Transforming Growth Factor-β Receptors and Smads: Regulatory Complexity and Functional Versatility

doi:10.1016/J.TCB.2017.04.005

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Transforming Growth Factor-β Receptors and Smads: Regulatory Complexity and Functional Versatility

Journal Article•DOI•

Transforming Growth Factor-β Receptors and Smads: Regulatory Complexity and Functional Versatility

Erine H. Budi¹, Dana Duan¹, Rik Derynck¹•Institutions (1)

University of California, San Francisco¹

01 Sep 2017-Trends in Cell Biology (Trends Cell Biol)-Vol. 27, Iss: 9, pp 658-672

TL;DR: New insights are summarized into how cells control TGF-β responsiveness by controlling the T GF-β receptors, and into the key roles and versatility of Smads in directing cell differentiation and cell fate selection.

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About: This article is published in Trends in Cell Biology.The article was published on 2017-09-01. It has received 214 citations till now. The article focuses on the topics: R-SMAD & SMAD.

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Journal Article•DOI•

Specificity, versatility, and control of TGF-β family signaling.

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Rik Derynck¹, Erine H. Budi¹•Institutions (1)

University of California, San Francisco¹

26 Feb 2019-Science Signaling

TL;DR: The exquisite nature of TGF-β family signaling in its roles in diverse and context-specific cellular behaviors is described and the mechanisms through which proteins called Smads act as intracellular effectors of ligand-induced gene expression responses are introduced, showing that the specificity and impressive versatility of Smad signaling depend on cross-talk from other pathways.

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Abstract: 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.

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389 citations

Journal Article•DOI•

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

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Lin Chen¹, Tian Yang¹, De-Wen Lu¹, Hui Zhao¹, Ya-Long Feng¹, Hua Chen¹, Dan-Qian Chen¹, Nosratola D. Vaziri², Ying-Yong Zhao¹ - Show less +5 more•Institutions (2)

Chinese Ministry of Education¹, University of California, Irvine²

01 May 2018-Biomedicine & Pharmacotherapy

TL;DR: TGF-β/Smad signaling is an important pathway that mediates renal fibrosis and inflammation and an effective target of anti-fibrotic therapies for treatment of CKD.

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227 citations

Cites background from "Transforming Growth Factor-β Recept..."

...By directly binding TGFβRII it blocks the TGF-β-induced signaling, thereby inhibits renal fibrosis [164]....
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...proteins (BMP) and anti-mullerian hormone [22,23]....
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...Abbreviations: ACE2, angiotensin-converting enzyme-2; AGE, advanced glycation end-product; AT1R, angiotensin type 1 receptor; BMP, bone morphogenetic proteins; BMP-7, bone morphogenetic protein 7; CKD, chronic kidney diseases; Co-Smads, common mediator Smads; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; ERK, extracellular regulated protein kinases; ESRD, end stage renal diseases; FSGS, focal and segmental glomerulosclerosis; HIPK2, Homeodomain interacting protein kinase 2; hRPTEC, human renal proximal tubule epithelial cells; ICAM-1, intercellular cell adhesion molecule-1; IgA, immunoglobulin A; interleukin-1β (IL-1β) I-Smads, inhibitory Smads; Keap1, Kelch-like ECHassociated protein 1; MAPK, mitogen-activated protein kinase; monocyte chemoattractant protein-1 (MCP-1) NEDD4-2, neural precursor cell expressed developmentally downregulated gene 4; Nrf2, nuclear factor- erythroid-2-related factor 2; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol-3 kinase; R-Smads, receptor-regulated Smads; Ski, Sloankettering institute; Smurf1, Smad ubiquitination regulatory factor-1; Smurf2, Smad ubiquitination regulatory factor-2; SnoN, Ski-related novel protein N; TGF-β, transforming growth factor-β; TGF-β1, transforming growth factor-β1; TGFβR, transforming growth factor-β receptor; TGFβRI, transforming growth factor-β receptor type I; TGFβRII, transforming growth factor-β receptor type II; TNF-α, tumor necrosis factor α; UUO, unilateral ureteral obstruction; WWP1, WW domain containing E3 ubiquitin protein ligase 1; α-SMA, alpha-smooth muscle actin Biomedicine & Pharmacotherapy 101 (2018) 670–681 0753-3322/ © 2018 Elsevier Masson SAS....
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...The contribution of TGF-β to severity of acute kidney injury is supported by experiments which demonstrated attenuation of proximal tubule injury in mice with selective deletion of TGFβRII in the proximal tubules [43]....
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...specific DNA-binding transcription factors and modulates target gene transcription [23,27,28]....
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Journal Article•DOI•

TGF-β receptors: In and beyond TGF-β signaling.

