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Kunxin Luo - One of the best experts on this subject based on the ideXlab platform.
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the integral inner nuclear membrane protein man1 physically interacts with the r smad proteins to repress signaling by the transforming growth factor β superfamily of cytokines
Journal of Biological Chemistry, 2005Co-Authors: Deng Pan, Luis D Estevezsalmeron, Shannon L Stroschein, Xueliang Zhu, Sharleen Zhou, Kunxin LuoAbstract:Smad proteins are critical intracellular mediators of the transforming growth factor-beta, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-SMADs are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-SMADs then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with various transcription factors to regulate the expression of downstream genes. Interaction of Smad proteins with cellular partners in the cytoplasm and nucleus is a critical mechanism by which the activities and expression of the Smad proteins are modulated. Here we report a novel step of regulation of the R-SMAD function at the inner nuclear membrane through a physical interaction between the integral inner nuclear membrane protein MAN1 and R-SMADs. MAN1, through the RNA recognition motif, associates with R-SMADs but not Smad4 at the inner nuclear membrane in a ligand-independent manner. Overexpression of MAN1 results in inhibition of R-SMAD phosphorylation, heterodimerization with Smad4 and nuclear translocation, and repression of transcriptional activation of the TGFbeta, BMP2, and activin-responsive promoters. This repression of TGFbeta, BMP2, and activin signaling is dependent on the MAN1-Smad interaction because a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-SMAD regulators and defines a previously unrecognized regulatory step at the nuclear periphery.
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the integral inner nuclear membrane protein man1 physically interacts with the r smad proteins to repress signaling by the transforming growth factor β superfamily of cytokines
Journal of Biological Chemistry, 2005Co-Authors: Deng Pan, Luis D Estevezsalmeron, Shannon L Stroschein, Xueliang Zhu, Sharleen Zhou, Kunxin LuoAbstract:Smad proteins are critical intracellular mediators of the transforming growth factor-β, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-SMADs are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-SMADs then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with various transcription factors to regulate the expression of downstream genes. Interaction of Smad proteins with cellular partners in the cytoplasm and nucleus is a critical mechanism by which the activities and expression of the Smad proteins are modulated. Here we report a novel step of regulation of the R-SMAD function at the inner nuclear membrane through a physical interaction between the integral inner nuclear membrane protein MAN1 and R-SMADs. MAN1, through the RNA recognition motif, associates with R-SMADs but not Smad4 at the inner nuclear membrane in a ligand-independent manner. Overexpression of MAN1 results in inhibition of R-SMAD phosphorylation, heterodimerization with Smad4 and nuclear translocation, and repression of transcriptional activation of the TGFβ, BMP2, and activin-responsive promoters. This repression of TGFβ, BMP2, and activin signaling is dependent on the MAN1-Smad interaction because a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-SMAD regulators and defines a previously unrecognized regulatory step at the nuclear periphery.
Luis D Estevezsalmeron - One of the best experts on this subject based on the ideXlab platform.
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the integral inner nuclear membrane protein man1 physically interacts with the r smad proteins to repress signaling by the transforming growth factor β superfamily of cytokines
Journal of Biological Chemistry, 2005Co-Authors: Deng Pan, Luis D Estevezsalmeron, Shannon L Stroschein, Xueliang Zhu, Sharleen Zhou, Kunxin LuoAbstract:Smad proteins are critical intracellular mediators of the transforming growth factor-beta, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-SMADs are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-SMADs then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with various transcription factors to regulate the expression of downstream genes. Interaction of Smad proteins with cellular partners in the cytoplasm and nucleus is a critical mechanism by which the activities and expression of the Smad proteins are modulated. Here we report a novel step of regulation of the R-SMAD function at the inner nuclear membrane through a physical interaction between the integral inner nuclear membrane protein MAN1 and R-SMADs. MAN1, through the RNA recognition motif, associates with R-SMADs but not Smad4 at the inner nuclear membrane in a ligand-independent manner. Overexpression of MAN1 results in inhibition of R-SMAD phosphorylation, heterodimerization with Smad4 and nuclear translocation, and repression of transcriptional activation of the TGFbeta, BMP2, and activin-responsive promoters. This repression of TGFbeta, BMP2, and activin signaling is dependent on the MAN1-Smad interaction because a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-SMAD regulators and defines a previously unrecognized regulatory step at the nuclear periphery.
