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TGF-Beta Super Family Signaling 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 63720

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Special Issue Editors

Dr. Jun-ichi Hanai

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Guest Editor

Department of Medicine, Massachusetts General Hospital, Center for Cancer Research, Harvard Medical School, Boston, MA 02215, USA
Interests: pathological stem cells; cancer biology; fibrosis and cellular plasticity; EMT; TGF-b signaling; epigenetics
Special Issues, Collections and Topics in MDPI journals

Dr. Noriko Ide

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Guest Editor

1. Division of Bone and Mineral Research, Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, USA
2. Division of Nephrology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, Japan
Interests: vascular biology; cellular plasticity; pathological stem cells; cellular senescence and aging; laminopathy; mechanotransduction; atherosclerosis; tissue fibrosis; mineral metabolism

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our 2018 Special Issue, “TGF-Beta Super Family Signaling”.

Our knowledge of this superfamily is quickly expanding into previously uncharted areas of biology and human pathogenesis. TGF-β superfamily members play pivotal roles throughout development and later in adult homeostasis to orchestrate complex processes. Consistent with their diversity of function, aberrant signaling by members of the TGF-β superfamily is associated with a wide range of human pathologies, including immune system compromise, cardiovascular and fibrotic diseases, aging processes, and, critically, cancer.

The goal of this Special Issue is to broaden the molecular understanding of the key roles of TGF-β superfamily members, including TGF-βs, nodal, activins, BMPs, and GDFs in pathophysiological processes. The mechanisms of aberrations in this signaling pathway, which lead to human disease pathologies, will be especially highlighted.

Topics will include (but are not limited to) cancer biology, stem cell biology, cellular plasticity, inflammation, immune surveillance escape, stress response, tissue fibrosis, vasculature and tissue transformation (EndMT/EMT), tissue microenvironment dynamics, and therapeutic frontiers of TGF-β signaling.

Up-to-date review articles and experimental papers are all welcome. We look forward to your contributions.

Dr. Jun-ichi Hanai
Dr. Noriko Ide
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Signaling crosstalk
EMT
EndoMT
Immune and inflammatory response
Stress response
Tissue morphogenesis and plasticity
Oncogenic stem cells (cancer initiating cells)
Tissue microenvironment dynamics
Tissue fibrosis
Epigenetic regulation
Senescence/aging
Therapeutic frontiers

Published Papers (13 papers)

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Research

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22 pages, 13549 KiB

Open AccessArticle

In Vivo Analysis of Optic Fissure Fusion in Zebrafish: Pioneer Cells, Basal Lamina, Hyaloid Vessels, and How Fissure Fusion is Affected by BMP

by Priska Eckert, Max D. Knickmeyer and Stephan Heermann

Int. J. Mol. Sci. 2020, 21(8), 2760; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082760 - 16 Apr 2020

Cited by 10 | Viewed by 2459

Abstract

Colobomata, persistent optic fissures, frequently cause congenital blindness. Here, we focused on optic fissure fusion using in vivo time-lapse imaging in zebrafish. We identified the fusion initiating cells, which we termed “pioneer cells.” Based on morphology, localization, and downregulation of the neuroretinal (NR) precursor marker rx2, these cells could be considered as retinal pigment epithelial (RPE) progenitors. Notably, pioneer cells regain rx2 expression and integrate into the NR after fusion, indicating that they do not belong to the pool of RPE progenitors, supported by the lack of RPE marker expression in pioneer cells. They establish the first cellular contact between the margins in the proximal fissure region and separate the hyaloid artery and vein. After initiation, the fusion site is progressing distally, increasing the distance between the hyaloid artery and vein. A timed BMP (Bone Morphogenetic Protein) induction, resulting in coloboma, did not alter the morphology of the fissure margins, but it did affect the expression of NR and RPE markers within the margins. In addition, it resulted in a persisting basal lamina and persisting remnants of periocular mesenchyme and hyaloid vasculature within the fissure, supporting the necessity of BMP antagonism within the fissure margins. The hampered fissure fusion had severe effects on the vasculature of the eye. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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20 pages, 2753 KiB

