Tabela com principais espec.
|Species Reactivity||Key Applications||Host||Format||Antibody Type|
|H, M, R||WB||Rb||Affinity Purified||Polyclonal Antibody|
|Presentation||Purified rabbit polyclonal IgG in buffer containing 0.07 M Tris-glycine, pH 7.4, 0.105 M NaCl, 0.035% sodium azide and 30% glycerol.|
|Safety Information according to GHS|
|Material Size||200 µL|
|Título||Número do lote|
|Anti-Smad2/3 - 2154184||2154184|
|Anti-Smad2/3 - 2433510||2433510|
|Anti-Smad2/3 - 2044109||2044109|
|Anti-Smad2/3 - 2073137||2073137|
|Anti-Smad2/3 - 2302184||2302184|
|Anti-Smad2/3 - 24340||24340|
|Anti-Smad2/3 - 26312||26312|
|Anti-Smad2/3 - 27969||27969|
|Anti-Smad2/3 - 32609||32609|
|Anti-Smad2/3 - DAM1472174||DAM1472174|
|Anti-Smad2/3 - DAM1514096||DAM1514096|
|Anti-Smad2/3 - DAM1780383||DAM1780383|
|Anti-Smad2/3 - DAM1817675||DAM1817675|
|Anti-Smad2/3 - JBC135570||JBC135570|
|Anti-Smad2/3 - JBC1888193||JBC1888193|
Referências | 15 Disponível | Ver todas as referências
|Visão geral das referências||Aplicação||Pub Med ID|
|Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. |
Yoshida, T; Ozawa, Y; Kimura, T; Sato, Y; Kuznetsov, G; Xu, S; Uesugi, M; Agoulnik, S; Taylor, N; Funahashi, Y; Matsui, J
British journal of cancer 110 1497-505 2014
Eribulin mesilate (eribulin), a non-taxane microtubule dynamics inhibitor, has shown trends towards greater overall survival (OS) compared with progression-free survival in late-stage metastatic breast cancer patients in the clinic. This finding suggests that eribulin may have additional, previously unrecognised antitumour mechanisms beyond its established antimitotic activity. To investigate this possibility, eribulin's effects on the balance between epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) in human breast cancer cells were investigated.Triple negative breast cancer (TNBC) cells, which are oestrogen receptor (ER-)/progesterone receptor (PR-)/human epithelial growth receptor 2 (HER2-) and have a mesenchymal phenotype, were treated with eribulin for 7 days, followed by measurement of EMT-related gene and protein expression changes in the surviving cells by quantitative real-time PCR (qPCR) and immunoblot, respectively. In addition, proliferation, migration, and invasion assays were also conducted in eribulin-treated cells. To investigate the effects of eribulin on TGF-β/Smad signalling, the phosphorylation status of Smad proteins was analysed. In vivo, the EMT/MET status of TNBC xenografts in mice treated with eribulin was examined by qPCR, immunoblot, and immunohistochemical analysis. Finally, an experimental lung metastasis model was utilised to gauge the metastatic activity of eribulin-treated TNBC in the in vivo setting.Treatment of TNBC cells with eribulin in vitro led to morphological changes consistent with transition from a mesenchymal to an epithelial phenotype. Expression analyses of EMT markers showed that eribulin treatment led to decreased expression of several mesenchymal marker genes, together with increased expression of several epithelial markers. In the TGF-β induced EMT model, eribulin treatment reversed EMT, coincident with inhibition of Smad2 and Smad3 phosphorylation. Consistent with these changes, TNBC cells treated with eribulin for 7 days showed decreased capacity for in vitro migration and invasiveness. In in vivo xenograft models, eribulin treatment reversed EMT and induced MET as assessed by qPCR, immunoblot, and immunohistochemical analyses of epithelial and mesenchymal marker proteins. Finally, surviving TNBC cells pretreated in vitro with eribulin for 7 days led to decreased numbers of lung metastasis when assessed in an in vivo experimental metastasis model.Eribulin exerted significant effects on EMT/MET-related pathway components in human breast cancer cells in vitro and in vivo, consistent with a phenotypic switch from mesenchymal to epithelial states, and corresponding to observed decreases in migration and invasiveness in vitro as well as experimental metastasis in vivo. These preclinical findings may provide a plausible scientific basis for clinical observations of prolonged OS by suppression of further spread of metastasis in breast cancer patients treated with eribulin.