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the integral inner nuclear membrane protein man1 physically interacts with the r smad proteins to repress signaling by the transforming growth factor β superfamily of cytokines
Journal of Biological Chemistry, 2005Co-Authors: Deng Pan, Luis D Estevezsalmeron, Shannon L Stroschein, Xueliang Zhu, Sharleen Zhou, Kunxin LuoAbstract:Smad proteins are critical intracellular mediators of the transforming growth factor-β, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-SMADs are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-SMADs then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with various transcription factors to regulate the expression of downstream genes. Interaction of Smad proteins with cellular partners in the cytoplasm and nucleus is a critical mechanism by which the activities and expression of the Smad proteins are modulated. Here we report a novel step of regulation of the R-SMAD function at the inner nuclear membrane through a physical interaction between the integral inner nuclear membrane protein MAN1 and R-SMADs. MAN1, through the RNA recognition motif, associates with R-SMADs but not Smad4 at the inner nuclear membrane in a ligand-independent manner. Overexpression of MAN1 results in inhibition of R-SMAD phosphorylation, heterodimerization with Smad4 and nuclear translocation, and repression of transcriptional activation of the TGFβ, BMP2, and activin-responsive promoters. This repression of TGFβ, BMP2, and activin signaling is dependent on the MAN1-Smad interaction because a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-SMAD regulators and defines a previously unrecognized regulatory step at the nuclear periphery.
Deng Pan - One of the best experts on this subject based on the ideXlab platform.
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the integral inner nuclear membrane protein man1 physically interacts with the r smad proteins to repress signaling by the transforming growth factor β superfamily of cytokines
Journal of Biological Chemistry, 2005Co-Authors: Deng Pan, Luis D Estevezsalmeron, Shannon L Stroschein, Xueliang Zhu, Sharleen Zhou, Kunxin LuoAbstract:Smad proteins are critical intracellular mediators of the transforming growth factor-beta, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-SMADs are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-SMADs then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with various transcription factors to regulate the expression of downstream genes. Interaction of Smad proteins with cellular partners in the cytoplasm and nucleus is a critical mechanism by which the activities and expression of the Smad proteins are modulated. Here we report a novel step of regulation of the R-SMAD function at the inner nuclear membrane through a physical interaction between the integral inner nuclear membrane protein MAN1 and R-SMADs. MAN1, through the RNA recognition motif, associates with R-SMADs but not Smad4 at the inner nuclear membrane in a ligand-independent manner. Overexpression of MAN1 results in inhibition of R-SMAD phosphorylation, heterodimerization with Smad4 and nuclear translocation, and repression of transcriptional activation of the TGFbeta, BMP2, and activin-responsive promoters. This repression of TGFbeta, BMP2, and activin signaling is dependent on the MAN1-Smad interaction because a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-SMAD regulators and defines a previously unrecognized regulatory step at the nuclear periphery.
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the integral inner nuclear membrane protein man1 physically interacts with the r smad proteins to repress signaling by the transforming growth factor β superfamily of cytokines
Journal of Biological Chemistry, 2005Co-Authors: Deng Pan, Luis D Estevezsalmeron, Shannon L Stroschein, Xueliang Zhu, Sharleen Zhou, Kunxin LuoAbstract:Smad proteins are critical intracellular mediators of the transforming growth factor-β, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-SMADs are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-SMADs then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with various transcription factors to regulate the expression of downstream genes. Interaction of Smad proteins with cellular partners in the cytoplasm and nucleus is a critical mechanism by which the activities and expression of the Smad proteins are modulated. Here we report a novel step of regulation of the R-SMAD function at the inner nuclear membrane through a physical interaction between the integral inner nuclear membrane protein MAN1 and R-SMADs. MAN1, through the RNA recognition motif, associates with R-SMADs but not Smad4 at the inner nuclear membrane in a ligand-independent manner. Overexpression of MAN1 results in inhibition of R-SMAD phosphorylation, heterodimerization with Smad4 and nuclear translocation, and repression of transcriptional activation of the TGFβ, BMP2, and activin-responsive promoters. This repression of TGFβ, BMP2, and activin signaling is dependent on the MAN1-Smad interaction because a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-SMAD regulators and defines a previously unrecognized regulatory step at the nuclear periphery.