Open AccessArticle

TGF-β Signaling Regulates SLC8A3 Expression and Prevents Oxidative Stress in Developing Midbrain Dopaminergic and Dorsal Raphe Serotonergic Neurons

by Enaam Chleilat, Abhishek Pethe, Dietmar Pfeifer, Kerstin Krieglstein and Eleni Roussa

Int. J. Mol. Sci. 2020, 21(8), 2735; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082735 - 15 Apr 2020

Cited by 8 | Viewed by 3044

Abstract

Calcium homeostasis is a cellular process required for proper cell function and survival, maintained by the coordinated action of several transporters, among them members of the Na⁺/Ca²⁺-exchanger family, such as SLC8A3. Transforming growth factor beta (TGF-β) signaling defines neuronal development and survival and may regulate the expression of channels and transporters. We investigated the regulation of SLC8A3 by TGF-β in a conditional knockout mouse with deletion of TGF-β signaling from Engrailed 1-expressing cells, i.e., in cells from the midbrain and rhombomere 1, and elucidated the underlying molecular mechanisms. The results show that SLC8A3 is significantly downregulated in developing dopaminergic and dorsal raphe serotonergic neurons in mutants and that low SLC8A3 abundance prevents the expression of the anti-apoptotic protein Bcl-xL. TGF-β signaling affects SLC8A3 via the canonical and p38 signaling pathway and may increase the binding of Smad4 to the Slc8a3 promoter. Expression of the lipid peroxidation marker malondialdehyde (MDA) was increased following knockdown of Slc8a3 expression in vitro. In neurons lacking TGF-β signaling, the number of MDA- and 4-hydroxynonenal (4-HNE)-positive cells was significantly increased, accompanied with increased cellular 4-HNE abundance. These results suggest that TGF-β contributes to the regulation of SLC8A3 expression in developing dopaminergic and dorsal raphe serotonergic neurons, thereby preventing oxidative stress. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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25 pages, 7780 KiB

Open AccessArticle

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

by Sabrina Kuespert, Rosmarie Heydn, Sebastian Peters, Eva Wirkert, Anne-Louise Meyer, Mareile Siebörger, Siw Johannesen, Ludwig Aigner, Ulrich Bogdahn and Tim-Henrik Bruun

Int. J. Mol. Sci. 2020, 21(6), 1952; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21061952 - 12 Mar 2020

Cited by 20 | Viewed by 4388

Abstract

Antisense Oligonucleotides (ASOs) are an emerging drug class in gene modification. In our study we developed a safe, stable, and effective ASO drug candidate in locked nucleic acid (LNA)-gapmer design, targeting TGFβ receptor II (TGFBR2) mRNA. Discovery was performed as a process using state-of-the-art library development and screening. We intended to identify a drug candidate optimized for clinical development, therefore human specificity and gymnotic delivery were favored by design. A staggered process was implemented spanning in-silico-design, in-vitro transfection, and in-vitro gymnotic delivery of small batch syntheses. Primary in-vitro and in-vivo toxicity studies and modification of pre-lead candidates were also part of this selection process. The resulting lead compound NVP-13 unites human specificity and highest efficacy with lowest toxicity. We particularly focused at attenuation of TGFβ signaling, addressing both safety and efficacy. Hence, developing a treatment to potentially recondition numerous pathological processes mediated by elevated TGFβ signaling, we have chosen to create our data in human lung cell lines and human neuronal stem cell lines, each representative for prospective drug developments in pulmonary fibrosis and neurodegeneration. We show that TGFBR2 mRNA as a single gene target for NVP-13 responds well, and that it bears great potential to be safe and efficient in TGFβ signaling related disorders. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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19 pages, 2336 KiB

Open AccessArticle

In Vivo Allergen-Activated Eosinophils Promote Collagen I and Fibronectin Gene Expression in Airway Smooth Muscle Cells via TGF-β1 Signaling Pathway in Asthma

by Ieva Janulaityte, Andrius Januskevicius, Virginija Kalinauskaite-Zukauske, Ieva Bajoriuniene and Kestutis Malakauskas

