scholarly journals Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2070
Author(s):  
Pasquale Esposito ◽  
Daniela Verzola ◽  
Daniela Picciotto ◽  
Leda Cipriani ◽  
Francesca Viazzi ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Vascular Inflammation ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Activin A ◽  
Premature Aging ◽  
High Morbidity ◽  
Type I

A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.

scholarly journals Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone β subunit transcription

2007 ◽  
Vol 38 (2) ◽  
pp. 315-330 ◽  
Author(s):  
Katharine B Lee ◽  
Vishal Khivansara ◽  
Michelle M Santos ◽  
Pankaj Lamba ◽  
Tony Yuen ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Activin A ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Mrna Levels ◽  
Signaling Mechanism ◽  
Morphogenetic Protein

Transforming growth factor β superfamily ligands regulate pituitary FSH production and secretion. The best-described examples are the activins and inhibins, which respectively stimulate and hinder Fshb subunit transcription in gonadotrope cells. More recently, members of the bone morphogenetic protein (BMP) sub-family were shown to regulate FSH production in a manner analogous to the activins. Here, we used the murine gonadotrope cell line, LβT2, to investigate mechanisms through which BMP2 regulates the Fshb gene. Although expressed at low levels in LβT2 cells, Bmp2 mRNA was readily detected in adult murine pituitary gland. Recombinant BMP2 stimulated Fshb promoter-reporter activity, although its effects were weaker than those of equimolar activin A or B. BMP4 stimulated transcription comparably with BMP2, but BMPs 6 and 7 were about tenfold less potent. Remarkably, BMP2 and activin A synergistically upregulated Fshb transcription and endogenous Fshb mRNA levels in LβT2 cells. Although functionally cooperative, the two ligands appeared to use distinct intracellular mechanisms to mediate their responses because neither ligand altered the timing or magnitude of the other’s effects. Receptor overexpression analyses suggested that BMP2 may preferentially signal through complexes of the type II receptor, BMPR2, and the type I receptor, activin receptor like kinase (ALK2; Acvr1), to stimulate Fshb transcription. BMP2 rapidly activated the Smad1/5/8 intracellular signaling cascade and Smad8 overexpression potentiated BMP2’s effects. In summary, BMPs regulate Fshb transcription in LβT2 cells and can amplify the already robust effects of the activins through a distinct signaling mechanism. Because BMP2 is expressed in the adult mouse pituitary, it may act as critical paracrine co-regulator of FSH synthesis by gonadotropes.

scholarly journals Integrin β1Signaling Is Necessary for Transforming Growth Factor-β Activation of p38MAPK and Epithelial Plasticity

2001 ◽  
Vol 276 (50) ◽  
pp. 46707-46713 ◽  
Author(s):  
Neil A. Bhowmick ◽  
Roy Zent ◽  
Mayshan Ghiassi ◽  
Maureen McDonnell ◽  
Harold L. Moses
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Transcriptional Activation ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Receptor Expression ◽  
Type I ◽  
Type Ii

Transforming growth factor-β (TGF-β) can induce epithelial to mesenchymal transdifferentiation (EMT) in mammary epithelial cells. TGF-β-meditated EMT involves the stimulation of a number of signaling pathways by the sequential binding of the type II and type I serine/threonine kinase receptors, respectively. Integrins comprise a family of heterodimeric extracellular matrix receptors that mediate cell adhesion and intracellular signaling, hence making them crucial for EMT progression. In light of substantial evidence indicating TGF-β regulation of various β1integrins and their extracellular matrix ligands, we examined the cross-talk between the TGF-β and integrin signal transduction pathways. Using an inducible system for the expression of a cytoplasmically truncated dominant negative TGF-β type II receptor, we blocked TGF-β-mediated growth inhibition, transcriptional activation, and EMT progression. Dominant negative TGF-β type II receptor expression inhibited TGF-β signaling to the SMAD and AKT pathways, but did not block TGF-β-mediated p38MAPK activation. Interestingly, blocking integrin β1function inhibited TGF-β-mediated p38MAPK activation and EMT progression. Limiting p38MAPK activity through the expression of a dominant negative-p38MAPK also blocked TGF-β-mediated EMT. In summary, TGF-β-mediated p38MAPK activation is dependent on functional integrin β1, and p38MAPK activity is required but is not sufficient to induce EMT.

