SEARCH · PubMed Health

Results for “Smad Proteins, Receptor-Regulated”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2000

TGF-beta signaling by Smad proteins.

Members of the transforming growth factor-beta (TGF-beta) family bind to type II and type I serine/threonine kinase receptors, which initiate intracellular signals through activation of Smad proteins. Receptor-regulated Smads (R-Smads) are anchored to the cell membrane by interaction with membrane-bound proteins, including Smad anchor for receptor activation (SARA). Upon ligand stimulation, R-Smads are phosphorylated by the receptors and form oligomeric complexes with common-partner Smads (Co-Smads). The oligomeric Smad complexes then translocate into the nucleus, where they regulate the transcription of target genes by direct binding to DNA, interaction with various DNA-binding proteins, and recruitment of transcriptional coactivators or corepressors. A third class of Smads, inhibitory Smads (I-Smads), inhibits the signals from the serine/threonine kinase receptors. Since the expression of I-Smads is induced by the TGF-beta superfamily proteins, Smads constitute an autoinhibitory signaling pathway. The functions of Smads are regulated by other signaling pathways, such as the MAP kinase pathway. Moreover, Smads interact with and modulate the functions of various transcription factors which are downstream targets of other signaling pathways. Loss of function of certain Smads is involved in tumorigenesis, e.g., pancreatic and colorectal cancers. Analyses by gene targeting revealed pivotal roles of Smads in early embryogenesis, angiogenesis, and immune functions in vivo.

Animals↗

PubMed1999

Signal transduction by bone morphogenetic protein receptors: functional roles of Smad proteins.

Intracellular signals for bone morphogenetic proteins (BMPs) and other members in the transforming growth factor (TGF)-beta superfamily are mediated by Smad proteins. Receptor-regulated Smads (R-Smads) are activated by serine/threonine kinase receptors upon ligand binding. R-Smads then form hetero-oligomeric complexes with a common-mediator Smad (co-Smad) and translocate into the nucleus, where they regulate transcription of target genes. Smads 1, 5, and 8 are R-Smads activated by BMP receptors, whereas Smads 2 and 3 are activated by TGF-beta and activin receptors. Smad4 is the only co-Smad isolated in mammals, and is shared by BMP and TGF-beta/activin signaling pathways. Smads 6 and 7 are anti-Smads, which block signals by preventing the activation of R-Smads by serine/threonine kinase receptors. Anti-Smads are induced by ligand stimulation, suggesting that they constitute a negative feedback loop in the signal transduction pathways of the TGF-beta superfamily.

Animals↗

PubMed2000

Signaling inputs converge on nuclear effectors in TGF-beta signaling.

Recent studies have consolidated the pivotal role of Smads as intracellular effectors of TGF-beta family members. Upon binding to their specific type I and type II serine/threonine kinase receptors, each family member activates a particular subset of Smad proteins. Activated, receptor-regulated Smads form hetero-oligomeric complexes with common-partner Smads that translocate into the nucleus, where they control the expression of target genes in a cell-type-specific manner. Smads appear to function not only as nuclear effectors for TGF-beta family members, but as signal integrators within an extensive intracellular network.

Animals↗

PubMedDate not supplied

Remarkable versatility of Smad proteins in the nucleus of transforming growth factor-beta activated cells.

Smad proteins were identified three years ago as intracellular mediators of signaling by Transforming Growth Factor-beta (TGF-beta) family members. Two subclasses of the Smad proteins, the receptor-regulated Smads and common mediator Smads, transduce signals from the cell surface to the nucleus, where they participate in the regulation of gene expression. Meanwhile, it has become evident that Smads should be envisaged as very versatile proteins, which integrate multiple signaling pathways and can directly affect target gene expression in many ways. Indeed, their direct binding to DNA and their interaction in the nucleus with non-Smad proteins, many of which are DNA-binding activators or repressors of transcription uncover a unique but complex mode of action. We summarize some of the most recent data with regard to this aspect in this rapidly advancing field.

Animals↗

PubMed1999

Specificity, diversity, and regulation in TGF-beta superfamily signaling.