Int. J. Mol. Sci. 2020, 21(5), 1837; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051837 - 06 Mar 2020

Cited by 17 | Viewed by 3010

Abstract

Eosinophils infiltration and releasing TGF-β1 in the airways has been implicated in the pathogenesis of asthma, especially during acute episodes provoked by an allergen. TGF-β1 is a major mediator involved in pro-inflammatory responses and fibrotic tissue remodeling in asthma. We aimed to evaluate the effect of in vivo allergen-activated eosinophils on the expression of COL1A1 and FN in ASM cells in asthma. A total of 12 allergic asthma patients and 11 healthy subjects were examined. All study subjects underwent bronchial challenge with D. pteronyssinus allergen. Eosinophils from peripheral blood were isolated before and 24 h after the bronchial allergen challenge using high-density centrifugation and magnetic separation. Individual co-cultures of blood eosinophils and immortalized human ASM cells were prepared. The TGF-β1 concentration in culture supernatants was analyzed using ELISA. Gene expression was analyzed using qRT-PCR. Eosinophils integrins were suppressed with linear RGDS peptide before co-culture with ASM cells. Results: The expression of TGF-β1 in asthmatic eosinophils significantly increased over non-activated asthmatic eosinophils after allergen challenge, p < 0.001. The TGF-β1 concentration in culture supernatants was significantly higher in samples with allergen-activated asthmatic eosinophils compared to baseline, p < 0.05. The effect of allergen-activated asthmatic eosinophils on the expression of TGF-β1, COL1A1, and FN in ASM cells was more significant compared to non-activated eosinophils, p < 0.05, however, no difference was found on WNT-5A expression. The incubation of allergen-activated asthmatic eosinophils with RGDS peptide was more effective compared to non-activated eosinophils as the gene expression in ASM cells was downregulated equally to the same level as healthy eosinophils. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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14 pages, 3370 KiB

Open AccessArticle

Syndecan-4 Inhibits the Development of Pulmonary Fibrosis by Attenuating TGF-β Signaling

by Yoshinori Tanino, Xintao Wang, Takefumi Nikaido, Kenichi Misa, Yuki Sato, Ryuichi Togawa, Takaya Kawamata, Masami Kikuchi, Charles W. Frevert, Mishie Tanino, Tetsuhito Kojima and Yoko Shibata

Int. J. Mol. Sci. 2019, 20(20), 4989; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20204989 - 09 Oct 2019

Cited by 17 | Viewed by 3609

Abstract

Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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21 pages, 4070 KiB

Open AccessArticle

Differential Role of TGF-β in Extracellular Matrix Regulation During Trypanosoma cruzi-Host Cell Interaction

by Tatiana Araújo Silva, Luis Felipe de Carvalho Ferreira, Mirian Claudia de Souza Pereira and Claudia Magalhães Calvet

Int. J. Mol. Sci. 2019, 20(19), 4836; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194836 - 29 Sep 2019

Cited by 10 | Viewed by 3188

Abstract

Transforming growth factor beta (TGF-β) is a determinant for inflammation and fibrosis in cardiac and skeletal muscle in Chagas disease. To determine its regulatory mechanisms, we investigated the response of Trypanosoma cruzi-infected cardiomyocytes (CM), cardiac fibroblasts (CF), and L6E9 skeletal myoblasts to TGF-β. Cultures of CM, CF, and L6E9 were infected with T. cruzi (Y strain) and treated with TGF-β (1–10 ng/mL, 1 h or 48 h). Fibronectin (FN) distribution was analyzed by immunofluorescence and Western blot (WB). Phosphorylated SMAD2 (PS2), phospho-p38 (p-p38), and phospho-c-Jun (p-c-Jun) signaling were evaluated by WB. CF and L6E9 showed an increase in FN from 1 ng/mL of TGF-β, while CM displayed FN modulation only after 10 ng/mL treatment. CF and L6E9 showed higher PS2 levels than CM, while p38 was less stimulated in CF than CM and L6E9. T. cruzi infection resulted in localized FN disorganization in CF and L6E9. T. cruzi induced an increase in FN in CF cultures, mainly in uninfected cells. Infected CF cultures treated with TGF-β showed a reduction in PS2 and an increase in p-p38 and p-c-Jun levels. Our data suggest that p38 and c-Jun pathways may be participating in the fibrosis regulatory process mediated by TGF-β after T. cruzi infection. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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17 pages, 3902 KiB