Smad7 selectively interferes with different pathways of activin signaling and inhibits erythroid leukemia cell differentiation

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3371-3379 ◽  
Author(s):  
Koki Kitamura ◽  
Shin-ichi Aota ◽  
Ruriko Sakamoto ◽  
Shun-Ichi Yoshikawa ◽  
Kenji Okazaki
Keyword(s):  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Leukemia Cell ◽  
Transcriptional Response ◽  
Erythroid Differentiation ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Type Ii ◽  
Smad7 Expression ◽  
Ectopic Production

Smad family proteins are essential for transforming growth factor β (TGF-β) signal mediation downstream of a heteromeric complex of the type I and type II receptor serine/threonine kinases. A distant family member, Smad7, is expressed in most mammalian tissues and cells and prevents TGF-β signaling. In this study, we examined the physiologic role of Smad7 in mediating the effects of activin, a member of the TGF-β superfamily of peptides that functions in a number of processes, including blood-cell development. We report here that Smad7 expression is specifically absent in particular hematopoietic cells that respond to activin by differentiating into the erythroid lineage and that ectopic production of Smad7 causes mouse erythroid leukemia (F5-5) cells to become resistant to activin induction of erythroid differentiation. When coexpressed with type I activin receptor ActR-I or ActR-IB in concert with type II receptor ActR-II, Smad7 efficiently reduced an early transcriptional response mediated by ActR-I but had only a minimal effect on the response mediated by ActR-IB. In the presence of Smad7, overexpression of an activated form of ActR-IB, but not of an activated form of ActR-I, induced F5-5 cells to differentiate. These results suggest that Smad7 selectively interferes with the ActR-I pathway in activin signal transduction. The findings also indicate the existence of a novel activity of Smad7 that inhibits erythroid differentiation by blocking intracellular signaling of activin.

scholarly journals Nodal signalling and apoptosis

Reproduction ◽  
2007 ◽  
Vol 133 (5) ◽  
pp. 847-853 ◽  
Author(s):  
Hongmei Wang ◽  
Benjamin K Tsang
Keyword(s):  
Transforming Growth Factor ◽  
Biological Effects ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Type I ◽  
Type Ii ◽  
Human Trophoblast ◽  
Adult Tissues ◽  
Ovarian Epithelial Cancer ◽  
Smad Proteins

Nodal, a member of the transforming growth factor β family, was first cloned from a 7.5 day post-coitum mouse embryo cDNA library. Nodal exerts its biological effects by signalling through its types I and II serine/threonine kinase receptor complex and intracellular Smad proteins. The type II receptors for Nodal are Activin type II receptors ActRIIA and ActRIIB, whereas the putative type I receptors are Activin receptor like kinase (ALK) 4 and ALK7. The main Smad proteins involved in Nodal signalling are Smad2 and Smad3. Studies of Nodal in adult tissues indicate that it is pro-apoptotic in rat ovarian granulosa cells, human trophoblast cells and human ovarian epithelial cancer cells and is growth inhibitory in the latter two cell types. This review summarises the progress made on the functions of Nodal in the apoptosis of adult tissues, especially in the ovary and placenta.

scholarly journals Activins regulate 17β-hydroxysteroid dehydrogenase type I transcription in murine gonadotrope cells

2009 ◽  
Vol 201 (1) ◽  
pp. 89-104 ◽  
Author(s):  
Beata Bak ◽  
Laura Carpio ◽  
Jinjing L Kipp ◽  
Pankaj Lamba ◽  
Ying Wang ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Intracellular Signaling ◽  
Cell Types ◽  
Hydroxysteroid Dehydrogenase ◽  
Activin A ◽  
Type I ◽  
Promoter Regions ◽  
Gene Encoding ◽  
17Β Estradiol ◽  
Smad Binding Element

Activins are pleiotropic members of the TGFβ superfamily and were initially characterized based on their abilities to stimulate FSH synthesis and secretion by gonadotrope cells of the anterior pituitary gland. Here, we identified the gene encoding the steroidogenic enzyme, 17β-hydroxysteroid dehydrogenase type I (17β-HSD1; Hsd17b1), as an activin-responsive gene in immortalized gonadotrope cells, LβT2. 17β-HSD1 catalyzes the conversion of estrone to the more active 17β-estradiol, and activin A stimulated an increase in this enzymatic activity in these cells. We demonstrated that activins signaled via the type I receptor, activin receptor-like kinase (ALK4), and the intracellular signaling protein, SMAD2, to regulate Hsd17b1 transcription in immediate-early fashion. Critical cis-elements, including a minimal SMAD-binding element, were mapped to within 100 bp of the start of transcription. Activin/ALK4 signaling also regulated Hsd17b1 transcription in both immortalized and primary cultured murine granulosa cells. The promoter regions mediating basal and activin/ALK4-regulated promoter activity were generally conserved across the different cell types. The data show that activin A rapidly regulates Hsd17b1 transcription in gonadotrope and granulosa cells and may thereby regulate local 17β-estradiol synthesis.