Catherine E. Campbell - One of the best experts on this subject based on the ideXlab platform.
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correction phosphoproteomic analysis reveals smad protein family activation following rift valley fever virus infection
PLOS ONE, 2018Co-Authors: Cynthia De La Fuente, Chelsea Pinkham, Deemah Dabbagh, Brett Beitzel, Aura R. Garrison, Gustavo Palacios, Kimberley Alex Hodge, Emanuel F. Petricoin, Connie S. Schmaljohn, Catherine E. CampbellAbstract:Rift Valley fever virus (RVFV) infects both ruminants and humans leading to a wide variance of pathologies dependent on host background and age. Utilizing a targeted reverse phase protein array (RPPA) to define changes in signaling cascades after in vitro infection of human cells with virulent and attenuated RVFV strains, we observed high phosphorylation of Smad transcription factors. This evolutionarily conserved family is phosphorylated by and transduces the activation of TGF-β superfamily receptors. Moreover, we observed that phosphorylation of Smad proteins required active RVFV replication and loss of NSs impaired this activation, further corroborating the RPPA results. Gene promoter analysis of transcripts altered after RVFV infection identified 913 genes that contained a Smad-response element. Functional annotation of these potential Smad-regulated genes clustered in axonal guidance, hepatic fibrosis and cell signaling pathways involved in cellular adhesion/migration, calcium influx, and cytoskeletal reorganization. Furthermore, chromatin immunoprecipitation confirmed the presence of a Smad complex on the interleukin 1 receptor type 2 (IL1R2) promoter, which acts as a decoy receptor for IL-1 activation.
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Phosphoproteomic analysis reveals Smad protein family activation following Rift Valley fever virus infection.
PloS one, 2018Co-Authors: Cynthia De La Fuente, Chelsea Pinkham, Deemah Dabbagh, Brett Beitzel, Aura R. Garrison, Gustavo Palacios, Kimberley Alex Hodge, Emanuel F. Petricoin, Connie S. Schmaljohn, Catherine E. CampbellAbstract:Rift Valley fever virus (RVFV) infects both ruminants and humans leading to a wide variance of pathologies dependent on host background and age. Utilizing a targeted reverse phase protein array (RPPA) to define changes in signaling cascades after in vitro infection of human cells with virulent and attenuated RVFV strains, we observed high phosphorylation of Smad transcription factors. This evolutionarily conserved family is phosphorylated by and transduces the activation of TGF-β superfamily receptors. Moreover, we observed that phosphorylation of Smad proteins required active RVFV replication and loss of NSs impaired this activation, further corroborating the RPPA results. Gene promoter analysis of transcripts altered after RVFV infection identified 913 genes that contained a Smad-response element. Functional annotation of these potential Smad-regulated genes clustered in axonal guidance, hepatic fibrosis and cell signaling pathways involved in cellular adhesion/migration, calcium influx, and cytoskeletal reorganization. Furthermore, chromatin immunoprecipitation confirmed the presence of a Smad complex on the interleukin 1 receptor type 2 (IL1R2) promoter, which acts as a decoy receptor for IL-1 activation.
Alain Mauviel - One of the best experts on this subject based on the ideXlab platform.
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crosstalk mechanisms between the mitogen activated protein kinase pathways and smad signaling downstream of tgf beta implications for carcinogenesis
Oncogene, 2005Co-Authors: Delphine Javelaud, Alain MauvielAbstract:Transforming growth factor-beta (TGF-beta) superfamily members signal via membrane-bound heteromeric serine-threonine kinase receptor complexes. Upon ligand-binding, receptor activation leads to phosphorylation of cytoplasmic protein substrates of the Smad family. Following phosphorylation and oligomerization, the latter move into the nucleus to act as transcription factors to regulate target gene expression. TGF-beta responses are not solely the result of the activation Smad cascade, but are highly cell-type specific and dependent upon interactions of Smad signaling with a variety of other intracellular signaling mechanisms, initiated or not by TGF-beta itself, that may either potentiate, synergize, or antagonize, the rather linear TGF-beta/Smad pathway. These include, (a), regulation of Smad activity by mitogen-activated protein kinases (MAPKs), (b), nuclear interaction of activated Smads with transcriptional cofactors, whether coactivators or corepressors, that may be themselves be regulated by diverse signaling mechanisms, and (c), negative feedback loops exerted by inhibitory Smads, transcriptional targets of the Smad cascade. This review focuses on how MAPKs modulate the outcome of Smad activation by TGF-beta, and how cross-signaling mechanisms between the Smad and MAPK pathways may take place and affect cell fate in the context of carcinogenesis.
