified a new motif, termed SMAD complex-associated (SCA), that is bound by SMAD2/3/4 and FOXH1 in human embryonic stem cells (hESCs) and derived endoderm."
USP15 is a deubiquitylating enzyme for receptor-activated SMADs.
PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3.
Toward an understanding of the protein interaction network of the human liver.
Ablation of Smurf2 reveals an inhibition in TGF-β signalling through multiple mono-ubiquitination of Smad3.
Bone morphogenetic protein-3b (BMP-3b) inhibits osteoblast differentiation via Smad2/3 pathway by counteracting Smad1/5/8 signaling.
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BMP3b inhibits osteoblast differentiation through SMAD2/3 signaling that opposes SMAD1/5/8 outputs.
"BMP-3b suppressed the expression of osteoblastic markers including Runx2, osteocalcin and type-1 collagen induced by BMP-2, -4, -6 and -7."
Intercellular variation in signaling through the TGF-β pathway and its relation to cell density and cell cycle phase.
Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor-β pathway.
C18 ORF1, a novel negative regulator of transforming growth factor-β signaling.
Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer's disease.
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PIN1 modulates SMAD2 localization, turnover and association with phosphorylated tau in an Alzheimer disease context.
"Pin1 does not only affect Smad phosphorylation and stability but also regulates subcellular localization of Smad2 and supports its binding to phosphorylated tau protein."
Using an in situ proximity ligation assay to systematically profile endogenous protein-protein interactions in a pathway network.
Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.
14-3-3ζ turns TGF-β's function from tumor suppressor to metastasis promoter in breast cancer by contextual changes of Smad partners from p53 to Gli2.
Syntenin regulates TGF-β1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-β type I receptor internalization.
Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy.
Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-β signaling.
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Properly folded human SMAD2 has E3-regulated intrinsic DNA-binding activity; SMAD4 also binds regulatory DNA directly.
"The SMAD2 MH1 domain and full-length proteins also bound to different 5GC probes (Gsc1 and Gsc2 probes) from the Gsc promoter in the 0.6–1.2 µM concentration range"
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Properly folded human SMAD2 has E3-regulated intrinsic DNA-binding activity; SMAD4 also binds regulatory DNA directly.
"the full-length SMAD4 protein bound the Gsc1 probe at values between 0.15 and 0.30 µM (Fig."
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Properly folded human SMAD2 has E3-regulated intrinsic DNA-binding activity; SMAD4 also binds regulatory DNA directly.
"Thus activated, SMAD2 and SMAD3 form complexes with SMAD4, accumulate in the nucleus, and recruit coactivators and repressors to regulate the expression of target genes."
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Properly folded human SMAD2 has E3-regulated intrinsic DNA-binding activity; SMAD4 also binds regulatory DNA directly.
"TGF-β, Nodal, and Activin receptors phosphorylate SMAD2 and SMAD3."
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Properly folded human SMAD2 has E3-regulated intrinsic DNA-binding activity; SMAD4 also binds regulatory DNA directly.
"We observe that properly folded SMAD2 protein has intrinsic DNA-binding activity, which is modulated by the ensemble of conformations adopted by the E3 insert in solution."
A reference map of the human binary protein interactome.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
GDF-8 stimulates trophoblast cell invasion by inducing ALK5-SMAD2/3-mediated MMP2 expression.
The Interplay Between TGF-β Signaling and Cell Metabolism.
Systematic discovery of mutation-directed neo-protein-protein interactions in cancer.
Multimodal cell maps as a foundation for structural and functional genomics.
MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.
MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling.
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SMAD2 docks to the TGF-beta receptor and requires receptor phosphorylation for nuclear signaling.
"MADR2 and not the related protein DPC4 transiently interacts with the TGFbeta receptor and is directly phosphorylated by the complex on C-terminal serines."
Heteromeric and homomeric interactions correlate with signaling activity and functional cooperativity of Smad3 and Smad4/DPC4.
Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium.
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SMAD6 interacts with assayed human SMAD2 and SMAD4 proteins.
"Smad6 interacted with all species tested (Smad1, Smad2, and Smad4), whereas Smad7 interacted only with Smad6 (Fig."
TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4.
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Receptor activation induces SMAD2/3/4 association, nuclear accumulation and synergistic transcription.
