scholarly journals Extracellular BMP Antagonists, Multifaceted Orchestrators in the Tumor and Its Microenvironment

2020 ◽  
Vol 21 (11) ◽  
pp. 3888
Author(s):  
Sarah Ouahoud ◽  
James C.H. Hardwick ◽  
Lukas J.A.C. Hawinkels
Keyword(s):  
Cancer Progression ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Biological Processes ◽  
Adult Tissue ◽  
Aberrant Expression ◽  
Bmp Pathway ◽  
Bmp Antagonists

The bone morphogenetic proteins (BMPs), a subgroup of the transforming growth factor-β (TGF-β) superfamily, are involved in multiple biological processes such as embryonic development and maintenance of adult tissue homeostasis. The importance of a functional BMP pathway is underlined by various diseases, including cancer, which can arise as a consequence of dysregulated BMP signaling. Mutations in crucial elements of this signaling pathway, such as receptors, have been reported to disrupt BMP signaling. Next to that, aberrant expression of BMP antagonists could also contribute to abrogated signaling. In this review we set out to highlight how BMP antagonists affect not only the cancer cells, but also the other cells present in the microenvironment to influence cancer progression.

scholarly journals Dichotomous roles of TGF-β in human cancer

2016 ◽  
Vol 44 (5) ◽  
pp. 1441-1454 ◽  
Author(s):  
Jennifer J. Huang ◽  
Gerard C. Blobe
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Human Cancer ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Biological Processes ◽  
Cellular Homeostasis ◽  
Angiogenic Therapy ◽  
Promising Strategy

Transforming growth factor-β (TGF-β) mediates numerous biological processes, including embryonic development and the maintenance of cellular homeostasis in a context-dependent manner. Consistent with its central role in maintaining cellular homeostasis, inhibition of TGF-β signaling results in disruption of normal homeostatic processes and subsequent carcinogenesis, defining the TGF-β signaling pathway as a tumor suppressor. However, once carcinogenesis is initiated, the TGF-β signaling pathway promotes cancer progression. This dichotomous function of the TGF-β signaling pathway is mediated through altering effects on both the cancer cells, by inducing apoptosis and inhibiting proliferation, and the tumor microenvironment, by promoting angiogenesis and inhibiting immunosurveillance. Current studies support inhibition of TGF-β signaling either alone, or in conjunction with anti-angiogenic therapy or immunotherapy as a promising strategy for the treatment of human cancers.

Bone Morphogenetic Proteins and Their Receptors in the Eye

2007 ◽  
Vol 232 (8) ◽  
pp. 979-992 ◽  
Author(s):  
Robert J. Wordinger ◽  
Abbot F. Clark
Keyword(s):  
Growth Factor ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Receptor Expression ◽  
Future Research ◽  
Cellular Functions ◽  
Ocular Tissues ◽  
Bmp Receptors

The human genome encodes at least 42 different members of the transforming growth factor-β superfamily of growth factors. Bone morphogenetic proteins (BMPs) are the largest subfamily of proteins within the transforming growth factor-β superfamily and are involved in numerous cellular functions including development, morphogenesis, cell proliferation, apoptosis, and extracellular matrix synthesis. This article first reviews BMPs and BMP receptors, BMP signaling pathways, and mechanisms controlling BMP signaling. Second, we review BMP and BMP receptor expression during embryonic ocular development/ differentiation and in adult ocular tissues. Lastly, future research directions with respect to BMP, BMP receptors, and ocular tissues are suggested.

scholarly journals The Role of BMP Signaling in Female Reproductive System Development and Function

2021 ◽  
Vol 22 (21) ◽  
pp. 11927
Author(s):  
Esmeralda Magro-Lopez ◽  
María Ángeles Muñoz-Fernández
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Reproductive System ◽  
Transforming Growth Factor ◽  
Current Knowledge ◽  
System Development ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Female Reproductive System ◽  
And Function

Bone morphogenetic proteins (BMPs) are a group of multifunctional growth factors that belong to the transforming growth factor-β (TGF-β) superfamily of proteins. Originally identified by their ability to induce bone formation, they are now known as essential signaling molecules that regulate the development and function of the female reproductive system (FRS). Several BMPs play key roles in aspects of reproductive system development. BMPs have also been described to be involved in the differentiation of human pluripotent stem cells (hPSCs) into reproductive system tissues or organoids. The role of BMPs in the reproductive system is still poorly understood and the use of FRS tissue or organoids generated from hPSCs would provide a powerful tool for the study of FRS development and the generation of new therapeutic perspectives for the treatment of FRS diseases. Therefore, the aim of this review is to summarize the current knowledge about BMP signaling in FRS development and function.