Transforming growth factor-beta (TGF-beta) superfamily members are multifunctional cell-cell signaling proteins that play pivotal roles in tissue homeostasis and development of multicellular animals. They mediate their pleiotropic effects from membrane to nucleus through distinct combinations of type I and type II serine/threonine kinase receptors and their downstream effectors, known as Smad proteins. Certain Smads, termed receptor-regulated Smads, become phosphorylated by activated type I receptors and form heteromeric complexes with a common-partner Smad4, which translocates into the nucleus to control gene transcription. In addition to these signal transducing Smads, inhibitory Smads have been identified that inhibit the activation of receptor-regulated Smads. In contrast to the still growing TGF-beta superfamily (with approximately 30 members in mammals), relatively few type I and type II receptors as well as Smads have been identified. We will focus on recent insights into the molecular mechanisms by which signaling specificity between different TGF-beta superfamily members is achieved and regulated, and how a single family member can elicit a broad scala of biological responses.-Piek, E., Heldin, C.-H., ten Dijke, P. Specificity, diversity, and regulation in TGF-beta superfamily signaling.

Animals↗

PubMed1998

Identification of a novel Drosophila SMAD on the X chromosome.

TGF-beta signaling from the cell surface to the nucleus is mediated by the SMAD family of proteins, which have been grouped into three classes based upon sequence identity and function. Receptor-regulated, or pathway-restricted, SMADs (R-SMADs) are phosphorylated by ligand-specific serine/threonine kinase receptors. Phosphorylated R-SMADs oligomerize with the coactivating, or shared, SMAD (Co-SMAD) mediator and translocate to the nucleus where the complex directs transcription of downstream target genes. Inhibitory SMADs (I-SMADs) block receptor-mediated phosphorylation of R-SMADs. In Drosophila, one member of each class of SMAD has been reported: MAD, an R-SMAD, MEDEA, a Co-SMAD, and DAD, an I-SMAD. Here, we report the first identification of a novel Drosophila R-SMAD, which we have named Smox for Smad on X. We have localized the Smox gene to a specific interval on the X chromosome and shown that Smox is transcribed throughout development.

Amino Acid Sequence↗

PubMed1999

SIP1, a novel zinc finger/homeodomain repressor, interacts with Smad proteins and binds to 5'-CACCT sequences in candidate target genes.

Activation of transforming growth factor beta receptors causes the phosphorylation and nuclear translocation of Smad proteins, which then participate in the regulation of expression of target genes. We describe a novel Smad-interacting protein, SIP1, which was identified using the yeast two-hybrid system. Although SIP1 interacts with the MH2 domain of receptor-regulated Smads in yeast and in vitro, its interaction with full-length Smads in mammalian cells requires receptor-mediated Smad activation. SIP1 is a new member of the deltaEF1/Zfh-1 family of two-handed zinc finger/homeodomain proteins. Like deltaEF1, SIP1 binds to 5'-CACCT sequences in different promoters, including the Xenopus brachyury promoter. Overexpression of either full-length SIP1 or its C-terminal zinc finger cluster, which bind to the Xbra2 promoter in vitro, prevented expression of the endogenous Xbra gene in early Xenopus embryos. Therefore, SIP1, like deltaEF1, is likely to be a transcriptional repressor, which may be involved in the regulation of at least one immediate response gene for activin-dependent signal transduction pathways. The identification of this Smad-interacting protein opens new routes to investigate the mechanisms by which transforming growth factor beta members exert their effects on expression of target genes in responsive cells and in the vertebrate embryo.

Amino Acid Sequence↗

PubMed2000

Regulatory mechanisms for transforming growth factor beta as an autocrine inhibitor in human hepatocellular carcinoma: implications for roles of smads in its growth.

Transforming growth factor beta (TGF-beta) initiates signaling through heteromeric complexes of transmembrane type I and type II serine/threonine kinase receptors. Activated TGF-beta type I receptor phosphorylates receptor-regulated Smads (2 and 3). Antagonistic Smad 7 forms stable association with the activated TGF-beta type I receptor, blocking phosphorylation of receptor-regulated Smads. On the other hand, elevated serum concentration of TGF-beta along with resistance to its growth-inhibitory effect is commonly observed in human hepatocellular carcinoma (HCC) patients. In this study, we investigated the mechanisms of resistance to tumor-derived TGF-beta in human HCC and hepatoblastoma-derived cell lines, focusing on the roles of receptor-regulated Smads and antagonistic Smad 7. HuH-7 and HepG2 cells showed poor response to TGF-beta-mediated growth inhibition. Because neutralization of TGF-beta in the medium or blockage of signal transduction pathway by inductions of dominant negative Smad 2/3 resulted in a stimulation of cell growth, tumor-derived TGF-beta signal acts on cell growth negatively. However, Smad 7 induced by TGF-beta negatively regulated Smad 2 action and rendered most Smad 2 proteins in the cytoplasm. Taken together, these results indicate that endogenous TGF-beta-mediated induction of Smad 7 results in a higher "threshold" for the antiproliferative signals mediated by receptor-regulated Smads, and can be involved in reduced responsiveness to the cytokine in some human HCC cells.