|Sphere formation reverses the metastatic and cancer stem cell phenotype of the murine mammary tumour 4T1, independently of the putative cancer stem cell marker Sca-1. |
Heli Matilainen,Xiao-Wen Yu,Ching-Wen Tang,Michael V Berridge,Melanie J McConnell
Cancer letters 323 2012
Breast cancer stem cells (BCSCs) initiate and sustain breast cancers, and several putative markers have been proposed to prospectively isolate BCSC from the non-cancer stem cell population. The candidate BCSC marker Sca-1 is a GPI-linked membrane protein expressed on activated lymphocytes, hematopoietic stem cells and mammary stem cells. Sca-1+ cells were purified from the murine mammary tumour cell line 4T1. However, this did not enrich for a stem-like, tumour initiating or metastatic cell population in vitro or in vivo. Sphere formation, which induced high levels of Sca-1, reduced BCSC gene expression with near complete loss of spontaneous metastasis from sphere-derived tumours. This was associated with decreased expression of TGFB2 and reduced activation of the TGFβ signalling pathway in spheres. Both TGFB2 expression in vitro and spontaneous metastasis in vivo could be restored upon re-differentiation of sphere cells by exposure to serum, and this occurred with retention of the majority of Sca-1 expression. We conclude that while putative BCSC, including spheres, can have high Sca-1 expression, Sca-1 itself is not a marker of BCSC in established 4T1 tumours or the cell line.
|Transcriptional integration of Wnt and Nodal pathways in establishment of the Spemann organizer. |
Reid, CD; Zhang, Y; Sheets, MD; Kessler, DS
Developmental biology 368 231-41 2012
Signaling inputs from multiple pathways are essential for the establishment of distinct cell and tissue types in the embryo. Therefore, multiple signals must be integrated to activate gene expression and confer cell fate, but little is known about how this occurs at the level of target gene promoters. During early embryogenesis, Wnt and Nodal signals are required for formation of the Spemann organizer, which is essential for germ layer patterning and axis formation. Signaling by both Wnt and Nodal pathways is required for the expression of multiple organizer genes, suggesting that integration of these signals is required for organizer formation. Here, we demonstrate transcriptional cooperation between the Wnt and Nodal pathways in the activation of the organizer genes Goosecoid (Gsc), Cerberus (Cer), and Chordin (Chd). Combined Wnt and Nodal signaling synergistically activates transcription of these organizer genes. Effectors of both pathways occupy the Gsc, Cer and Chd promoters and effector occupancy is enhanced with active Wnt and Nodal signaling. This suggests that, at organizer gene promoters, a stable transcriptional complex containing effectors of both pathways forms in response to combined Wnt and Nodal signaling. Consistent with this idea, the histone acetyltransferase p300 is recruited to organizer promoters in a Wnt and Nodal effector-dependent manner. Taken together, these results offer a mechanism for spatial and temporal restriction of organizer gene transcription by the integration of two major signaling pathways, thus establishing the Spemann organizer domain.
|An essential role for transcription before the MBT in Xenopus laevis. |
Skirkanich, J; Luxardi, G; Yang, J; Kodjabachian, L; Klein, PS
Developmental biology 357 478-91 2011
Most zygotic genes remain transcriptionally silent in Drosophila, Xenopus, and zebrafish embryos through multiple mitotic divisions until the midblastula transition (MBT). Several genes have been identified in each of these organisms that are transcribed before the MBT, but whether precocious expression of specific mRNAs is important for later development has not been examined in detail. Here, we identify a class of protein coding transcripts activated before the MBT by the maternal T-box factor VegT that are components of an established transcriptional regulatory network required for mesendoderm induction in Xenopus laevis, including the Nodal related ligands xnr5, xnr6, and derrière and the transcription factors bix4, and sox17α. Accumulation of phospho-Smad2, a hallmark of active Nodal signaling, at the onset of the MBT requires preMBT transcription and activity of xnr5 and xnr6. Furthermore, preMBT activation of the Nodal pathway is essential for mesendodermal gene expression and patterning of the embryo. Finally, xnr5 and xnr6 can also activate their own expression during cleavage stages, indicating that preMBT transcription contributes to a feed-forward system that allows robust activation of Nodal signaling at the MBT.
