scholarly journals Msk is required for nuclear import of TGF-β/BMP-activated Smads

2007 ◽  
Vol 178 (6) ◽  
pp. 981-994 ◽  
Author(s):  
Lan Xu ◽  
Xiaohao Yao ◽  
Xiaochu Chen ◽  
Peiyuan Lu ◽  
Biliang Zhang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Bone Morphogenetic Proteins ◽  
Nuclear Import ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Nuclear Accumulation ◽  
Smad Proteins ◽  
Evolutionarily Conserved ◽  
Drosophila Cells

Nuclear translocation of Smad proteins is a critical step in signal transduction of transforming growth factor β (TGF-β) and bone morphogenetic proteins (BMPs). Using nuclear accumulation of the Drosophila Smad Mothers against Decapentaplegic (Mad) as the readout, we carried out a whole-genome RNAi screening in Drosophila cells. The screen identified moleskin (msk) as important for the nuclear import of phosphorylated Mad. Genetic evidence in the developing eye imaginal discs also demonstrates the critical functions of msk in regulating phospho-Mad. Moreover, knockdown of importin 7 and 8 (Imp7 and 8), the mammalian orthologues of Msk, markedly impaired nuclear accumulation of Smad1 in response to BMP2 and of Smad2/3 in response to TGF-β. Biochemical studies further suggest that Smads are novel nuclear import substrates of Imp7 and 8. We have thus identified new evolutionarily conserved proteins that are important in the signal transduction of TGF-β and BMP into the nucleus.

scholarly journals Eps15R is required for bone morphogenetic protein signalling and differentially compartmentalizes with Smad proteins

Open Biology ◽  
2012 ◽  
Vol 2 (4) ◽  
pp. 120060 ◽  
Author(s):  
Elizabeth M. Callery ◽  
Chong Yon Park ◽  
Xin Xu ◽  
Haitao Zhu ◽  
James C. Smith ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bone Morphogenetic Proteins ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Adaptor Protein ◽  
Transforming Growth Factor Β ◽  
Morphogenetic Protein ◽  
Smad Proteins ◽  
Epidermal Growth ◽  
Bmp Signalling

Transforming growth factor β superfamily members signal through Smad transcription factors. Bone morphogenetic proteins (BMPs) act via Smads 1, 5 and 8 and TGF-βs signal through Smads 2 and 3. The endocytic adaptor protein Eps15R, or ‘epidermal growth factor (EGF) receptor pathway substrate 15-related protein’ is a component of EGF signal transduction, mediating internalization of the EGF receptor. We show that it interacts with Smad proteins, is required for BMP signalling in animal caps and stimulates Smad1 transcriptional activity. This function resides in the Asp-Pro-Phe motif-enriched ‘DPF domain’ of Eps15R, which activates transcription and antagonizes Smad2 signalling. In living cells, Eps15R segregates into spatially distinct regions with different Smads, indicating an unrecognized level of Smad compartmentalization.

scholarly journals Characterization of a Bone Morphogenetic Protein-responsive Smad-binding Element

2000 ◽  
Vol 11 (2) ◽  
pp. 555-565 ◽  
Author(s):  
Kiyoshi Kusanagi ◽  
Hirofumi Inoue ◽  
Yasuhiro Ishidou ◽  
Hiromu K. Mishima ◽  
Masahiro Kawabata ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Specific Interaction ◽  
Transforming Growth Factor Β ◽  
Serine Threonine Kinase ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Smad Phosphorylation ◽  
Smad Proteins ◽  
Smad Binding Element