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Alexandra Vander Ark¹, Jingchen Cao¹, Xiaohong Li¹•Institutions (1)

Van Andel Institute¹

07 Sep 2018-Cellular Signalling

TL;DR: Focusing on the receptors in events in and beyond TGF-β signaling, this work reviews the membrane trafficking of TGFBRs, the kinase activity of T GFBR1 and 2, the direct interactions between TGF BR2 and other receptors, and the novel roles of TDFBR3.

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224 citations

Membrane protein GARP is a receptor for latent TGF-β on the surface of activated human Tregs.

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Sophie Lucas

01 Jan 2009

TL;DR: The authors showed that latent TGF-β mediated by binding to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, may be necessary for the ability of Treg to activate TGF−β upon TCR stimulation.

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Abstract: Human Treg and Th clones secrete the latent form of TGF‐β, in which the mature TGF‐β protein is bound to the latency‐associated peptide (LAP), and is thereby prevented from binding to the TGF‐β receptor. We previously showed that upon TCR stimulation, human Treg clones but not Th clones produce active TGF‐β and bear LAP on their surface. Here, we show that latent TGF‐β, i.e. both LAP and mature TGF‐β, binds to glycoprotein A repetitions predominant (GARP), a transmembrane protein containing leucine rich repeats, which is present on the surface of stimulated Treg clones but not on Th clones. Membrane localization of latent TGF‐β mediated by binding to GARP may be necessary for the ability of Treg to activate TGF‐β upon TCR stimulation. However, it is not sufficient as lentiviral‐mediated expression of GARP in human Th cells induces binding of latent TGF‐β to the cell surface, but does not result in the production of active TGF‐β upon stimulation of these Th cells.

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185 citations

Journal Article•DOI•

The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms

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Hiroki Kabata, Kazuyo Moro¹, Shigeo Koyasu²•Institutions (2)

Yokohama City University¹, Keio University²

01 Nov 2018-Immunological Reviews

TL;DR: This comprehensive review affords a better understanding of the regulatory network system for ILC2s, providing impetus to develop new treatment strategies for I LC2‐related health problems.

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Abstract: Group 2 innate lymphoid cells (ILC2s) play critical roles in the induction of type 2 inflammation, response to parasite infection, metabolic homeostasis, and tissue repair. These multifunctional roles of ILC2s are tightly controlled by complex regulatory systems in the local microenvironment, the disruption of which may cause various health problems. This review summarizes up-to-date knowledge regarding positive and negative regulators for ILC2s based on their function and signaling pathways, including activating cytokines (IL-33, IL-25; MAPK, NF-κB pathways), co-stimulatory cytokines (IL-2, IL-7, IL-9, TSLP; STAT5, IL-4; STAT6, TNF superfamily; MAPK, NF-κB pathways), suppressive cytokines (type1 IFNs, IFN-γ, IL-27; STAT1, IL-10, TGF-β), transdifferentiation cytokines (IL-12; STAT4, IL-1β, IL-18), lipid mediators (LTC4, LTD4, LTE4, PGD2; Ca2+ -NFAT pathways, PGE2, PGI2; AC/cAMP/PKA pathways, LXA4, LTB4), neuropeptides (NMU; Ca2+ -NFAT, MAPK pathways, VIP, CGRP, catecholamine, acetylcholine), sex hormones (androgen, estrogen), nutrients (butyrate; HDAC inhibitors, vitamins), and cell-to-cell interactions (ICOSL-ICOS; STAT5, B7-H6-NKp30, E-cadherin-KLRG1). This comprehensive review affords a better understanding of the regulatory network system for ILC2s, providing impetus to develop new treatment strategies for ILC2-related health problems.

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177 citations

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References

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Cell signaling by receptor-tyrosine kinases

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Mark A. Lemmon¹, Joseph Schlessinger²•Institutions (2)

University of Pennsylvania¹, Yale University²

13 Oct 2000-Cell

TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.

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7,056 citations

"Transforming Growth Factor-β Recept..." refers background in this paper

...This scenario is suggested by growth factor-induced auto-/transphosphorylation and activation of receptor tyrosine kinases (RTKs) [32,33], and may explain why immunoprecipitated TbRII is seen phosphorylated and with kinase activity [34], as a result of antibody-induced TbRII dimerization and phosphorylation....
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Samy Lamouille¹, Jian Xu², Rik Derynck¹•Institutions (2)

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01 Mar 2014-Nature Reviews Molecular Cell Biology

TL;DR: The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues, and the convergence of signalling pathways is essential for EMT.

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6,036 citations

"Transforming Growth Factor-β Recept..." refers background in this paper

...TGF-b-activated Smad3– Smad4 complexes directly activate the expression of the EMT master transcription factors, such as Snail1 or Snail2/Slug and ZEB1 and ZEB2, and then cooperate with these transcription factors in the repression of epithelial genes and activation of a mesenchymal gene expression program [94]....
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Steven K. Hanks¹, Tony Hunter²•Institutions (2)

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01 May 1995-The FASEB Journal

TL;DR: The eukaryotic protein kinases make up a large superfamily of homologous proteins, and a classification scheme can be founded on a kinase domain phylogeny, which reveals families of enzymes that have related substrate specificities and modes of regulation.