Carcinoma, Hepatocellular↗

PubMed1999

E1A inhibits transforming growth factor-beta signaling through binding to Smad proteins.

Smads form a recently identified family of proteins that mediate intracellular signaling of the transforming growth factor (TGF)-beta superfamily. Smads bind to DNA and act as transcriptional regulators. Smads interact with a variety of transcription factors, and the interaction is likely to determine the target specificity of gene induction. Smads also associate with transcriptional coactivators such as p300 and CBP. E1A, an adenoviral oncoprotein, inhibits TGF-beta-induced transactivation, and the ability of E1A to bind p300/CBP is required for the inhibition. Here we determined the Smad interaction domain (SID) in p300 and found that two adjacent regions are required for the interaction. One of the regions is the C/H3 domain conserved between p300 and CBP, and the other is a nonconserved region. p300 mutants containing SID inhibit transactivation by TGF-beta in a dose-dependent manner. E1A inhibits the interaction of Smad3 with a p300 mutant that contains SID but lacks the E1A binding domain. We found that E1A interacts specifically with receptor-regulated Smads, suggesting a novel mechanism whereby E1A antagonizes TGF-beta signaling.

Adenovirus E1A Proteins↗

PubMed1999

A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation.

The TGF-beta superfamily of proteins regulates many different biological processes, including cell growth, differentiation and embryonic pattern formation. TGF-beta-like factors signal across cell membranes through complexes of transmembrane receptors known as type I and type II serine/threonine-kinase receptors, which in turn activate the SMAD signalling pathway. On the inside of the cell membrane, a receptor-regulated class of SMADs are phosphorylated by the type-I-receptor kinase. In this way, receptors for different factors are able to pass on specific signals along the pathway: for example, receptors for bone morphogenetic protein (BMP) target SMADs 1, 5 and 8, whereas receptors for activin and TGF-beta target SMADs 2 and 3. Phosphorylation of receptor-regulated SMADs induces their association with Smad4, the 'common-partner' SMAD, and stimulates accumulation of this complex in the nucleus, where it regulates transcriptional responses. Here we describe Smurf1, a new member of the Hect family of E3 ubiquitin ligases. Smurf1 selectively interacts with receptor-regulated SMADs specific for the BMP pathway in order to trigger their ubiquitination and degradation, and hence their inactivation. In the amphibian Xenopus laevis, Smurf1 messenger RNA is localized to the animal pole of the egg; in Xenopus embryos, ectopic Smurf1 inhibits the transmission of BMP signals and thereby affects pattern formation. Smurf1 also enhances cellular responsiveness to the Smad2 (activin/TGF-beta) pathway. Thus, targeted ubiquitination of SMADs may serve to control both embryonic development and a wide variety of cellular responses to TGF-beta signals.

Animals↗

PubMed1999

The Smads.

The Smads are a family of intracellular signalling molecules that act downstream of receptors for the transforming growth factor (TGF)-beta family of ligands. Three classes of Smads have been identified. The receptor-regulated Smads are direct substrates for the type I receptors, which are serine/threonine kinases. Once phosphorylated and activated, these Smads form hetero-oligomeric complexes with a second class of Smad, the common mediator Smads. These Smad complexes translocate to the nucleus, where they are recruited to DNA primarily by site-specific DNA binding transcription factors, and participate in regulating the transcription of target genes. Inhibitory Smads are the third identified class which antagonise the activity of the receptor-regulated Smads. Aberrant TGF-beta signalling has been associated with several human diseases such as cancer and fibrosis. The identification of the Smads as primary transducers of TGF-beta signals raises the possibility that agents directed at modulating Smad activity would have therapeutic applications.

Animals↗

PubMed2000

Smad6 as a transcriptional corepressor.