Bone morphogenetic proteins (BMPs) are pleiotropic growth and differentiation factors belonging to the transforming growth factor-β (TGF-β) superfamily. Signals of the TGF-β-like ligands are propagated to the nucleus through specific interaction of transmembrane serine/threonine kinase receptors and Smad proteins. GCCGnCGC has been suggested as a consensus binding sequence for DrosophilaMad regulated by a BMP-like ligand, Decapentaplegic. Smad1 is one of the mammalian Smads activated by BMPs. Here we show that Smad1 binds to this motif upon BMP stimulation in the presence of the common Smad, Smad4. The binding affinity is likely to be relatively low, because Smad1 binds to three copies of the motif weakly, but more repeats of the motif significantly enhance the binding. Heterologous reporter genes (GCCG-Lux) with multiple repeats of the motif respond to BMP stimulation but not to TGF-β or activin. Mutational analyses reveal several bases critical for the responsiveness. A natural BMP-responsive reporter, pTlx-Lux, is activated by BMP receptors in P19 cells but not in mink lung cells. In contrast, GCCG-Lux responds to BMP stimulation in both cells, suggesting that it is a universal reporter that directly detects Smad phosphorylation by BMP receptors.

scholarly journals Tumor-derived TGF-β inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells

2019 ◽  
Vol 12 (599) ◽  
pp. eaav3334 ◽  
Author(s):  
Sarah Dimeloe ◽  
Patrick Gubser ◽  
Jordan Loeliger ◽  
Corina Frick ◽  
Leyla Develioglu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Atp Synthase ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Nuclear Translocation ◽  
Cell Metabolism ◽  
Transforming Growth Factor Β ◽  
Smad Proteins ◽  
Ifn Γ

Transforming growth factor–β (TGF-β) is produced by tumors, and increased amounts of this cytokine in the tumor microenvironment and serum are associated with poor patient survival. TGF-β–mediated suppression of antitumor T cell responses contributes to tumor growth and survival. However, TGF-β also has tumor-suppressive activity; thus, dissecting cell type–specific molecular effects may inform therapeutic strategies targeting this cytokine. Here, using human peripheral and tumor-associated lymphocytes, we investigated how tumor-derived TGF-β suppresses a key antitumor function of CD4+ T cells, interferon-γ (IFN-γ) production. Suppression required the expression and phosphorylation of Smad proteins in the TGF-β signaling pathway, but not their nuclear translocation, and depended on oxygen availability, suggesting a metabolic basis for these effects. Smad proteins were detected in the mitochondria of CD4+ T cells, where they were phosphorylated upon treatment with TGF-β. Phosphorylated Smad proteins were also detected in the mitochondria of isolated tumor-associated lymphocytes. TGF-β substantially impaired the ATP-coupled respiration of CD4+ T cells and specifically inhibited mitochondrial complex V (ATP synthase) activity. Last, inhibition of ATP synthase alone was sufficient to impair IFN-γ production by CD4+ T cells. These results, which have implications for human antitumor immunity, suggest that TGF-β targets T cell metabolism directly, thus diminishing T cell function through metabolic paralysis.

scholarly journals Sorting nexin 9 differentiates ligand-activated Smad3 from Smad2 for nuclear import and transforming growth factor β signaling

2015 ◽  
Vol 26 (21) ◽  
pp. 3879-3891 ◽  
Author(s):  
Mark C. Wilkes ◽  
Claire E. Repellin ◽  
Jeong-Han Kang ◽  
Mahefatiana Andrianifahanana ◽  
Xueqian Yin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Receptor Activation ◽  
Signaling Networks ◽  
Sorting Nexin ◽  
Cytoplasmic Proteins ◽  
Smad Proteins

Transforming growth factor β (TGFβ) is a pleiotropic protein secreted from essentially all cell types and primary tissues. While TGFβ’s actions reflect the activity of a number of signaling networks, the primary mediator of TGFβ responses are the Smad proteins. Following receptor activation, these cytoplasmic proteins form hetero-oligomeric complexes that translocate to the nucleus and affect gene transcription. Here, through biological, biochemical, and immunofluorescence approaches, sorting nexin 9 (SNX9) is identified as being required for Smad3-dependent responses. SNX9 interacts with phosphorylated (p) Smad3 independent of Smad2 or Smad4 and promotes more rapid nuclear delivery than that observed independent of ligand. Although SNX9 does not bind nucleoporins Nup153 or Nup214 or some β importins (Imp7 or Impβ), it mediates the association of pSmad3 with Imp8 and the nuclear membrane. This facilitates nuclear translocation of pSmad3 but not SNX9.

scholarly journals Transforming growth factor (TGF) – is it a key protein in mammalian reproductive biology?