Open AccessArticle

Cell Type-Specific TGF-β Mediated EMT in 3D and 2D Models and Its Reversal by TGF-β Receptor Kinase Inhibitor in Ovarian Cancer Cell Lines

by Wafa Al Ameri, Ikhlak Ahmed, Fatima M. Al-Dasim, Yasmin Ali Mohamoud, Iman K. Al-Azwani, Joel A. Malek and Thasni Karedath

Int. J. Mol. Sci. 2019, 20(14), 3568; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143568 - 22 Jul 2019

Cited by 19 | Viewed by 4489

Abstract

Transcriptome profiling of 3D models compared to 2D models in various cancer cell lines shows differential expression of TGF-β-mediated and cell adhesion pathways. Presence of TGF-β in these cell lines shows an increased invasion potential which is specific to cell type. In the present study, we identified exogenous addition of TGF-β can induce Epithelial to Mesenchymal Transition (EMT) in a few cancer cell lines. RNA sequencing and real time PCR were carried out in different ovarian cancer cell lines to identify molecular profiling and metabolic profiling. Since EMT induction by TGF-β is cell-type specific, we decided to select two promising ovarian cancer cell lines as model systems to study EMT. TGF-β modulation in EMT and cancer invasion were successfully depicted in both 2D and 3D models of SKOV3 and CAOV3 cell lines. Functional evaluation in 3D and 2D models demonstrates that the addition of the exogenous TGF-β can induce EMT and invasion in cancer cells by turning them into aggressive phenotypes. TGF-β receptor kinase I inhibitor (LY364947) can revert the TGF-β effect in these cells. In a nutshell, TGF-β can induce EMT and migration, increase aggressiveness, increase cell survival, alter cell characteristics, remodel the Extracellular Matrix (ECM) and increase cell metabolism favorable for tumor invasion and metastasis. We concluded that transcriptomic and phenotypic effect of TGF-β and its inhibitor is cell-type specific and not cancer specific. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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14 pages, 2678 KiB

Open AccessArticle

Smad4 Feedback Enhances BMPR1B Transcription in Ovine Granulosa Cells

by Anwar Abdurahman, Xing Du, Yilong Yao, Yiming Sulaiman, Jueken Aniwashi and Qifa Li

Int. J. Mol. Sci. 2019, 20(11), 2732; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20112732 - 04 Jun 2019

Cited by 18 | Viewed by 4813

Abstract

BMPR1B is a type 1B receptor of the canonical bone morphogenetic protein (BMP)/Sma- and mad-related protein (Smad) signaling pathway and is well known as the first major gene associated with sheep prolificacy. However, little is known about the transcriptional regulation of the ovine BMPR1B gene. In this study, we identified the ovine BMPR1B gene promoter and demonstrated that its transcription was regulated by Smad4. In sheep ovarian follicles, three transcriptional variants of BMPR1B gene with distinct transcription start sites were identified using 5′ RACE assay while variants II and III were more strongly expressed. Luciferase assay showed that the region −405 to −200 nt is the PII promoter region of variant II. Interestingly, two putative Smad4-binding elements (SBEs) were detected in this region. Luciferase and ChIP assay revealed that Smad4 enhances PII promoter activity of the ovine BMPR1B gene by directly interacting with SBE1 motif. Furthermore, in the ovine granulosa cells, Smad4 regulated BMPRIB expression, and BMPRIB-mediated granulosa cells apoptosis. Overall, our findings not only characterized the 5’ regulatory region of the ovine BMPR1B gene, but also uncovered a feedback regulatory mechanism of the canonical BMP/Smad signaling pathway and provided an insight into the transcriptional regulation of BMPR1B gene and sheep prolificacy. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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16 pages, 4153 KiB