Smad6 and Smad7, a subgroup of Smad proteins, antagonize the signals elicited by transforming growth factor-beta. These two Smads, induced by transforming growth factor-beta or bone morphogenetic protein (BMP) stimulation, form stable associations with their activated type I receptors, blocking phosphorylation of receptor-regulated Smads in the cytoplasm. Here we show that Smad6 interacts with homeobox (Hox) c-8 as a transcriptional corepressor, inhibiting BMP signaling in the nucleus. The interaction between Smad6 and Hoxc-8 was identified by a yeast two-hybrid approach and further demonstrated by co-immunoprecipitation assays in cells. Gel shift assays show that Smad6, but not Smad7, interacts with both Hoxc-8 and Hoxa-9 as a heterodimer when binding to DNA. More importantly, the Smad6-Hoxc-8 complex inhibits interaction of Smad1 with Hoxc-8- and Smad1-induced transcription activity. These data indicate that Smad6 interacts with Hox transcription factors as part of the negative feedback circuit in the BMP signaling pathway.

Bone Morphogenetic Proteins↗

PubMed1999

Xenopus Smad4beta is the co-Smad component of developmentally regulated transcription factor complexes responsible for induction of early mesodermal genes.

Smad4 is defined as the common-mediator Smad (co-Smad) required for transducing signals for all TGF-beta superfamily members. This paper describes two Smad4s in Xenopus: XSmad4alpha, which is probably the Xenopus orthologue of human Smad4, and a distinct family member, XSmad4beta, which differs primarily at the extreme N-terminus and in the linker region. Both XSmad4s act as co-Smads, forming ligand-dependent complexes with receptor-regulated Smads 1 and 2 and synergizing with them to activate transcription of mesodermal genes in Xenopus embryos. The two XSmad4 genes have reciprocal temporal expression patterns in Xenopus embryos and are expressed in varying ratios in adult tissues, suggesting distinct functional roles in vivo. XSmad4beta is the predominant maternal co-Smad and we go on to demonstrate its role in the transcriptional regulation of early mesodermal genes. We have identified two distinct nuclear complexes that bind the activin-responsive element of the Xenopus Mix.2 promoter: one formed in response to high levels of activin signaling and the other activated by endogenous signaling pathways. Using specific antisera we demonstrate the presence of endogenous XSmad4beta and also XSmad2 in both of these complexes, and our data indicate that the DNA-binding components of the complexes are different. Furthermore, we show that the presence of these complexes in the nucleus perfectly correlates with the transcriptional activity of the target gene, Mix.2, and we show that one of the XSmad4beta-containing transcription factor complexes undergoes a developmentally regulated nuclear translocation.

Activins↗

PubMedDate not supplied

TGF-beta signaling by Smad proteins.

Smads are signal transducers for the members of the transforming growth factor-beta (TGF-beta) superfamily. Bone morphogenetic proteins (BMPs) and their receptors induce differentiation of C2C12 cells into osteoblast-like cells. Using an adenoviral expression vector system, we showed that receptor-regulated Smads (R-Smads) activated by BMPs can induce the differentiation of C2C12 cells. Inhibitory Smads (I-Smads) interfere with the osteoblast differentiation of C2C12 cells by preventing the nuclear translocation of R-Smads. After translocation into the nucleus, Smad oligomers regulate the transcription of target genes through binding to DNA directly, interaction with other DNA binding proteins, and recruitment of transcriptional co-activators or co-repressors. Through interaction with different transcription factors and transcriptional co-activators or co-repressors, Smads may exhibit specific effects in various cell types.

Adenoviridae↗

PubMed1999

Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Calpha promoter.

Smads are signal transducers for members of the transforming growth factor-beta (TGF-beta) superfamily. Upon ligand stimulation, receptor-regulated Smads (R-Smads) are phosphorylated by serine/threonine kinase receptors, form complexes with common-partner Smad, and translocate into the nucleus, where they regulate the transcription of target genes together with other transcription factors. Polyomavirus enhancer binding protein 2/core binding factor (PEBP2/CBF) is a transcription factor complex composed of alpha and beta subunits. The alpha subunits of PEBP2/CBF, which contain the highly conserved Runt domain, play essential roles in hematopoiesis and osteogenesis. Here we show that three mammalian alpha subunits of PEBP2/CBF form complexes with R-Smads that act in TGF-beta/activin pathways as well as those acting in bone morphogenetic protein (BMP) pathways. Among them, PEBP2alphaC/CBFA3/AML2 forms a complex with Smad3 and stimulates transcription of the germline Ig Calpha promoter in a cooperative manner, for which binding of both factors to their specific binding sites is essential. PEBP2 may thus be a nuclear target of TGF-beta/BMP signaling.