"Smads 2, 3 and 4 accumulated in the nucleus upon TGF-beta1 treatment in Mv1Lu cells, and showed a synergistic effect in a transcriptional reporter assay using the TGF-beta-inducible plasminogen activator inhibitor-1 promoter."
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Receptor activation induces SMAD2/3/4 association, nuclear accumulation and synergistic transcription.
"Smads 2 and 3 interacted with Smad4 after TbetaR activation in transfected COS cells."
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Receptor activation induces SMAD2/3/4 association, nuclear accumulation and synergistic transcription.
"we observed TbetaR-activation-dependent interaction between Smad2 and Smad3."
Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes.
Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor.
Characterization of human FAST-1, a TGF beta and activin signal transducer.
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Human FAST1 binds SMAD2 and activates a ligand-responsive reporter that requires endogenous SMAD4.
"hFAST-1 shared with xFAST-1 the ability to bind to human Smad2 and activate an activin response element (ARE)."
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Human FAST1 binds SMAD2 and activates a ligand-responsive reporter that requires endogenous SMAD4.
"The hFAST-1-dependent activation of ARE was completely dependent on endogenous Smad4 and stimulation by a TGF beta-like ligand."
Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription.
SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor.
Roles of pathway-specific and inhibitory Smads in activin receptor signaling.
POU5F1 (OCT4), SOX2, NANOG, ZSCAN10, PRDM14, SMAD2, FOXP1-ES bind the POU5F1 (OCT4) promoter
Phospho R-SMAD(SMAD2/3):CO-SMAD(SMAD4):FOXO3 binds FoxO3a-binding elements
Phosphorylation of SMAD2,3 by Activin:Activin Receptor
An anchoring protein, ZFYVE9 (SARA), recruits SMAD2/3
Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4
Phosphorylated SMAD2/3 dissociates from TGFBR
Activated type I receptor phosphorylates SMAD2/3 directly
SKI/SKIL binds SMAD complex, suppressing TGF-beta signaling
The SMAD2/3:SMAD4 complex transfers to the nucleus
SMURF2 ubiquitinates SMAD2
Ubiquitin-dependent degradation of the SMAD complex terminates TGF-beta signaling
WWTR1 binds SMAD2/3:SMAD4 heterotrimer
PPM1A dephosphorylates nuclear SMAD2/3
WWTR1:SMAD translocates to the nucleus
SMAD2/3:SMAD4 heterotrimer forms a complex with RBL1, E2F4/5 and DP1/2
Degradation of ubiquitinated SMAD2
Phosphorylation of SMAD2 and SMAD3 linker regions by CDK8 or CDK9
NEDD4L binds phosphorylated linker region of SMAD2/3
NEDD4L ubiquitinates SMAD2/3
Degradation of SMAD2/3:SMAD4 complex
SMURF2 binds SMAD3 phosphorylated in the linker region
SMURF2 monoubiquitinates SMAD3
TGIF recruits HDAC1 to SMAD2/3:SMAD4 heterotrimer
MEN1 binds SMAD2/3:SMAD4 heterotrimer
SMAD2/3:SMAD4 heterotrimer binds SP1
PARP1 ADP-ribosylates SMAD3 and SMAD4
PARP1 binds SMAD2/3:SMAD4 heterotrimer
PMEPA1 sequesters phosphorylated SMAD2/3
PMEPA1 sequesters unphosphorylated SMAD2/3
PPM1A protein phosphatase binds phosphorylated SMAD2/3
Dephosphorylated SMAD2/3 translocates to the cytosol
MTMR4 dephosphorylates SMAD2/3
MTMR4 binds phosphorylated SMAD2/3
Activated TGFBR1 cannot phosphorylate SMAD2 and SMAD3 Phosphorylation Motif Mutants
SMAD4 MH2 Domain Mutants do not bind phosphorylated SMAD2 and SMAD3
Phosphorylated SMAD2/3 MH2 Domain Mutants do not bind SMAD4
An anchoring protein ZFYVE9 (SARA) does not recruit SMAD2/3 to TGFB1:TGFBR2:p-TGFBR1 KD Mutants
POU5F1 (OCT4), SOX2, NANOG, KLF4, PBX1, SMAD2 bind the NANOG promoter
USP15 deubiquitinates SMAD1,SMAD2,SMAD3, SMAD7:SMURF,KEAP1
TRIM33 monoubiquitinates SMAD4
TRIM33 (Ectodermin) binds SMAD heterotrimer in the nucleus
FOXO1,FOXO3,FOXO4 bind p-2S-SMAD2/3:SMAD4
FOXO:SMAD complex binds CDKN1A gene promoter
FOXG1 binds FOXO:SMAD complexes
