Structural basis for transcriptional coactivator recognition by SMAD2 in TGF-β signaling

2020 ◽  
Vol 13 (662) ◽  
pp. eabb9043
Author(s):  
Ken-ichi Miyazono ◽  
Tomoko Ito ◽  
Yui Fukatsu ◽  
Hikaru Wada ◽  
Akira Kurisaki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transforming Growth Factor ◽  
Cultured Cells ◽  
Hydrophobic Surface ◽  
Transforming Growth Factor Β ◽  
Structural Basis ◽  
Transcriptional Coactivator ◽  
Cellular Functions ◽  
Biochemical Basis ◽  
Smad Proteins

Transforming growth factor–β (TGF-β) proteins regulate multiple cellular functions, including cell proliferation, apoptosis, and extracellular matrix formation. The dysregulation of TGF-β signaling causes diseases such as cancer and fibrosis, and therefore, understanding the biochemical basis of TGF-β signal transduction is important for elucidating pathogenic mechanisms in these diseases. SMAD proteins are transcription factors that mediate TGF-β signaling–dependent gene expression. The transcriptional coactivator CBP directly interacts with the MH2 domains of SMAD2 to activate SMAD complex–dependent gene expression. Here, we report the structural basis for CBP recognition by SMAD2. The crystal structures of the SMAD2 MH2 domain in complex with the SMAD2-binding region of CBP showed that CBP forms an amphiphilic helix on the hydrophobic surface of SMAD2. The expression of a mutated CBP peptide that showed increased SMAD2 binding repressed SMAD2-dependent gene expression in response to TGF-β signaling in cultured cells. Disrupting the interaction between SMAD2 and CBP may therefore be a promising strategy for suppressing SMAD-dependent gene expression.

scholarly journals A Transforming Growth Factor β-Induced Smad3/Smad4 Complex Directly Activates Protein Kinase A

2004 ◽  
Vol 24 (5) ◽  
pp. 2169-2180 ◽  
Author(s):  
Lizhi Zhang ◽  
Chao Jun Duan ◽  
Charles Binkley ◽  
Gangyong Li ◽  
Michael D. Uhler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Transforming Growth Factor ◽  
Direct Interaction ◽  
Transforming Growth Factor Β ◽  
Regulatory Subunit ◽  
Smad Proteins ◽  
Kinase A

ABSTRACT Transforming growth factor β (TGFβ) interacts with cell surface receptors to initiate a signaling cascade critical in regulating growth, differentiation, and development of many cell types. TGFβ signaling involves activation of Smad proteins which directly regulate target gene expression. Here we show that Smad proteins also regulate gene expression by using a previously unrecognized pathway involving direct interaction with protein kinase A (PKA). PKA has numerous effects on growth, differentiation, and apoptosis, and activation of PKA is generally initiated by increased cellular cyclic AMP (cAMP). However, we found that TGFβ activates PKA independent of increased cAMP, and our observations support the conclusion that there is formation of a complex between Smad proteins and the regulatory subunit of PKA, with release of the catalytic subunit from the PKA holoenzyme. We also found that the activation of PKA was required for TGFβ activation of CREB, induction of p21Cip1, and inhibition of cell growth. Taken together, these data indicate an important and previously unrecognized interaction between the TGFβ and PKA signaling pathways.

Cellular response to hypoxia involves signaling via Smad proteins

Blood ◽  
2003 ◽  
Vol 101 (6) ◽  
pp. 2253-2260 ◽  
Author(s):  
Hong Zhang ◽  
Hasan O. Akman ◽  
Eric L. P. Smith ◽  
Jin Zhao ◽  
Joanne E. Murphy-Ullrich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Cellular Response ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Umbilical Vein ◽  
Hypoxia Inducible Factor ◽  
Transforming Growth Factor Β ◽  
Smad Proteins ◽  
Umbilical Vein Endothelial Cells