GDF-15: A Multifunctional Modulator and Potential Therapeutic Target in Cancer

2019 ◽  
Vol 25 (6) ◽  
pp. 654-662 ◽  
Author(s):  
Lei Fang ◽  
Fengzhou Li ◽  
Chundong Gu
Keyword(s):  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Immune Escape ◽  
Cell Formation ◽  
Transforming Growth Factor Β ◽  
Response To Therapy ◽  
Potential Therapeutic Target ◽  
Aberrant Expression ◽  
Basic Functions ◽  
And Function

Various pathological processes are associated with the aberrant expression and function of cytokines, especially those belonging to the transforming growth factor-β (TGF-β) family. Nevertheless, the functions of members of the TGF-β family in cancer progression and therapy are still uncertain. Growth differentiation factor- 15, which exists in intracellular and extracellular forms, is classified as a divergent member of the TGF-β superfamily. It has been indicated that GDF-15 is also connected to the evolution of cancer both positively and negatively depending upon the cellular state and environment. Under normal physiological conditions, GDF-15 inhibits early tumour promotion. However, its abnormal expression in advanced cancers causes proliferation, invasion, metastasis, cancer stem cell formation, immune escape and a reduced response to therapy. As a clinical indicator, GDF-15 can be used as a tool for the diagnosis and therapy of an extensive scope of cancers. Although some basic functions of GDF-15 are noncontroversial, their mechanisms remain unclear and complicated at the molecular level. Therefore, GDF-15 needs to be further explored and reviewed.

scholarly journals The N domain of Smad7 is essential for specific inhibition of transforming growth factor-β signaling

2001 ◽  
Vol 155 (6) ◽  
pp. 1017-1028 ◽  
Author(s):  
Aki Hanyu ◽  
Yasuhiro Ishidou ◽  
Takanori Ebisawa ◽  
Tomomasa Shimanuki ◽  
Takeshi Imamura ◽  
...  
Keyword(s):  
Growth Factor ◽  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Amino Acid Sequences ◽  
Bmp Signaling ◽  
Type I ◽  
Specific Inhibition ◽  
Amino Terminal ◽  
Carboxy Terminal

Inhibitory Smads (I-Smads) repress signaling by cytokines of the transforming growth factor-β (TGF-β) superfamily. I-Smads have conserved carboxy-terminal Mad homology 2 (MH2) domains, whereas the amino acid sequences of their amino-terminal regions (N domains) are highly divergent from those of other Smads. Of the two different I-Smads in mammals, Smad7 inhibited signaling by both TGF-β and bone morphogenetic proteins (BMPs), whereas Smad6 was less effective in inhibiting TGF-β signaling. Analyses using deletion mutants and chimeras of Smad6 and Smad7 revealed that the MH2 domains were responsible for the inhibition of both TGF-β and BMP signaling by I-Smads, but the isolated MH2 domains of Smad6 and Smad7 were less potent than the full-length Smad7 in inhibiting TGF-β signaling. The N domains of I-Smads determined the subcellular localization of these molecules. Chimeras containing the N domain of Smad7 interacted with the TGF-β type I receptor (TβR-I) more efficiently, and were more potent in repressing TGF-β signaling, than those containing the N domain of Smad6. The isolated N domain of Smad7 physically interacted with the MH2 domain of Smad7, and enhanced the inhibitory activity of the latter through facilitating interaction with TGF-β receptors. The N domain of Smad7 thus plays an important role in the specific inhibition of TGF-β signaling.

scholarly journals Cooperative Inhibition of Bone Morphogenetic Protein Signaling by Smurf1 and Inhibitory Smads

2003 ◽  
Vol 14 (7) ◽  
pp. 2809-2817 ◽  
Author(s):  
Gyo Murakami ◽  
Tetsuro Watabe ◽  
Kunio Takaoka ◽  
Kohei Miyazono ◽  
Takeshi Imamura
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Type I ◽  
Protein Signaling ◽  
Reporter Construct ◽  
Bone Morphogenetic Protein Signaling ◽  
Morphogenetic Protein

Smad ubiquitin regulatory factor (Smurf) 1 binds to receptor-regulated Smads for bone morphogenetic proteins (BMPs) Smad1/5 and promotes their degradation. In addition, Smurf1 associates with transforming growth factor-β type I receptor through the inhibitory Smad (I-Smad) Smad7 and induces their degradation. Herein, we examined whether Smurf1 negatively regulates BMP signaling together with the I-Smads Smad6/7. Smurf1 and Smad6 cooperatively induced secondary axes in Xenopus embryos. Using a BMP-responsive promoter-reporter construct in mammalian cells, we found that Smurf1 cooperated with I-Smad in inhibiting BMP signaling and that the inhibitory activity of Smurf1 was not necessarily correlated with its ability to bind to Smad1/5 directly. Smurf1 bound to BMP type I receptors via I-Smads and induced ubiquitination and degradation of these receptors. Moreover, Smurf1 associated with Smad1/5 indirectly through I-Smads and induced their ubiquitination and degradation. Smurf1 thus controls BMP signaling with and without I-Smads through multiple mechanisms.