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cyclic adenosine 3 5 monophosphate elevating agents inhibit transforming growth factor beta induced smad3 4 dependent transcription via a protein kinase a dependent mechanism
Oncogene, 2003Co-Authors: Meinhard Schiller, Frank Verrecchia, Alain MauvielAbstract:Transforming growth factor-beta (TGF-beta) plays complex roles in carcinogenesis, as it may exert both tumor suppressor and pro-oncogenic activities depending on the stage of the tumor. SMAD proteins transduce signals from the TGF-beta receptors to regulate the transcription of specific target genes. Crosstalks with other signaling pathways may contribute to the specificity of TGF-beta effects. In this report, we have investigated the effects of cyclic adenosine 3',5'-monophosphate (cAMP), a key second messenger in the cellular response to various hormones, on SMAD-dependent signaling in human HaCaT keratinocytes. Using either an artificial SMAD3/4-dependent reporter construct or the natural TGF-beta target, plasminogen activator inhibitor-1, we show that membrane-permeable dibutyryl cAMP, and other intracellular cAMP-elevating agents such as the phosphodiesterase inhibitor isobutyl-methylxanthine, the adenylate cyclase activator forskolin, or exogenous prostaglandin E2 (PGE2), interfere with TGF-beta-induced SMAD-specific gene transactivation. Inhibition of protein kinase A (PKA), the main downstream effector of cAMP, with H-89, suppressed cAMP-dependent repression of SMAD-driven gene expression. Inversely, coexpression of either an active PKA catalytic subunit or that of the cAMP response element (CRE)-binding protein (CREB) blocked SMAD-driven gene transactivation. cAMP-elevating agents did not inhibit nuclear translocation and DNA binding of SMAD3/4 complexes, but abolished the interactions of SMAD3 with the transcription coactivators CREB-binding protein (CBP) and p300 in a PKA-dependent manner. These results suggest that suppression of TGF-beta/SMAD signaling and resulting gene transactivation by cAMP-inducing agents occurs via PKA-dependent, CREB-mediated, disruption of SMAD-CBP/p300 complexes.
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induction of the ap 1 members c jun and junb by tgf β smad suppresses early smad driven gene activation
Oncogene, 2001Co-Authors: Franck Verrecchia, Marina Schorppkistner, Peter Angel, Charlotte Tacheau, Alain MauvielAbstract:Smad proteins transduce signals from TGF-β receptors and regulate transcription of target genes. Among the latter are c-jun and junB, which encode members of the AP-1 family of transcription factors. In this study, we have investigated the functional interactions of the Smad and AP-1 transcription factors in the context of Smad-specific gene transactivation in both fibroblasts and keratinocytes. We demonstrate that overexpression of either junB or c-jun prevents TGF-β- or Smad3-induced transactivation of the Smad-specific promoter construct (SBE)4-Lux. Inversely, Smad-driven promoter transactivation by TGF-β/Smad is significantly enhanced when c-jun expression is abolished in HaCaT keratinocytes, and when junB expression is prevented in fibroblasts, consistent with the cell-type specific induction of jun members by TGF-β. We also demonstrate that Smad-specific gene transactivation in junB−/− mouse embryonic fibroblasts is significantly higher than in embryonic fibroblasts from the control parental mouse line, and that this difference is abolished by rescuing junB expression in junB−/− cells. Finally, we have determined that off-DNA interactions between Smad3 and both c-Jun and JunB result in the reduction of Smad3/DNA interactions. From these results, we provide a model in which jun expression in response to the initial Smad cascade represents a negative feed-back mechanism counteracting Smad-driven gene transactivation.