Open AccessArticle

Graptopetalum paraguayense Inhibits Liver Fibrosis by Blocking TGF-β Signaling In Vivo and In Vitro

by Wei-Hsiang Hsu, Se-Chun Liao, Yau-Jan Chyan, Kai-Wen Huang, Shih-Lan Hsu, Yi-Chen Chen, Ma-Li Siu, Chia-Chuan Chang, Yuh-Shan Chung and Chi-Ying F. Huang

Int. J. Mol. Sci. 2019, 20(10), 2592; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102592 - 27 May 2019

Cited by 11 | Viewed by 4248

Abstract

Background and Aims: Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, which occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension. Activated hepatic perivascular stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines, such as TGF-β1. The inhibition of TGF-β1 function or synthesis is a major target for the development of antifibrotic therapies. Our previous study showed that the water and ethanol extracts of Graptopetalum paraguayense (GP), a Chinese herbal medicine, can prevent dimethylnitrosamine (DMN)-induced hepatic inflammation and fibrosis in rats. Methods: We used rat hepatic stellate HSC-T6 cells and a diethylnitrosamine (DEN)-induced rat liver injury model to test the potential mechanism of GP extracts and its fraction, HH-F3. Results: We demonstrated that GP extracts and HH-F3 downregulated the expression levels of extracellular matrix (ECM) proteins and inhibited the proliferation and migration via suppression of the TGF-β1 pathway in rat hepatic stellate HSC-T6 cells. Moreover, the HH-F3 fraction decreased hepatic collagen content and reduced plasma AST, ALT, and γ-GT activities in a DEN-induced rat liver injury model, suggesting that GP/HH-F3 has hepatoprotective effects against DEN-induced liver fibrosis. Conclusion: These findings indicate that GP/HH-F3 may be a potential therapeutic agent for the treatment of liver fibrosis. The inhibition of TGF-β-mediated fibrogenesis may be a central mechanism by which GP/HH-F3 protects the liver from injury. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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Review

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15 pages, 858 KiB

Open AccessReview

The Distinct Roles of Transcriptional Factor KLF11 in Normal Cell Growth Regulation and Cancer as a Mediator of TGF-β Signaling Pathway

by Lili Lin, Sven Mahner, Udo Jeschke and Anna Hester

Int. J. Mol. Sci. 2020, 21(8), 2928; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082928 - 22 Apr 2020

Cited by 14 | Viewed by 4663

Abstract

KLF11 (Krüppel-like factor 11) belongs to the family of Sp1/Krüppel-like zinc finger transcription factors that play important roles in a variety of cell types and tissues. KLF11 was initially described as a transforming growth factor-beta (TGF-β) inducible immediate early gene (TIEG). KLF11 promotes the effects of TGF-β on cell growth control by influencing the TGFβ–Smads signaling pathway and regulating the transcription of genes that induce either apoptosis or cell cycle arrest. In carcinogenesis, KLF11 can show diverse effects. Its function as a tumor suppressor gene can be suppressed by phosphorylation of its binding domains via oncogenic pathways. However, KLF 11 can itself also show tumor-promoting effects and seems to have a crucial role in the epithelial–mesenchymal transition process. Here, we review the current knowledge about the function of KLF11 in cell growth regulation. We focus on its transcriptional regulatory function and its influence on the TGF-β signaling pathway. We further discuss its possible role in mediating crosstalk between various signaling pathways in normal cell growth and in carcinogenesis. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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15 pages, 1641 KiB

Open AccessReview

AGAP2: Modulating TGFβ1-Signaling in the Regulation of Liver Fibrosis

by Amaia Navarro-Corcuera, Eduardo Ansorena, Cristina Montiel-Duarte and María J. Iraburu

Int. J. Mol. Sci. 2020, 21(4), 1400; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041400 - 19 Feb 2020