|Extracellular matrix metalloproteinase inducer (EMMPRINCD147) as a novel regulator of myogenic cell differentiation. |
Attia M, Huet E, Delbé J, Ledoux D, Menashi S, Martelly I
J Cell Physiol 226 141-9. 2011
Matrix metalloproteinases (MMPs) are thought to play an important role in skeletal muscle cell growth and differentiation. In view of the MMP inducing function of EMMPRIN/CD147, its role in myogenic cell differentiation was investigated. EMMPRIN level increased during differentiation of both rat primary myoblasts derived from satellite cells and mouse C2.7 myogenic cells and was associated with an alteration in its molecular forms. In parallel, expression of pro-MMP-9 gradually decreased and that of pro-MMP-2 and active MMP-2 increased. While small interfering RNA (siRNA) inhibition of EMMPRIN expression accelerated cell differentiation, exogenously added recombinant EMMPRIN inhibited differentiation by an MMP-mediated mechanism, as the MMP inhibitor marimastat abrogated EMMPRIN\'s effect. Our results further suggest that EMMPRIN regulates differentiation through an MMP activation of transforming growth factor beta (TGFβ), a known inhibitor of myoblast\'s differentiation, as the increased activation and signaling of TGFβ by EMMPRIN was attenuated in the presence of marimastat. EMMPRIN inhibition may thus represent a novel strategy in the treatment of muscular degenerative disorders.
|SMAD3 and EGR1 physically and functionally interact in promoter-specific fashion. |
Jérôme Fortin,Daniel J Bernard
Cellular signalling 22 2010
Gonadotropin-releasing hormone (GNRH1) stimulates luteinizing hormone beta subunit (LHB/Lhb) transcription. The transforming growth factor beta superfamily ligand activin A partially inhibits this effect on the human LHB promoter while potentiating GNRH1-induction of the murine Lhb gene. Here, we investigated the mechanisms underlying the species-specific modulation of the GNRH1 response by activin signalling. GNRH1 stimulates LHB/Lhb transcription via induction of early-growth response 1 (EGR1), which binds to the proximal promoter of both species. Activin A decreased GNRH1-induced recruitment of EGR1 to the human, but not murine, promoter. We hypothesized that the activin A signalling protein, SMAD3, might play a role in this system. Indeed, we observed both physical and functional interactions between SMAD3 and EGR1. The two proteins interacted via the SMAD3 MH2 domain and the EGR1 DNA-binding domain. Analogous to the species-specific activin A effect on the GNRH1 response, SMAD3 over-expression partially inhibited EGR1-induction of the human promoter, while potentiating EGR1-induced murine Lhb promoter activity. The proximal murine Lhb promoter contains three minimal SMAD-binding elements (SBEs) that are absent from human LHB. Introduction of the SBEs into the human promoter converted SMAD3 from an inhibitor to a stimulator of EGR1-induced transcription. The converse was observed when the SBEs in the murine promoter were replaced by the corresponding human sequences. Together, our results suggest a model in which activin A inhibits GNRH1-induction of human LHB transcription via an interaction between SMAD3 and EGR1 that inhibits the latter's recruitment to the proximal promoter. In contrast, in mouse, the presence of SBEs in the promoter allows SMAD3 and EGR1 to function synergistically to regulate Lhb transcription. The basis for their functional cooperativity is not completely clear, but may involve enhancement of EGR1's physical interaction with other important co-factors, including paired-like homeodomain transcription factor 1 (PITX1).