The transforming growth factor-β (TGF-β) family of cytokines regulates vascular development and inflammatory responses. We have recently shown that exposure of human umbilical vein endothelial cells (HUVECs) to hypoxia (1% O2) increases gene expression and bioactivation of TGF-β2 and induces its downstream effectors, Smad proteins (Smads), to associate with DNA. In the present study, we show that hypoxia-induced TGF-β2 gene expression is dependent on thrombospondin-1–mediated bioactivation of latent TGF-β. Blocking TGF-β2 but not TGF-β1 in hypoxic endothelial cell cultures inhibited induction of the TGF-β2 gene, indicating that an autocrine mechanism driven by bioactivation of TGF-β2 leads to its gene expression in hypoxic HUVECs. Exposure of HUVECs to hypoxia resulted in phosphorylation and nuclear transportation of Smad2 and Smad3 proteins as well as stimulation of transcriptional activities of Smad3 and the transcription factor hypoxia-inducible factor-1α and culminated in up-regulation of TGF-β2 gene expression. Autocrine regulation of TGF-β2 production in hypoxia may involve cross-talk between Smad3 and HIF-1α signaling pathways, and could be an important mechanism by which endothelial cells respond to hypoxic stress.

scholarly journals Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 336
Author(s):  
Roberta Melchionna ◽  
Paola Trono ◽  
Annalisa Tocci ◽  
Paola Nisticò
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tissue Homeostasis ◽  
Actin Dynamics ◽  
Human Tissues ◽  
Cellular Functions ◽  
Tgfβ Signaling ◽  
Physical Mechanisms ◽  
And Function

Human tissues, to maintain their architecture and function, respond to injuries by activating intricate biochemical and physical mechanisms that regulates intercellular communication crucial in maintaining tissue homeostasis. Coordination of the communication occurs through the activity of different actin cytoskeletal regulators, physically connected to extracellular matrix through integrins, generating a platform of biochemical and biomechanical signaling that is deregulated in cancer. Among the major pathways, a controller of cellular functions is the cytokine transforming growth factor β (TGFβ), which remains a complex and central signaling network still to be interpreted and explained in cancer progression. Here, we discuss the link between actin dynamics and TGFβ signaling with the aim of exploring their aberrant interaction in cancer.

scholarly journals Enhanced Intestinal TGF-β/SMAD-Dependent Signaling in Simian Immunodeficiency Virus Infected Rhesus Macaques

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 806
Author(s):  
Nongthombam Boby ◽  
Alyssa Ransom ◽  
Barcley T. Pace ◽  
Kelsey M. Williams ◽  
Christopher Mabee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Simian Immunodeficiency Virus ◽  
Transforming Growth Factor ◽  
Rhesus Macaques ◽  
Transforming Growth Factor Β ◽  
Immunodeficiency Virus ◽  
Cellular Source ◽  
Siv Infection ◽  
Β Receptor ◽  
Differentiation And Proliferation

Transforming growth factor-β signaling (TGF-β) maintains a balanced physiological function including cell growth, differentiation, and proliferation and regulation of immune system by modulating either SMAD2/3 and SMAD7 (SMAD-dependent) or SMAD-independent signaling pathways under normal conditions. Increased production of TGF-β promotes immunosuppression in Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection. However, the cellular source and downstream events of increased TGF-β production that attributes to its pathological manifestations remain unknown. Here, we have shown increased production of TGF-β in a majority of intestinal CD3−CD20−CD68+ cells from acute and chronically SIV infected rhesus macaques, which negatively correlated with the frequency of jejunum CD4+ T cells. No significant changes in intestinal TGF-β receptor II expression were observed but increased production of the pSMAD2/3 protein and SMAD3 gene expression in jejunum tissues that were accompanied by a downregulation of SMAD7 protein and gene expression. Enhanced TGF-β production by intestinal CD3−CD20−CD68+ cells and increased TGF-β/SMAD-dependent signaling might be due to a disruption of a negative feedback loop mediated by SMAD7. This suggests that SIV infection impacts the SMAD-dependent signaling pathway of TGF-β and provides a potential framework for further study to understand the role of viral factor(s) in modulating TGF-β production and downregulating SMAD7 expression in SIV. Regulation of mucosal TGF-β expression by therapeutic TGF-β blockers may help to create effective antiviral mucosal immune responses.

scholarly journals Transforming growth factor β-1 enhances Smad transcriptional activity through activation of p8 gene expression

2001 ◽  
Vol 357 (1) ◽  
pp. 249 ◽  
Author(s):  
Andrés C. GARCÍA-MONTERO ◽  
Sophie VASSEUR ◽  
Luciana E. GIONO ◽  
Eduardo CANEPA ◽  
Silvia MORENO ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Transcriptional Activity ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β
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