Cited by 14 | Viewed by 3910

Abstract

AGAP2 (Arf GAP with GTP-binding protein-like domain, Ankyrin repeat and PH domain 2) isoform 2 is a protein that belongs to the Arf GAP (GTPase activating protein) protein family. These proteins act as GTPase switches for Arfs, which are Ras superfamily members, being therefore involved in signaling regulation. Arf GAP proteins have been shown to participate in several cellular functions including membrane trafficking and actin cytoskeleton remodeling. AGAP2 is a multi-tasking Arf GAP that also presents GTPase activity and is involved in several signaling pathways related with apoptosis, cell survival, migration, and receptor trafficking. The increase of AGAP2 levels is associated with pathologies as cancer and fibrosis. Transforming growth factor beta-1 (TGF-β1) is the most potent pro-fibrotic cytokine identified to date, currently accepted as the principal mediator of the fibrotic response in liver, lung, and kidney. Recent literature has described that the expression of AGAP2 modulates some of the pro-fibrotic effects described for TGF-β1 in the liver. The present review is focused on the interrelated molecular effects between AGAP2 and TGFβ1 expression, presenting AGAP2 as a new player in the signaling of this pro-fibrotic cytokine, thereby contributing to the progression of hepatic fibrosis. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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18 pages, 1191 KiB

Open AccessReview

TGF-β Signaling in Cellular Senescence and Aging-Related Pathology

by Kana Tominaga and Hiroshi I. Suzuki

Int. J. Mol. Sci. 2019, 20(20), 5002; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20205002 - 10 Oct 2019

Cited by 166 | Viewed by 14869

Abstract

Aging is broadly defined as the functional decline that occurs in all body systems. The accumulation of senescent cells is considered a hallmark of aging and thought to contribute to the aging pathologies. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that regulates a myriad of cellular processes and has important roles in embryonic development, physiological tissue homeostasis, and various pathological conditions. TGF-β exerts potent growth inhibitory activities in various cell types, and multiple growth regulatory mechanisms have reportedly been linked to the phenotypes of cellular senescence and stem cell aging in previous studies. In addition, accumulated evidence has indicated a multifaceted association between TGF-β signaling and aging-associated disorders, including Alzheimer’s disease, muscle atrophy, and obesity. The findings regarding these diseases suggest that the impairment of TGF-β signaling in certain cell types and the upregulation of TGF-β ligands contribute to cell degeneration, tissue fibrosis, inflammation, decreased regeneration capacity, and metabolic malfunction. While the biological roles of TGF-β depend highly on cell types and cellular contexts, aging-associated changes are an important additional context which warrants further investigation to better understand the involvement in various diseases and develop therapeutic options. The present review summarizes the relationships between TGF-β signaling and cellular senescence, stem cell aging, and aging-related diseases. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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11 pages, 1237 KiB

Open AccessReview

The Activation Status of the TGF-β Transducer Smad2 Is Associated with a Reduced Survival in Gastrointestinal Cancers: A Systematic Review and Meta-Analysis

by Ilaria Girolami, Nicola Veronese, Lee Smith, Maria G. Caruso, Rosa Reddavide, Gioacchino Leandro, Jacopo Demurtas and Alessia Nottegar

Int. J. Mol. Sci. 2019, 20(15), 3831; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20153831 - 05 Aug 2019

Cited by 6 | Viewed by 6149

Abstract

Aberrant function of Smad2, a crucial member of transforming growth factor beta (TGF-β) signaling, is associated with the development of malignancies, particularly in the gastrointestinal district. However, little is known about its possible prognostic role in such tumor types. With the first meta-analysis on this topic, we demonstrated that the lack of the activated form of Smad2 (phosphor-Smad2 or pSmad2), which was meant to be the C-terminally phosphorylated form, showed a statistically significant association with an increased risk of all-cause mortality in patients with gastrointestinal cancers (RR, 1.58; 95% CI, 1.05–2.37, p = 0.029, I² = 84%), also after having adjusted for potential confounders (RR, 1.65; 95% CI, 1.24–2.18; p < 0.001; I² = 4%). This finding highlights the importance of the TGF-β signaling in this type of cancer. In this line, further studies are needed to explore more in depth this important molecular pathway, focusing also on potential therapeutic strategies based on its effectors or molecular targets. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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