|Embryonic overexpression of Galgt2 inhibits skeletal muscle growth via activation of myostatin signaling. |
Kumaran Chandraskeharan,Paul T Martin
Muscle & nerve 39 2009
Many proteins that affect skeletal muscle growth are secreted glycoproteins, yet the nature of how glycosylation regulates the expression and growth-promoting properties of such factors is not well understood. One type of glycosylation that affects muscle growth is that controlled by the CT GalNAc transferase (Galgt2), the enzyme responsible for the synthesis of the beta1,4GalNAc linkage on the CT carbohydrate antigen (GalNAcbeta1,4[Neu5Ac(or Gc)alpha2,3]Galbeta1,4GlcNAcbeta-R). In the mouse, both Galgt2 protein and the CT carbohydrate become confined to the neuromuscular synapse in skeletal muscle by the second postnatal week. Galgt2 transgenic mice that overexpress the CT carbohydrate from embryonic time-points onward in skeletal muscle had profoundly impaired muscle growth that was maintained throughout adulthood. Transgenic overexpression of Galgt2 increased myostatin protein expression and stimulated myostatin signaling, whereas expression of follistatin protein, a myostatin inhibitor, was decreased. Changed myostatin and follistatin protein levels were controlled at a posttranslational level, and inhibition of muscle growth was overcome if serum follistatin levels were normalized to wild-type levels. In contrast to embryonic Galgt2 overexpression, postnatal overexpression of Galgt2 had no effect on either myostatin or follistatin expression or muscle growth. These experiments demonstrate that Galgt2 can control growth by modulating the expression of myostatin and myostatin inhibitors during particular periods of muscle development.
|A positive role for Myc in TGFbeta-induced Snail transcription and epithelial-to-mesenchymal transition. |
Smith, AP; Verrecchia, A; Fagà, G; Doni, M; Perna, D; Martinato, F; Guccione, E; Amati, B
Oncogene 28 422-30 2009
Myc and transforming growth factor-beta (TGFbeta) signaling are mutually antagonistic, that is Myc suppresses the activation of TGFbeta-induced genes, whereas TGFbeta represses c-myc transcription. Here, we report a positive role for Myc in the TGFbeta response, consisting in the induction of an epithelial-to-mesenchymal transition (EMT) and the activation of the EMT-associated gene Snail. Knockdown of either Myc or the TGFbeta effectors SMAD3/4 in epithelial cells eliminated Snail induction by TGFbeta. Both Myc and SMAD complexes targeted the Snail promoter in vivo, DNA binding occurring in a mutually independent manner. Myc was bound prior to TGFbeta treatment, and was required for rapid Snail activation upon SMAD binding induced by TGFbeta. On the other hand, c-myc downregulation by TGFbeta was a slower event, occurring after Snail induction. The response of Snail to another cytokine, hepatocyte growth factor (HGF), also depended on Myc and SMAD4. Thus, contrary to their antagonistic effects on Cip1 and INK4b, Myc and SMADs cooperate in signal-dependent activation of Snail in epithelial cells. Although Myc also targeted the Snail promoter in serum-stimulated fibroblasts, it was dispensable for its activation in these conditions, further illustrating that the action of Myc in transcriptional regulation is context-dependent. Our findings suggest that Myc and TGFbeta signaling may cooperate in promoting EMT and metastasis in carcinomas.
|Expression of transforming growth factor-beta (TGF-beta) in chronic idiopathic cough. |
Xie, S; Macedo, P; Hew, M; Nassenstein, C; Lee, KY; Chung, KF
Respiratory research 10 40 2009
In patients with chronic idiopathic cough, there is a chronic inflammatory response together with evidence of airway wall remodelling and an increase in airway epithelial nerves expressing TRPV-1. We hypothesised that these changes could result from an increase in growth factors such as TGFbeta and neurotrophins. We recruited 13 patients with persistent non-asthmatic cough despite specific treatment of associated primary cause(s), or without associated primary cause, and 19 normal non-coughing volunteers without cough as controls, who underwent fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsies. There was a significant increase in the levels of TGFbeta in BAL fluid, but not of nerve growth factor(NGF) and brain-derived nerve growth factor(BDNF) compared to normal volunteers. Levels of TFGbeta gene and protein expression were assessed in bronchial biopsies. mRNA expression for TGFbeta was observed in laser-captured airway smooth muscle and epithelial cells, and protein expression by immunohistochemistry was increased in ASM cells in chronic cough patients, associated with an increase in nuclear expression of the transcription factor, smad 2/3. Subbasement membrane thickness was significantly higher in cough patients compared to normal subjects and there was a positive correlation between TGF-beta levels in BAL and basement membrane thickening. TGFbeta in the airways may be important in the airway remodelling changes observed in chronic idiopathic cough patients, that could in turn lead to activation of the cough reflex.