scholarly journals TGFβ/BMP Signaling Pathway in Cartilage Homeostasis

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 969 ◽  
Author(s):  
Nathalie Thielen ◽  
Peter van der Kraan ◽  
Arjan van Caam
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Articular Chondrocytes ◽  
Family Members ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Cartilage Homeostasis ◽  
Cartilage Biology ◽  
Matrix Production

Cartilage homeostasis is governed by articular chondrocytes via their ability to modulate extracellular matrix production and degradation. In turn, chondrocyte activity is regulated by growth factors such as those of the transforming growth factor β (TGFβ) family. Members of this family include the TGFβs, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs). Signaling by this protein family uniquely activates SMAD-dependent signaling and transcription but also activates SMAD-independent signaling via MAPKs such as ERK and TAK1. This review will address the pivotal role of the TGFβ family in cartilage biology by listing several TGFβ family members and describing their signaling and importance for cartilage maintenance. In addition, it is discussed how (pathological) processes such as aging, mechanical stress, and inflammation contribute to altered TGFβ family signaling, leading to disturbed cartilage metabolism and disease.

scholarly journals The Interactivity between TGFβ and BMP Signaling in Organogenesis, Fibrosis, and Cancer

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1130 ◽  
Author(s):  
Francesco Dituri ◽  
Carla Cossu ◽  
Serena Mancarella ◽  
Gianluigi Giannelli
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Bmp Signaling ◽  
Tissue Homeostasis ◽  
Adult Tissue ◽  
Developmental Defects ◽  
Cellular Processes ◽  
Bmp Pathway ◽  
Growth Factor Beta ◽  
Multiple Signaling

The Transforming Growth Factor beta (TGFβ) and Bone Morphogenic Protein (BMP) pathways intersect at multiple signaling hubs and cooperatively or counteractively participate to bring about cellular processes which are critical not only for tissue morphogenesis and organogenesis during development, but also for adult tissue homeostasis. The proper functioning of the TGFβ/BMP pathway depends on its communication with other signaling pathways and any deregulation leads to developmental defects or diseases, including fibrosis and cancer. In this review we explore the cellular and physio-pathological contexts in which the synergism or antagonism between the TGFβ and BMP pathways are crucial determinants for the normal developmental processes, as well as the progression of fibrosis and malignancies.

scholarly journals Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski

2004 ◽  
Vol 15 (3) ◽  
pp. 963-972 ◽  
Author(s):  
Masafumi Takeda ◽  
Masafumi Mizuide ◽  
Masako Oka ◽  
Tetsuro Watabe ◽  
Hirofumi Inoue ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Histone Deacetylases ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Osteoblastic Differentiation ◽  
Bmp Signaling ◽  
C2c12 Cells ◽  
Luciferase Reporter ◽  
Activin Signaling

c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor-β (TGF-β) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-β/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-β–induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-β/activin signaling.

Inhibition of apelin expression by BMP signaling in endothelial cells

2012 ◽  
Vol 303 (11) ◽  
pp. C1139-C1145 ◽  
Author(s):  
Odette Poirier ◽  
Mariana Ciumas ◽  
Mélanie Eyries ◽  
Kevin Montagne ◽  
Sophie Nadaud ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Vascular Diseases ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Bmp Signaling ◽  
Gene Encoding ◽  
Major Pathway ◽  
Bmp Pathway ◽  
Microvascular Cells

The transforming growth factor-β/bone morphogenic protein (BMP) system is a major pathway for angiogenesis and is involved in hereditary vascular diseases. Here we report that the gene encoding the vasoactive and vascular cell growth-regulating peptide apelin is a target of the BMP pathway. We demonstrate that apelin expression is strongly downregulated by BMP in an endothelial cell line as well as in lung endothelial microvascular cells. We show that BMP signals through the BMPR2-SMAD pathway to downregulate apelin expression and that a transcriptional direct and indirect mechanism is required. The BMP-induced downregulation of apelin expression was found to be critical for hypoxia-induced growth of endothelial cells, because the growth inhibitory effect of BMP in this condition is suppressed by enforced expression of apelin. Thus, we describe an important link between a signaling pathway involved in angiogenesis and vascular diseases and a peptide regulating vascular homeostasis.

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