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24 pages, 5404 KiB

Open AccessArticle

Differentiation of Murine C2C12 Myoblasts Strongly Reduces the Effects of Myostatin on Intracellular Signaling

by Juulia H. Lautaoja, Satu Pekkala, Arja Pasternack, Mika Laitinen, Olli Ritvos and Juha J. Hulmi

Biomolecules 2020, 10(5), 695; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050695 - 30 Apr 2020

Cited by 18 | Viewed by 7710

Abstract

Alongside in vivo models, a simpler and more mechanistic approach is required to study the effects of myostatin on skeletal muscle because myostatin is an important negative regulator of muscle size. In this study, myostatin was administered to murine (C2C12) and human (CHQ) [...] Read more.

Alongside in vivo models, a simpler and more mechanistic approach is required to study the effects of myostatin on skeletal muscle because myostatin is an important negative regulator of muscle size. In this study, myostatin was administered to murine (C2C12) and human (CHQ) myoblasts and myotubes. Canonical and noncanonical signaling downstream to myostatin, related ligands, and their receptor were analyzed. The effects of tumorkines were analyzed after coculture of C2C12 and colon cancer-C26 cells. The effects of myostatin on canonical and noncanonical signaling were strongly reduced in C2C12 cells after differentiation. This may be explained by increased follistatin, an endogenous blocker of myostatin and altered expression of activin receptor ligands. In contrast, CHQ cells were equally responsive to myostatin, and follistatin remained unaltered. Both myostatin administration and the coculture stimulated pathways associated with inflammation, especially in C2C12 cells. In conclusion, the effects of myostatin on intracellular signaling may be cell line- or organism-specific, and C2C12 myotubes seem to be a nonoptimal in vitro model for investigating the effects of myostatin on canonical and noncanonical signaling in skeletal muscle. This may be due to altered expression of activin receptor ligands and their regulators during muscle cell differentiation. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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15 pages, 2903 KiB

Open AccessArticle

Activins as Dual Specificity TGF-β Family Molecules: SMAD-Activation via Activin- and BMP-Type 1 Receptors

by Oddrun Elise Olsen, Hanne Hella, Samah Elsaadi, Carsten Jacobi, Erik Martinez-Hackert and Toril Holien

Biomolecules 2020, 10(4), 519; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040519 - 29 Mar 2020

Cited by 30 | Viewed by 7498

Abstract

Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of [...] Read more.

Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of the SMAD1/5/8 pathway. In this study, we aimed to dissect how activin A and activin B homodimers, and activin AB and AC heterodimers activate the two main SMAD branches. We compared the activin-induced signaling dynamics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via the ALK2-SMAD1/5 pathway exhibited greater differences between ligands than signaling via ALK4/ALK7-SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs. As SMAD1/5 was also activated by activins in other cell types, we propose that dual specificity is a general mechanism for activin ligands. In addition, we found that the antagonist follistatin inhibited signaling by all the tested activins, whereas the antagonist cerberus specifically inhibited activin B. Taken together, we propose that activins may be considered dual specificity TGF-β family members, critically affecting how activins may be considered and targeted clinically. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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11 pages, 2545 KiB

Open AccessArticle

BMP-SMAD1/5 Signaling Regulates Retinal Vascular Development

by Andreas Benn, Florian Alonso, Jo Mangelschots, Elisabeth Génot, Marleen Lox and An Zwijsen

Biomolecules 2020, 10(3), 488; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030488 - 23 Mar 2020

Cited by 23 | Viewed by 4895

Abstract

Vascular development is an orchestrated process of vessel formation from pre-existing vessels via sprouting and intussusceptive angiogenesis as well as vascular remodeling to generate the mature vasculature. Bone morphogenetic protein (BMP) signaling via intracellular SMAD1 and SMAD5 effectors regulates sprouting angiogenesis in the [...] Read more.

Vascular development is an orchestrated process of vessel formation from pre-existing vessels via sprouting and intussusceptive angiogenesis as well as vascular remodeling to generate the mature vasculature. Bone morphogenetic protein (BMP) signaling via intracellular SMAD1 and SMAD5 effectors regulates sprouting angiogenesis in the early mouse embryo, but its role in other processes of vascular development and in other vascular beds remains incompletely understood. Here, we investigate the function of SMAD1/5 during early postnatal retinal vascular development using inducible, endothelium-specific deletion of Smad1 and Smad5. We observe the formation of arterial-venous malformations in areas with high blood flow, and fewer and less functional tip cells at the angiogenic front. The vascular plexus region is remarkably hyperdense and this is associated with reduced vessel regression and aberrant vascular loop formation. Taken together, our results highlight important functions of SMAD1/5 during vessel formation and remodeling in the early postnatal retina. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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Review

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38 pages, 4508 KiB

Open AccessReview

TGF-β Signaling

by Kalliopi Tzavlaki and Aristidis Moustakas

Biomolecules 2020, 10(3), 487; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030487 - 23 Mar 2020

Cited by 326 | Viewed by 19224

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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20 pages, 1894 KiB

Open AccessReview

The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

by Susana M. Chuva de Sousa Lopes, Marta S. Alexdottir and Gudrun Valdimarsdottir

Biomolecules 2020, 10(3), 453; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030453 - 13 Mar 2020

Cited by 23 | Viewed by 4456

Abstract

Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of [...] Read more.

Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGFβ) family as it has been shown that the TGFβ family has an important role in human placental development and disease. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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25 pages, 1396 KiB

Open AccessReview

Epicardial TGFβ and BMP Signaling in Cardiac Regeneration: What Lesson Can We Learn from the Developing Heart?

by Esther Dronkers, Manon M. M. Wauters, Marie José Goumans and Anke M. Smits

Biomolecules 2020, 10(3), 404; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030404 - 05 Mar 2020

Cited by 14 | Viewed by 4012

Abstract

The epicardium, the outer layer of the heart, has been of interest in cardiac research due to its vital role in the developing and diseased heart. During development, epicardial cells are active and supply cells and paracrine cues to the myocardium. In the [...] Read more.

The epicardium, the outer layer of the heart, has been of interest in cardiac research due to its vital role in the developing and diseased heart. During development, epicardial cells are active and supply cells and paracrine cues to the myocardium. In the injured adult heart, the epicardium is re-activated and recapitulates embryonic behavior that is essential for a proper repair response. Two indispensable processes for epicardial contribution to heart tissue formation are epithelial to mesenchymal transition (EMT), and tissue invasion. One of the key groups of cytokines regulating both EMT and invasion is the transforming growth factor β (TGFβ) family, including TGFβ and Bone Morphogenetic Protein (BMP). Abundant research has been performed to understand the role of TGFβ family signaling in the developing epicardium. However, less is known about signaling in the adult epicardium. This review provides an overview of the current knowledge on the role of TGFβ in epicardial behavior both in the development and in the repair of the heart. We aim to describe the presence of involved ligands and receptors to establish if and when signaling can occur. Finally, we discuss potential targets to improve the epicardial contribution to cardiac repair as a starting point for future investigation. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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17 pages, 1268 KiB

Open AccessFeature PaperReview

Endoglin: Beyond the Endothelium

by Mark J.A. Schoonderwoerd, Marie-Jose T.H. Goumans and Lukas J.A.C. Hawinkels

Biomolecules 2020, 10(2), 289; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020289 - 12 Feb 2020

Cited by 62 | Viewed by 5135

Abstract

Keywords: endoglin; CD105 TGF-β; BMP9; ALK-1; TRC105; tumor microenvironment Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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18 pages, 1971 KiB

Open AccessFeature PaperEditor’s ChoiceReview

A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment

by Linh Khanh Huynh, Christopher John Hipolito and Peter ten Dijke

Biomolecules 2019, 9(11), 743; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9110743 - 17 Nov 2019

Cited by 128 | Viewed by 11873

Abstract

Transforming growth factor (TGF)-β is a secreted multifunctional cytokine that signals via plasma membrane TGF-β type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-β signaling can contribute to cancer progression. In normal cells and early stages [...] Read more.

Transforming growth factor (TGF)-β is a secreted multifunctional cytokine that signals via plasma membrane TGF-β type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-β signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-β can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-β in cancer cells are blocked, TGF-β signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-β signaling in cancer and summarize the clinical status of TGF-β signaling inhibitors that interfere with TGF−β bioavailability, TGF-β/receptor interaction, or TGF-β receptor kinase function. Moreover, we will discuss targeting of TGF-β signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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23 pages, 2682 KiB

Open AccessReview

Interplay between BMPs and Reactive Oxygen Species in Cell Signaling and Pathology

by Cristina Sánchez-de-Diego, José Antonio Valer, Carolina Pimenta-Lopes, José Luis Rosa and Francesc Ventura

Biomolecules 2019, 9(10), 534; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9100534 - 26 Sep 2019

Cited by 27 | Viewed by 5214

Abstract

The integration of cell extrinsic and intrinsic signals is required to maintain appropriate cell physiology and homeostasis. Bone morphogenetic proteins (BMPs) are cytokines that belong to the transforming growth factor-β (TGF-β) superfamily, which play a key role in embryogenesis, organogenesis and regulation of [...] Read more.

The integration of cell extrinsic and intrinsic signals is required to maintain appropriate cell physiology and homeostasis. Bone morphogenetic proteins (BMPs) are cytokines that belong to the transforming growth factor-β (TGF-β) superfamily, which play a key role in embryogenesis, organogenesis and regulation of whole-body homeostasis. BMPs interact with membrane receptors that transduce information to the nucleus through SMAD-dependent and independent pathways, including PI3K-AKT and MAPKs. Reactive oxygen species (ROS) are intracellular molecules derived from the partial reduction of oxygen. ROS are highly reactive and govern cellular processes by their capacity to regulate signaling pathways (e.g., NF-κB, MAPKs, KEAP1-NRF2 and PI3K-AKT). Emerging evidence indicates that BMPs and ROS interplay in a number of ways. BMPs stimulate ROS production by inducing NOX expression, while ROS regulate the expression of several BMPs. Moreover, BMPs and ROS influence common signaling pathways, including PI3K/AKT and MAPK. Additionally, dysregulation of BMPs and ROS occurs in several pathologies, including vascular and musculoskeletal diseases, obesity, diabetes and kidney injury. Here, we review the current knowledge on the integration between BMP and ROS signals and its potential applications in the development of new therapeutic strategies. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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14 pages, 826 KiB

Open AccessReview

The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

by Chia-Jung Li, Pei-Yi Chu, Giou-Teng Yiang and Meng-Yu Wu

Biomolecules 2019, 9(9), 476; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9090476 - 11 Sep 2019

Cited by 22 | Viewed by 4004

Abstract

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of [...] Read more.

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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