2018 ◽  
Vol 6 (3) ◽  
pp. 125-130 ◽  
Author(s):  
Marta Rybska ◽  
Sandra Knap ◽  
Katarzyna Stefańska ◽  
Maurycy Jankowski ◽  
Agata Chamier-Gliszczyńska ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Growth Factors ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Family Members ◽  
Signal Transduction Pathway ◽  
Membrane Receptors ◽  
Transduction Pathway ◽  
Smad Proteins ◽  
Cell Growth And Differentiation

AbstractThe superfamily of transforming growth factors β (TGF-β) consists of cytokines that are crucial in regulating the organism’s biological functions and includes three isoforms of TGF-β protein, Anti-Müllerian Hormone (AMH), inhibin A and B, activins, 20 bone morphogenetic proteins (BMP1-20) and 9 growth factors (GDF1-9). Their signal transduction pathway involves three types of membrane receptors that exhibit a serine/threonine kinase activity, as well as the Smad proteins. After ligand binding, the Smad proteins are phosphorylated and translocated to the nucleus, where they interact with transcription factors and affect gene expression. TGF-β family members are involved in cell growth and differentiation, as well as chemo-taxis and apoptosis, and play an important role during an inflammation. Defects in TGF-β proteins or in their signalling pathway underlie many severe diseases, such as systemic lupus, systemic scleroderma, bronchial asthma, atherosclerosis, hyperthyroidism or cancer. These factors are also crucial in mammal reproductive functions, as they are involved in folliculogenesis, steroidogenesis, ovulation, maternal-embryo interaction, embryo development and uterine decidualization. Their defects result in issues with fertility. This review focuses on the relevance of TGF-β family members in a mammal reproduction with an emphasis on three TGF-β isoforms, inhibins A and B, GDF-9 and their signal transduction pathway.

scholarly journals TGFβ family signaling and development

Development ◽  
2021 ◽  
Vol 148 (5) ◽  
Author(s):  
Shunji Jia ◽  
Anming Meng
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Family Members ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Dorsoventral Patterning ◽  
Tgfβ Signaling ◽  
Evolutionarily Conserved ◽  
Transduction Mechanisms

ABSTRACT The transforming growth factor β (TGFβ) signaling family is evolutionarily conserved in metazoans. The signal transduction mechanisms of TGFβ family members have been expansively investigated and are well understood. During development and homeostasis, numerous TGFβ family members are expressed in various cell types with temporally changing levels, playing diverse roles in embryonic development, adult tissue homeostasis and human diseases by regulating cell proliferation, differentiation, adhesion, migration and apoptosis. Here, we discuss the molecular mechanisms underlying signal transduction and regulation of the TGFβ subfamily pathways, and then highlight their key functions in mesendoderm induction, dorsoventral patterning and laterality development, as well as in the formation of several representative tissues/organs.

scholarly journals TGF-β Signaling

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 487 ◽  
Author(s):  
Kalliopi Tzavlaki ◽  
Aristidis Moustakas
Keyword(s):  
Target Genes ◽  
Transforming Growth Factor ◽  
Mrna Translation ◽  
Transforming Growth Factor Β ◽  
Signaling Mechanisms ◽  
Smad Proteins ◽  
Evolutionarily Conserved ◽  
The Family ◽  
Cell Type Specific ◽  
Extracellular Level

