scholarly journals Specificity, versatility, and control of TGF-β family signaling

2019 ◽  
Vol 12 (570) ◽  
pp. eaav5183 ◽  
Author(s):  
Rik Derynck ◽  
Erine H. Budi
Keyword(s):  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Smad Signaling ◽  
Surface Receptors ◽  
Cell Lineages ◽  
Receptor Complexes ◽  
Signaling Mechanisms ◽  
Dual Specificity ◽  
And Control

Encoded in mammalian cells by 33 genes, the transforming growth factor–β (TGF-β) family of secreted, homodimeric and heterodimeric proteins controls the differentiation of most, if not all, cell lineages and many aspects of cell and tissue physiology in multicellular eukaryotes. Deregulation of TGF-β family signaling leads to developmental anomalies and disease, whereas enhanced TGF-β signaling contributes to cancer and fibrosis. Here, we review the fundamentals of the signaling mechanisms that are initiated upon TGF-β ligand binding to its cell surface receptors and the dependence of the signaling responses on input from and cooperation with other signaling pathways. We discuss how cells exquisitely control the functional presentation and activation of heteromeric receptor complexes of transmembrane, dual-specificity kinases and, thus, define their context-dependent responsiveness to ligands. We also introduce the mechanisms through which proteins called Smads act as intracellular effectors of ligand-induced gene expression responses and show that the specificity and impressive versatility of Smad signaling depend on cross-talk from other pathways. Last, we discuss how non-Smad signaling mechanisms, initiated by distinct ligand-activated receptor complexes, complement Smad signaling and thus contribute to cellular responses.

scholarly journals The evolutionarily conserved deubiquitinase UBH1/UCH-L1 augments DAF7/TGF-β signaling, inhibits dauer larva formation, and enhances lung tumorigenesis

2020 ◽  
Vol 295 (27) ◽  
pp. 9105-9120 ◽  
Author(s):  
Asami Nagata ◽  
Fumiko Itoh ◽  
Ayaka Sasho ◽  
Kaho Sugita ◽  
Riko Suzuki ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
A549 Cells ◽  
Transforming Growth Factor Β ◽  
Human Homolog ◽  
Loss Of Function ◽  
Lung Tumorigenesis ◽  
Smad Signaling ◽  
C Elegans ◽  
Dauer Larva

Modification of the transforming growth factor β (TGF-β) signaling components by (de)ubiquitination is emerging as a key regulatory mechanism that controls cell signaling responses in health and disease. Here, we show that the deubiquitinating enzyme UBH-1 in Caenorhabditis elegans and its human homolog, ubiquitin C-terminal hydrolase-L1 (UCH-L1), stimulate DAF-7/TGF-β signaling, suggesting that this mode of regulation of TGF-β signaling is conserved across animal species. The dauer larva–constitutive C. elegans phenotype caused by defective DAF-7/TGF-β signaling was enhanced and suppressed, respectively, by ubh-1 deletion and overexpression in the loss-of-function genetic backgrounds of daf7, daf-1/TGF-βRI, and daf4/R-SMAD, but not of daf-8/R-SMAD. This suggested that UBH-1 may stimulate DAF-7/TGF-β signaling via DAF-8/R-SMAD. Therefore, we investigated the effect of UCH-L1 on TGF-β signaling via its intracellular effectors, i.e. SMAD2 and SMAD3, in mammalian cells. Overexpression of UCH-L1, but not of UCH-L3 (the other human homolog of UBH1) or of the catalytic mutant UCH-L1C90A, enhanced TGF-β/SMAD-induced transcriptional activity, indicating that the deubiquitination activity of UCH-L1 is indispensable for enhancing TGF-β/SMAD signaling. We also found that UCH-L1 interacts, deubiquitinates, and stabilizes SMAD2 and SMAD3. Under hypoxia, UCH-L1 expression increased and TGF-β/SMAD signaling was potentiated in the A549 human lung adenocarcinoma cell line. Notably, UCH-L1–deficient A549 cells were impaired in tumorigenesis, and, unlike WT UCH-L1, a UCH-L1 variant lacking deubiquitinating activity was unable to restore tumorigenesis in these cells. These results indicate that UCH-L1 activity supports DAF-7/TGF-β signaling and suggest that UCH-L1's deubiquitination activity is a potential therapeutic target for managing lung cancer.

scholarly journals SARP, a new alternatively spliced protein phosphatase 1 and DNA interacting protein

2007 ◽  
Vol 402 (1) ◽  
pp. 187-196 ◽  
Author(s):  
Gareth J. Browne ◽  
Margarida Fardilha ◽  
Senga K. Oxenham ◽  
Wenjuan Wu ◽  
Nicholas R. Helps ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Mammalian Cells ◽  
Leucine Zipper ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Transforming Growth Factor Β ◽  
Ankyrin Repeat ◽  
Protein Phosphatase 1 ◽  
Binding Motif ◽  
Alternative Mrna Splicing