Activin Receptors, Type I↗

PubMed1999

Roles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation.

The biological effects of type I serine/threonine kinase receptors and Smad proteins were examined using an adenovirus-based vector system. Constitutively active forms of bone morphogenetic protein (BMP) type I receptors (BMPR-IA and BMPR-IB; BMPR-I group) and those of activin receptor-like kinase (ALK)-1 and ALK-2 (ALK-1 group) induced alkaline phosphatase activity in C2C12 cells. Receptor-regulated Smads (R-Smads) that act in the BMP pathways, such as Smad1 and Smad5, also induced the alkaline phosphatase activity in C2C12 cells. BMP-6 dramatically enhanced alkaline phosphatase activity induced by Smad1 or Smad5, probably because of the nuclear translocation of R-Smads triggered by the ligand. Inhibitory Smads, i.e., Smad6 and Smad7, repressed the alkaline phosphatase activity induced by BMP-6 or the type I receptors. Chondrogenic differentiation of ATDC5 cells was induced by the receptors of the BMPR-I group but not by those of the ALK-1 group. However, kinase-inactive forms of the receptors of the ALK-1 and BMPR-I groups blocked chondrogenic differentiation. Although R-Smads failed to induce cartilage nodule formation, inhibitory Smads blocked it. Osteoblast differentiation induced by BMPs is thus mediated mainly via the Smad-signaling pathway, whereas chondrogenic differentiation may be transmitted by Smad-dependent and independent pathways.

Activin Receptors↗

PubMed2000

Structural basis of Smad2 recognition by the Smad anchor for receptor activation.

The Smad proteins mediate transforming growth factor-beta (TGFbeta) signaling from the transmembrane serine-threonine receptor kinases to the nucleus. The Smad anchor for receptor activation (SARA) recruits Smad2 to the TGFbeta receptors for phosphorylation. The crystal structure of a Smad2 MH2 domain in complex with the Smad-binding domain (SBD) of SARA has been determined at 2.2 angstrom resolution. SARA SBD, in an extended conformation comprising a rigid coil, an alpha helix, and a beta strand, interacts with the beta sheet and the three-helix bundle of Smad2. Recognition between the SARA rigid coil and the Smad2 beta sheet is essential for specificity, whereas interactions between the SARA beta strand and the Smad2 three-helix bundle contribute significantly to binding affinity. Comparison of the structures between Smad2 and a comediator Smad suggests a model for how receptor-regulated Smads are recognized by the type I receptors.

Activin Receptors, Type I↗

PubMed1998

TGF-beta receptors and signalling mechanisms.

Transforming growth factor-beta (TGF-beta) is the founding member of a large superfamily of related growth and differentiation factors that include bone morphogenetic proteins and activins. TGF-beta signals through two related transmembrane ser/thr kinase receptors, the type I and type II receptors. Signalling is initiated when the ligand binds to the type II receptor which is followed by recruitment of the type I receptor into a heteromeric complex. Within the complex the type II receptor transphosphorylates and activates the type I receptor kinase which targets downstream signalling components of the pathway. Proteins related to the Drosophila gene Mothers against dpp (MAD) are critical downstream substrates of the type I kinase. The vertebrate members of the MAD-related family, termed Smad2 and Smad3, interact specifically with the TGF-beta type I receptor and are phosphorylated on the last two serines of a conserved C-terminal SSXS motif. This phosphorylation induces association between these receptor-regulated Smads and Smad4 followed by translocation of the heteromeric complex to the nucleus. In the nucleus, heteromeric complexes of Smads can interact with DNA and with specific DNA binding transcription factors to elicit gene responses to TGF-beta. Thus TGF-beta signalling involves a direct pathway from the cell surface receptors to the nucleus. Recently, a novel mechanism to negatively regulate TGF-beta signalling was described that involves another class of MADR proteins. These anti-MADR proteins potently inhibit TGF-beta signalling by functioning as direct antagonists of the TGF-beta receptor type I kinase domain.

Animals↗