Transforming growth factor-β (TGF-β) represents an evolutionarily conserved family of secreted polypeptide factors that regulate many aspects of physiological embryogenesis and adult tissue homeostasis. The TGF-β family members are also involved in pathophysiological mechanisms that underlie many diseases. Although the family comprises many factors, which exhibit cell type-specific and developmental stage-dependent biological actions, they all signal via conserved signaling pathways. The signaling mechanisms of the TGF-β family are controlled at the extracellular level, where ligand secretion, deposition to the extracellular matrix and activation prior to signaling play important roles. At the plasma membrane level, TGF-βs associate with receptor kinases that mediate phosphorylation-dependent signaling to downstream mediators, mainly the SMAD proteins, and mediate oligomerization-dependent signaling to ubiquitin ligases and intracellular protein kinases. The interplay between SMADs and other signaling proteins mediate regulatory signals that control expression of target genes, RNA processing at multiple levels, mRNA translation and nuclear or cytoplasmic protein regulation. This article emphasizes signaling mechanisms and the importance of biochemical control in executing biological functions by the prototype member of the family, TGF-β.

Smad regulation in TGF-β signal transduction

2001 ◽  
Vol 114 (24) ◽  
pp. 4359-4369 ◽  
Author(s):  
Aristidis Moustakas ◽  
Serhiy Souchelnytskyi ◽  
Carl-Henrik Heldin
Keyword(s):  
Signal Transduction ◽  
Target Gene ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Transcriptional Repressors ◽  
Receptor Complexes ◽  
Smad Proteins ◽  
The Common ◽  
Formation Of Complexes

Smad proteins transduce signals from transforming growth factor-β (TGF-β) superfamily ligands that regulate cell proliferation, differentiation and death through activation of receptor serine/threonine kinases. Phosphorylation of receptor-activated Smads (R-Smads) leads to formation of complexes with the common mediator Smad (Co-Smad), which are imported to the nucleus. Nuclear Smad oligomers bind to DNA and associate with transcription factors to regulate expression of target genes. Alternatively, nuclear R-Smads associate with ubiquitin ligases and promote degradation of transcriptional repressors, thus facilitating target gene regulation by TGF-β. Smads themselves can also become ubiquitinated and are degraded by proteasomes. Finally, the inhibitory Smads (I-Smads) block phosphorylation of R-Smads by the receptors and promote ubiquitination and degradation of receptor complexes, thus inhibiting signalling.

scholarly journals Optogenetic control of the Bone Morphogenetic Protein signalling pathway through engineered blue light-sensitive receptors

2020 ◽  
Author(s):  
Paul A. Humphreys ◽  
Steven Woods ◽  
Christopher A. Smith ◽  
Stuart A. Cain ◽  
Robert Lucas ◽  
...  
Keyword(s):  
Blue Light ◽  
Bone Morphogenetic Proteins ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Signalling Pathway ◽  
Bmp Signalling ◽  
Optogenetic Control

AbstractBone Morphogenetic Proteins (BMPs) are members of the Transforming Growth Factor β (TGFβ) superfamily and have crucial roles during development; including mesodermal patterning and specification of renal, hepatic and skeletal tissues. In vitro developmental models currently rely upon costly and unreliable recombinant BMP proteins that do not enable dynamic or precise perturbation of the BMP signalling pathway. Here, we develop a novel optogenetic BMP signalling system (optoBMP) that enables rapid induction of the canonical BMP signalling pathway through illumination with blue light. We demonstrate the utility of the optoBMP system in multiple human cell lines to initiate signal transduction through phosphorylation and nuclear translocation of SMAD1/5, leading to upregulation of BMP target genes including Inhibitors of DNA binding ID2 and ID4. Furthermore, we demonstrate how the optoBMP system can be used to fine-tune activation of the BMP signalling pathway through variable light stimulation. Optogenetic control of BMP signalling will enable dynamic and high-throughput intervention across a variety of applications in cellular and developmental systems.

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