PP1 (protein phosphatase 1) is a ubiquitously expressed serine/threonine-specific protein phosphatase whose activity towards different substrates appears to be mediated via binding to specific proteins that play critical regulatory and targeting roles. In the present paper we report the cloning and characterization of a new protein, termed SARP (several ankyrin repeat protein), which is shown to interact with all isoforms of PP1 by a variety of techniques. A region encompassing a consensus PP1-binding motif in SARP (K354VHF357) modulates endogenous SARP–PP1 activity in mammalian cells. This SARP–PP1 interaction motif lies partially within the first ankyrin repeat in contrast with other proteins [53BP2 (p53 binding protein 2), MYPT1/M110/MBS (myosin binding protein of PP1) and TIMAP (transforming growth factor β inhibited, membrane-associated protein)], where a PP1-binding motif precedes the ankyrin repeats. Alternative mRNA splicing produces several isoforms of SARP from a single human gene at locus 11q14. SARP1 and/or SARP2 (92–95 kDa) are ubiquitously expressed in all tissues with high levels in testis and sperm, where they are shown to interact with both PP1γ1 and PP1γ2. SARP3 (65 kDa) is most abundant in brain where SARP isoforms interact with both PP1α and PP1γ1. SARP is highly abundant in the nucleus of mammalian cells, consistent with the putative nuclear localization signal at the N-terminus. The presence of a leucine zipper near the C-terminus of SARP1 and SARP2, and the binding of mammalian DNA to SARP2, suggests that SARP1 and SARP2 may be transcription factors or DNA-associated proteins that modulate gene expression.

scholarly journals Oral administration ofLactobacillus acidophilusinduces IL-12 production in spleen cell culture of BALB/c mice bearing transplanted breast tumour

2010 ◽  
Vol 104 (2) ◽  
pp. 227-232 ◽  
Author(s):  
Mohammad Hossein Yazdi ◽  
Mohammad Mehdi Soltan Dallal ◽  
Zuhair Mohammad Hassan ◽  
Marzieh Holakuyee ◽  
Solmaz Agha Amiri ◽  
...  
Keyword(s):  
Immune Responses ◽  
Oral Administration ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Breast Tumour ◽  
Delayed Type Hypersensitivity ◽  
Daily Consumption ◽  
Colony Forming Units ◽  
And Control ◽  
Tumour Transplantation

Lactic acid bacteria can affect the maturation of immune cells and their products not only in the gut but also on the systemic immune organs such as lymph nodes and spleen. In the present work, we studied the effects of oral administration ofLactobacillus acidophiluson the immune responses of BALB/c mice bearing transplanted breast tumour. Two groups of female inbred BALB/c mice, each containing nine mice as test and control, were used. TheL. acidophilusATCC4356 strain was inoculated in DeMan–Rogosa–Sharpe broth and cultivated for 24 h at 37°C. Then, it was collected by centrifugation, and was washed and suspended in PBS. Afterwards, 0·5 ml/d of this suspension, which contained 2·7 × 108 colony forming units/ml of bacteria, was orally administered to the mice by gavage, 14 d before tumour transplantation and 30 d after that with 3-d intervals. Similar to the test mice, the control mice received an equal volume of PBS. The results showed that oral administration ofL. acidophilusincreased the production of IL-12 (P < 0·05) and decreased the level of transforming growth factor β (P = 0·05) in the splenocyte culture. Moreover, the growth rate of tumour in the test mice decreased (P < 0·01), and the results of delayed-type hypersensitivity assay after 48 h were risen (P < 0·05) in comparison with the controls. Results suggest that daily consumption ofL. acidophiluscan improve the production of immunomodulatory cytokine IL-12 in the splenocyte culture, which was stimulated by tumour antigen in BALB/c mice bearing transplanted breast tumour. But further studies are needed to find out some other possible mechanisms of this effect.

scholarly journals Extracellular Matrix and Cytokines: A Functional Unit

2000 ◽  
Vol 7 (2-4) ◽  
pp. 89-101 ◽  
Author(s):  
Elke Schönherr ◽  
Heinz-JüRgen Hausser
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Heparan Sulfate ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Heparin Binding ◽  
Cytokine Network ◽  
Surface Receptors ◽  
Core Proteins ◽  
The Matrix

The extracellular matrix (ECM) as well as soluble mediators like cytokines can influence the behavior of cells in very distinct as well as cooperative ways. One group of ECM molecules which shows an especially broad cooperativety with cytokines and growth factors are the proteoglycans. Proteoglycans can interact with their core proteins as well as their glycosaminoglycan chains with cytokines. These interactions can modify the binding of cytokines to their cell surface receptors or they can lead to the storage of the soluble factors in the matrix. Proteoglycans themselves may even have cytokine activity. In this review we describe different proteoglycans and their interactions and relationships with cytokines and we discuss in more detail the extracellular regulation of the activity of transforming growth factor-β (TGF-β) by proteoglycans and other ECM molecules. In the third part the interaction of heparan sulfate chains with fibroblast growth factor-2 (FGF-2, basic FGF) as a prototype example for the interaction of heparin-binding cytokines with heparan sulfate proteoglycans is presented to illustrate the different levels of mutual dependence of the cytokine network and the ECM.