MAPK1 and MAPK3 phosphorylate SMAD2 and SMAD3
WWTR1:p-2S-SMAD2,3:SMAD4 binds SERPINE1 gene promoter
WWTR1:p-2S-SMAD2,3:SMAD4 binds SMAD7 gene promoter
p-2S-SMAD2,3:SMAD4:SP1 binds CDKN2B gene promoter
p-2S-SMAD2,3:SMAD4:RBL1:E2F4,5:DP1,2 binds MYC gene promoter
p-2S-SMAD2,3:SMAD4 binds JUNB gene promoter
EOMES, SMAD2,3, and GATA6 bind the CXCR4 gene
SMAD2,3 and GATA6-AS1 lncRNA bind the GATA6 gene
Rnf111 binds SKI/SKIL in complex with SMAD2/3:SMAD4 upon TGF-beta stimulation
Ubiquitination of SKI/SKIL by Rnf111
FOXO1,FOXO3 and SMAD3 bind Trim63 gene promoter
Smad expression during kidney development.
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Renal SMAD expression patterns suggest developmental hypotheses but do not directly establish ureteric-bud function.
"Based on the observed patterns of expression, we speculate that individual or combinations of Smads may play specific roles in cell-fate determination during kidney development."
Combinatorial activities of Smad2 and Smad3 regulate mesoderm formation and patterning in the mouse embryo.
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Combined epiblast loss of Smad2 and Smad3 disrupts mesoderm specification and patterning in mouse embryos.
"selective removal of both Smad2 and Smad3 from the epiblast additionally disrupts specification of axial and paraxial mesodermal derivatives."
Cell fate decisions within the mouse organizer are governed by graded Nodal signals.
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Graded Nodal-SMAD2 signaling allocates axial mesendoderm precursors in the mouse organizer.
"graded Nodal/Smad2 signals govern allocation of the axial mesendoderm precursors that selectively give rise to the ADE and PCP mesoderm."
Insufficient versican cleavage and Smad2 phosphorylation results in bicuspid aortic and pulmonary valves.
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ADAMTS5-dependent versican cleavage and SMAD2 signaling contribute to semilunar valve development.
"faulty versican clearance due to ADAMTS5 deficiency blocks the initiation of pSmad2 signaling, which is required for excavation of endocardial cushions during aortic and pulmonary valve development."
SMAD2 manual primary-source research notes
TGFbeta3 signaling activates transcription of the LEF1 gene to induce epithelial mesenchymal transformation during mouse palate development.
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SMAD2/4-LEF1 complexes promote transcription and epithelial remodeling during mouse palate development.
"Our paper is the first to show that the Smad2,4/LEF1 complex replaces beta-catenin/LEF1 during activation of EMT in vivo by TGFbeta3."
Effects of transforming growth factor-β1 on odontoblastic differentiation in dental papilla cells is determined by IPO7 expression level.
Crystal structure of a transcriptionally active Smad4 fragment.
Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator.
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SMAD4 transcriptional activation requires hetero-oligomerization and is enhanced by associated transactivators.
"Hetero-oligomerization of Smad4 with the pathway-restricted SMAD proteins is essential for Smad4-mediated transcription."
Smad2 is essential for maintenance of the human and mouse primed pluripotent stem cell state.
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SMAD2 maintains primed pluripotency through Nanog activation and restraint of autocrine BMP signaling.
"We found that Smad2, but not Smad3, is required to maintain the undifferentiated pluripotent state."
UniProt Q15796 curated record
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Curated experimental localization places SMAD2 in a cytoplasmic pool that translocates to the nucleus during signaling.
"Cytoplasmic and nuclear in the absence of TGF-beta. On TGF-beta stimulation, migrates to the nucleus when complexed with SMAD4 or with IPO7"