|Eomesodermin requires transforming growth factor-beta/activin signaling and binds Smad2 to activate mesodermal genes. |
Picozzi, P; Wang, F; Cronk, K; Ryan, K
The Journal of biological chemistry 284 2397-408 2009
The T-box gene Eomesodermin (Eomes) is required for early embryonic mesoderm differentiation in mouse, frog (Xenopus laevis), and zebrafish, is important in late cardiac development in Xenopus, and for CD8+ T effector cell function in mouse. Eomes can ectopically activate many mesodermal genes. However, the mechanism by which Eomes activates transcription of these genes is poorly understood. We report that Eomes protein interacts with Smad2 and is capable of working in a non-cell autonomous manner via transfer of Eomes protein between adjacent embryonic cells. Blocking of Eomes protein transfer using a farnesylated red fluorescent protein (CherryF) also prevents Eomes nuclear accumulation. Transfer of Eomes protein between cells is mediated by the Eomes carboxyl terminus (456-692). A carbohydrate binding domain within the Eomes carboxyl-terminal region is sufficient for transfer and important for gene activation. We propose a novel mechanism by which Eomes helps effect a cellular response to a morphogen gradient.
|EGF antagonizes TGF-beta-induced tropoelastin expression in lung fibroblasts via stabilization of Smad corepressor TGIF. |
Yang, S; Nugent, MA; Panchenko, MP
American journal of physiology. Lung cellular and molecular physiology 295 L143-51 2008
We previously reported that neutrophil elastase (NE) downregulates transforming growth factor-beta (TGF-beta)-maintained tropoelastin mRNA levels in lung fibroblasts through transactivation of the epidermal growth factor (EGF) receptor (EGFR)/Mek/Erk pathway, which is dependent on the NE-initiated release of soluble EGFR ligands. In the present study, we investigated the mechanism by which EGF downregulates tropoelastin expression. We found that EGF downregulates tropoelastin expression through inhibition of TGF-beta signaling. We show that EGF does not prevent the TGF-beta-induced nuclear accumulation of Smad2/3; rather, EGF stabilizes the short-lived Smad transcriptional corepressor TG-interacting factor (TGIF) via EGFR/Mek/Erk-mediated phosphorylation of TGIF. Elevation of TGIF levels, either by TGIF overexpression or prevention of TGIF degradation, is sufficient to inhibit TGF-beta-induced tropoelastin expression. Moreover, TGIF is essential for EGF-mediated downregulation of tropoelastin expression, inasmuch as small interfering RNA knockdown of TGIF blocked EGF-induced downregulation of tropoelastin. Finally, we demonstrated that NE treatment, which releases EGF-like growth factors, causes stabilization of TGIF through the EGFR/Mek/Erk pathway. These results suggest that EGFR/Mek/Erk signaling specifically antagonizes the proelastogenic action of TGF-beta in lung fibroblasts by stabilizing the Smad transcriptional corepressor TGIF.Texto completo do artigo
|Expression and activation of TGF-beta isoforms in acute allergen-induced remodelling in asthma. |
Torrego, A; Hew, M; Oates, T; Sukkar, M; Fan Chung, K
Thorax 62 307-13 2007
Airway wall remodelling and inflammation are features of chronic asthma. Transforming growth factor beta (TGF-beta) has been implicated in these processes.To determine the effect of allergen challenge on airway inflammation and remodelling and whether TGF-beta isoforms and the Smad signalling pathways are involved.Thirteen patients with atopic asthma underwent inhalational challenge with 0.9% saline, followed by allergen 3-4 weeks later. After both challenges, fibreoptic bronchoscopy was undertaken to obtain bronchial biopsies and tissue samples were processed for immunohistochemistry and examined by microscopy.Forced expiratory volume in 1 s (FEV(1)) fell after allergen challenge (mean (SE) -28.1 (0.9)% at 30 min with a late response at 7 hours (-23.0 (1.2)%). Allergen challenge caused an increase in neutrophils and eosinophils in the bronchial mucosa compared with saline. Sub-basement membrane (SBM) thickness did not change after allergen, but tenascin deposition in SBM was increased. Intranuclear (activated) Smad 2/3 and Smad 4 detected by immunohistochemistry were increased after allergen challenge in epithelial and subepithelial cells of bronchial biopsies. No inhibitory Smad (Smad 7) protein was detected. TGF-beta isoforms 1, 2 and 3 were expressed predominantly in bronchial epithelium after saline and allergen challenges, but only TGF-beta(2) expression was increased after allergen. Double immunostaining showed an increase in TGF-beta(2) positive eosinophils and neutrophils but not in TGF-beta(1) positive eosinophils and neutrophils after allergen challenge.TGF-beta(2) may contribute to the remodelling changes in allergic asthma following single allergen exposure.Texto completo do artigo
|Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-beta on tropoelastin mRNA in lung fibroblasts. |
DiCamillo, SJ; Yang, S; Panchenko, MV; Toselli, PA; Naggar, EF; Rich, CB; Stone, PJ; Nugent, MA; Panchenko, MP
American journal of physiology. Lung cellular and molecular physiology 291 L232-43 2006
Neutrophil elastase (NE) plays an important role in emphysema, a pulmonary disease associated with excessive elastolysis and ineffective repair of interstitial elastin. Besides its direct elastolytic activity, NE releases soluble epidermal growth factor receptor (EGFR) ligands and initiates EGFR/MEK/ERK signaling to downregulate tropoelastin mRNA in neonatal rat lung fibroblasts (DiCamillo SJ, Carreras I, Panchenko MV, Stone PJ, Nugent MA, Foster JA, and Panchenko MP. J Biol Chem 277: 18938-18946, 2002). We now report that NE downregulates tropoelastin mRNA in the rat fetal lung fibroblast line RFL-6. The tropoelastin mRNA downregulation is preceded by release of EGF-like and TGF-alpha-like polypeptides and requires EGFR/MEK/ERK signaling, because it is prevented by the EGFR inhibitor AG1478 and the MEK/ERK uncoupler U0126. Tropoelastin expression in RFL-6 fibroblasts is governed by autocrine TGF-beta signaling, because TGF-beta type I receptor kinase inhibitor or TGF-beta neutralizing antibody dramatically decreases tropoelastin mRNA and protein levels. Half-life of tropoelastin mRNA in RFL-6 cells is greater than 24 h, but it is decreased to approximately 8 h by addition of TGF-beta neutralizing antibody, EGF, TGF-alpha, or NE. Tropoelastin mRNA destabilization by NE, EGF, or TGF-alpha is abolished by AG1478 or U0126. EGF-dependent tropoelastin mRNA downregulation is reversed upon ligand withdrawal, whereas chronic EGF treatment leads to persistent downregulation of tropoelastin mRNA and protein levels and decreases insoluble elastin deposition. We conclude that NE-initiated EGFR/MEK/ERK signaling cascade overrides the autocrine TGF-beta signaling on tropoelastin mRNA stability and, therefore, decreases the elastogenic response in RFL-6 fibroblasts. We hypothesize that persistent EGFR/MEK/ERK signaling could impede the TGF-beta-induced elastogenesis/elastin repair in the chronically inflamed, elastase/anti-elastase imbalanced lung in emphysema.
|TGFbeta signaling: receptors, transducers, and Mad proteins. |
Cell, 85: 947-50 (1996) 1996
|Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. |
Lagna, G, et al.
Nature, 383: 832-6 (1996) 1996
The TGF-beta/activin/BMP superfamily of growth factors signals through heteromeric receptor complexes of type I and type II serine/threonine kinase receptors. The signal originated by TGF-beta-like molecules appears to be transduced by a set of evolutionarily conserved proteins known as SMADs, which upon activation directly translocate to the nucleus where they may activate transcription. Five SMAD proteins have so far been characterized in vertebrates. These factors are related to the mediator of decapentaplegic (dpp) signalling, mothers against dpp (Mad), in Drosophila and to the Sma genes from Caenorhabditis elegans. Smad1 and Smad2 have been shown to mimic the effects of BMP and activin, respectively, both in Xenopus and in mammalian cells, whereas Smad3 (a close homologue of Smad2) and the related protein DPC4, a tumour-suppressor gene product, mediate TGF-beta actions. We report here that DPC4 is essential for the function of Smad1 and Smad2 in pathways that signal mesoderm induction and patterning in Xenopus embryos, as well as antimitogenic and transcriptional responses in breast epithelial cells. DPC4 associates with Smad1 in response to BMP and with Smad2 in response to activin or TGF-beta. DPC4 is therefore a regulated partner of SMADs that function in different signalling pathways of the TGF-beta family.