scholarly journals Bone Morphogenetic Protein Receptor Complexes on the Surface of Live Cells: A New Oligomerization Mode for Serine/Threonine Kinase Receptors

2000 ◽  
Vol 11 (3) ◽  
pp. 1023-1035 ◽  
Author(s):  
Lilach Gilboa ◽  
Anja Nohe ◽  
Tanja Geissendörfer ◽  
Walter Sebald ◽  
Yoav I. Henis ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Live Cells ◽  
Type I ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Receptor Complexes ◽  
Bmp Receptors ◽  
Protein Receptor

The bone morphogenetic proteins (BMPs) play important roles in embryogenesis and normal cell growth. The BMP receptors belong to the family of serine/threonine kinase receptors, whose activation has been investigated intensively for the transforming growth factor-β (TGF-β) receptor subfamily. However, the interactions between the BMP receptors, the composition of the active receptor complex, and the role of the ligand in its formation have not yet been investigated and were usually assumed to follow the same pattern as the TGF-β receptors. Here we demonstrate that the oligomerization pattern of the BMP receptors is different and is more flexible and susceptible to modulation by ligand. Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known BMP type I receptors (BR-Ia and BR-Ib) and the BMP type II receptor (BR-II). Coimmunoprecipitation studies detected the formation of heteromeric and homomeric complexes among all the BMP receptor types even in the absence of ligand. These complexes were also detected at the cell surface after BMP-2 binding and cross-linking. Using antibody-mediated immunofluorescence copatching of epitope-tagged receptors, we provide evidence in live cells for preexisting heteromeric (BR-II/BR-Ia and BR-II/BR-Ib) and homomeric (BR-II/BR-II, BR-Ia/ BR-Ia, BR-Ib/ BR-Ib, and also BR-Ia/ BR-Ib) oligomers in the absence of ligand. BMP-2 binding significantly increased hetero- and homo-oligomerization (except for the BR-II homo-oligomer, which binds ligand poorly in the absence of BR-I). In contrast to previous observations on TGF-β receptors, which were found to be fully homodimeric in the absence of ligand, the BMP receptors show a much more flexible oligomerization pattern. This novel feature in the oligomerization mode of the BMP receptors allows higher variety and flexibility in their responses to various ligands as compared with the TGF-β receptors.

scholarly journals Dimethylfumarate Attenuates Renal Fibrosis via NF-E2-Related Factor 2-Mediated Inhibition of Transforming Growth Factor-β/Smad Signaling

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e45870 ◽  
Author(s):  
Chang Joo Oh ◽  
Joon-Young Kim ◽  
Young-Keun Choi ◽  
Han-Jong Kim ◽  
Ji-Yun Jeong ◽  
...  
Keyword(s):  
Growth Factor ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Related Factor ◽  
Smad Signaling

scholarly journals A mechanism of suppression of TGF–β/SMAD signaling by NF-κB/RelA

2000 ◽  
Vol 14 (2) ◽  
pp. 187-197 ◽  
Author(s):  
Markus Bitzer ◽  
Gero von Gersdorff ◽  
Dan Liang ◽  
Alfredo Dominguez-Rosales ◽  
Amer A. Beg ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β ◽  
Nuclear Factor Κb ◽  
Transcriptional Responses ◽  
Smad Signaling ◽  
Antisense Mrna ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

A number of pathogenic and proinflammatory stimuli, and the transforming growth factor-β (TGF-β) exert opposing activities in cellular and immune responses. Here we show that the RelA subunit of nuclear factor κB (NF-κB/RelA) is necessary for the inhibition of TGF-β-induced phosphorylation, nuclear translocation, and DNA binding of SMAD signaling complexes by tumor necrosis factor-α (TNF-α). The antagonism is mediated through up-regulation of Smad7 synthesis and induction of stable associations between ligand-activated TGF-β receptors and inhibitory Smad7. Down-regulation of endogenous Smad7 by expression of antisense mRNA releases TGF-β/SMAD-induced transcriptional responses from suppression by cytokine-activated NF-κB/RelA. Following stimulation with bacterial lipopolysaccharide (LPS), or the proinflammatory cytokines TNF-α and interleukin-1β (IL-1β, NF-κB/RelA induces Smad7 synthesis through activation of Smad7 gene transcription. These results suggest a mechanism of suppression of TGF-β/SMAD signaling by opposing stimuli mediated through the activation of inhibitory Smad7 by NF-κB/RelA.

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