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Abstract: The eukaryotic protein kinases make up a large superfamily of homologous proteins. They are related by virtue of their kinase domains (also known as catalytic domains), which consist of approximately 250-300 amino acid residues. The kinase domains that define this group of enzymes contain 12 conserved subdomains that fold into a common catalytic core structure, as revealed by the 3-dimensional structures of several protein-serine kinases. There are two main subdivisions within the superfamily: the protein-serine/threonine kinases and the protein-tyrosine kinases. A classification scheme can be founded on a kinase domain phylogeny, which reveals families of enzymes that have related substrate specificities and modes of regulation.

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2,730 citations

"Transforming Growth Factor-β Recept..." refers background in this paper

...Predicted by phylogenetic sequence alignments [35,36], the type II and type I receptors phosphorylate not only on serine and threonine, but also on tyrosine [37,38], even though the type I receptors phosphorylate the Smads only at C-terminal serines and are therefore often seen as serine/threonine kinases [3]....
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Journal Article•DOI•

Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells

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Xi Chen¹, Han Xu¹, Ping Yuan¹, Fang Fang¹, Fang Fang², Mikael Huss¹, Vinsensius B. Vega¹, Eleanor Wong¹, Yuriy L. Orlov¹, Weiwei Zhang¹, Weiwei Zhang², Jianming Jiang¹, Jianming Jiang², Yuin-Han Loh¹, Yuin-Han Loh², Hock Chuan Yeo¹, Zhen Xuan Yeo¹, Vipin Narang¹, Kunde R Govindarajan¹, Bernard Leong¹, Atif Shahab¹, Yijun Ruan¹, Guillaume Bourque¹, Wing-Kin Sung¹, Neil D. Clarke¹, Chia-Lin Wei¹, Huck-Hui Ng¹, Huck-Hui Ng² - Show less +24 more•Institutions (2)

Genome Institute of Singapore¹, National University of Singapore²

13 Jun 2008-Cell

TL;DR: This study uses chromatin immunoprecipitation coupled with ultra-high-throughput DNA sequencing to map the locations of TF-binding sites and identifies important features of the transcriptional regulatory networks that define ES-cell identity.

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2,519 citations

"Transforming Growth Factor-β Recept..." refers background in this paper

...In human embryonic stem cells, TGF-b-activated Smad2 and/or Smad3 associate with master transcription factors that define the pluripotent state, and thus colocalize with octamer-binding transcription factor [191_TD$DIFF]4 (Oct 4 or POU5F1), Nanog, or Sox2 in the genome, including at the genes encoding Oct4, Nanog, and Sox2....
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...In this transdifferentiation context, Smad-mediated reprogramming of gene and regulatory RNA (miRNAs 10 Trends in Cell Biology, Month Year, Vol. xx, No. yy Osteoblast genes Osteoblast differen a on HDAC Runx2 Osteoblast genesRunx2 Myogenesis genes (MyoD, myogenin) Myogenic differen a onE47 Myogenesis genes MEF2 MyoD P Smad3 P Pluripotency genesSox2 P Smad4 Smad3 P P Smad4 Smad3 P Pluripotency genesOct4 Nanog E-Box Klf5Sox4 Klf5Sox4 Maintanence of stemness Sox2 P Smad4 Smad1 P P Smad4 Smad3 P P Smad4 Smad3 P Self renewal Apoptosis Sox4 Sox4 MEF2 MyoD E47 Figure 3....
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...In glioblastoma multiforme, Sox4 expression under the control of autocrine TGF-b/Smad3 signaling enables cooperation of Sox4 with Oct4 in the activation of Sox2 expression, which is necessary for the stemness of neuronal and glioblastoma stem cells [106,107]....
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...Abbreviations: HDAC, histone deacetylase; Klf5, Krueppel-like factor 5; Oct4, octamer-binding transcription factor; Runt-related transcription factor Runx2. and long noncoding RNAs) expression greatly contributes to the transition of epithelial cells toward a mesenchymal phenotype, with the apical–basal polarity redirected to a front–rear polarity, which enables the cells to directionally migrate [94–96]....
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...In embryonic stem cells, activated Smads partner with pluripotency master regulators such as Sox2, Nanog, and Oct4 to drive gene expression programs necessary to maintain pluripotency....
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Journal Article•DOI•

TGFβ signalling in context.

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Joan Massagué¹•Institutions (1)

Memorial Sloan Kettering Cancer Center¹

01 Oct 2012-Nature Reviews Molecular Cell Biology

TL;DR: The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed and the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings.

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Abstract: The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: how does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions. Recent progress is pointing at answers.

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2,481 citations

"Transforming Growth Factor-β Recept..." refers background in this paper

...Further complexity of the transcription response is dictated by interacting co-regulators that define the amplitude of the transcription response of the target gene [5,87]....
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