Smad7 selectively interferes with different pathways of activin signaling and inhibits erythroid leukemia cell differentiation

Blood ◽  
2000 ◽  
Vol 95 (11) ◽  
pp. 3371-3379 ◽  
Author(s):  
Koki Kitamura ◽  
Shin-ichi Aota ◽  
Ruriko Sakamoto ◽  
Shun-Ichi Yoshikawa ◽  
Kenji Okazaki
Keyword(s):  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Leukemia Cell ◽  
Transcriptional Response ◽  
Erythroid Differentiation ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Type Ii ◽  
Smad7 Expression ◽  
Ectopic Production

Abstract Smad family proteins are essential for transforming growth factor β (TGF-β) signal mediation downstream of a heteromeric complex of the type I and type II receptor serine/threonine kinases. A distant family member, Smad7, is expressed in most mammalian tissues and cells and prevents TGF-β signaling. In this study, we examined the physiologic role of Smad7 in mediating the effects of activin, a member of the TGF-β superfamily of peptides that functions in a number of processes, including blood-cell development. We report here that Smad7 expression is specifically absent in particular hematopoietic cells that respond to activin by differentiating into the erythroid lineage and that ectopic production of Smad7 causes mouse erythroid leukemia (F5-5) cells to become resistant to activin induction of erythroid differentiation. When coexpressed with type I activin receptor ActR-I or ActR-IB in concert with type II receptor ActR-II, Smad7 efficiently reduced an early transcriptional response mediated by ActR-I but had only a minimal effect on the response mediated by ActR-IB. In the presence of Smad7, overexpression of an activated form of ActR-IB, but not of an activated form of ActR-I, induced F5-5 cells to differentiate. These results suggest that Smad7 selectively interferes with the ActR-I pathway in activin signal transduction. The findings also indicate the existence of a novel activity of Smad7 that inhibits erythroid differentiation by blocking intracellular signaling of activin.

Activin-A: a novel dendritic cell–derived cytokine that potently attenuates CD40 ligand–specific cytokine and chemokine production

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2733-2743 ◽  
Author(s):  
Neil C. Robson ◽  
David J. Phillips ◽  
Tristan McAlpine ◽  
Amanda Shin ◽  
Suzanne Svobodova ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Human Monocyte ◽  
Transforming Growth Factor Β ◽  
Cd40 Ligand ◽  
Activin A ◽  
Type I ◽  
Chemokine Production ◽  
Specific Effector ◽  
Factor Α

Activin-A is a transforming growth factor-β (TGF-β) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immune-regulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells (DCs) to stimulate immune responses. Human monocyte-derived DCs (MoDCs) and the CD1c+ and CD123+ peripheral blood DC populations express both activin-A and the type I and II activin receptors. Furthermore, MoDCs and CD1c+ myeloid DCs rapidly secrete high levels of activin-A after exposure to bacteria, specific toll-like receptor (TLR) ligands, or CD40 ligand (CD40L). Blocking autocrine activin-A signaling in DCs using its antagonist, follistatin, enhanced DC cytokine (IL-6, IL-10, IL-12p70, and tumor necrosis factor-α [TNF-α]) and chemokine (IL-8, IP-10, RANTES, and MCP-1) production during CD40L stimulation, but not TLR-4 ligation. Moreover, antagonizing DC-derived activin-A resulted in significantly enhanced expansion of viral antigen-specific effector CD8+ T cells. These findings establish an immune-regulatory role for activin-A in DCs, highlighting the potential of antagonizing activin-A signaling in vivo to enhance vaccine immunogenicity.

scholarly journals Therapeutic blockade of activin-A improves NK cell function and antitumor immunity

2019 ◽  
Vol 12 (596) ◽  
pp. eaat7527 ◽  
Author(s):  
Jai Rautela ◽  
Laura F. Dagley ◽  
Carolina C. de Oliveira ◽  
Iona S. Schuster ◽  
Soroor Hediyeh-Zadeh ◽  
...  
Keyword(s):  
Nk Cells ◽  
Antitumor Immunity ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Nk Cell ◽  
Transforming Growth Factor Β ◽  
Activin A ◽  
Cell Surface Expression ◽  
Type I ◽  
Cell Suppression

Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastatic spread. The signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming growth factor–β (TGF-β) is a suppressor of NK cells that inhibits interleukin-15 (IL-15)–dependent signaling events and increases the abundance of receptors that promote tissue residency. Here, we showed that NK cells express the type I activin receptor ALK4, which, upon binding to its ligand activin-A, phosphorylated SMAD2/3 to suppress IL-15–mediated NK cell metabolism. Activin-A impaired human and mouse NK cell proliferation and reduced the production of granzyme B to impair tumor killing. Similar to TGF-β, activin-A also induced SMAD2/3 phosphorylation and stimulated NK cells to increase their cell surface expression of several markers of ILC1 cells. Activin-A also induced these changes in TGF-β receptor–deficient NK cells, suggesting that activin-A and TGF-β stimulate independent pathways that drive SMAD2/3-mediated NK cell suppression. Last, inhibition of activin-A by follistatin substantially slowed orthotopic melanoma growth in mice. These data highlight the relevance of examining TGF-β–independent SMAD2/3 signaling mechanisms as a therapeutic axis to relieve NK cell suppression and promote antitumor immunity.

scholarly journals Activin A upregulates PTGS2 expression and increases PGE2 production in human granulosa-lutein cells

Reproduction ◽  
2016 ◽  
Vol 152 (6) ◽  
pp. 655-664 ◽  
Author(s):  
Pang-Pin Liu ◽  
Hsun-Ming Chang ◽  
Jung-Chien Cheng ◽  
Peter C K Leung
Keyword(s):  
Corpus Luteum ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Activin A ◽  
Pge2 Production ◽  
Type I ◽  
Small Interfering Rnas ◽  
Luteal Function ◽  
Downstream Signaling

Activin A is one of the members of transforming growth factor-β superfamily that is expressed in human large luteal cells, and may act in an autocrine/paracrine manner to regulate luteal function. Prostaglandin-endoperoxide synthase 2 (PTGS2) enzyme and its derivative, prostaglandin E2 (PGE2), play significant roles in the regulation of corpus luteum formation and maintenance. To date, whether activin A can induce the expression of PTGS2 and the production of PGE2 in human granulosa-lutein cells is largely unknown. The aim of this study was to examine the effects of activin A on the regulation of PTGS2 expression and PGE2 production in human granulosa-lutein cells, and to investigate the underlying signal transduction mechanisms. In this study, the immortalized (SVOG cells) and primary human granulosa-lutein cells were used as the cell models. A TGF-β/activin type I receptor inhibitor, SB431542 and small interfering RNAs were used to investigate the activin A-induced downstream signaling pathway. We have demonstrated that activin A upregulated the expression of PTGS2 and increased the production of PGE2 via an ACVR1B-mediated SMAD2/3–SMAD4 signaling pathway. Our results suggest that activin A may be involved in the modulation of human corpus luteum formation via the induction of PTGS2 expression and PGE2 production.

scholarly journals TGFβ induces SIK to negatively regulate type I receptor kinase signaling

2008 ◽  
Vol 182 (4) ◽  
pp. 655-662 ◽  
Author(s):  
Marcin Kowanetz ◽  
Peter Lönn ◽  
Michael Vanlandewijck ◽  
Katarzyna Kowanetz ◽  
Carl-Henrik Heldin ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Negative Regulator ◽  
Type I ◽  
Gene Target ◽  
Smad Proteins ◽  
Tgfβ Receptor ◽  
Receptor Kinase Signaling ◽  
Feedback Program

Signal transduction by transforming growth factor β (TGFβ) coordinates physiological responses in diverse cell types. TGFβ signals via type I and type II receptor serine/threonine kinases and intracellular Smad proteins that regulate transcription. Strength and duration of TGFβ signaling is largely dependent on a negative-feedback program initiated during signal progression. We have identified an inducible gene target of TGFβ/Smad signaling, the salt-inducible kinase (SIK), which negatively regulates signaling together with Smad7. SIK and Smad7 form a complex and cooperate to down-regulate the activated type I receptor ALK5. We further show that both the kinase and ubiquitin-associated domain of SIK are required for proper ALK5 degradation, with ubiquitin functioning to enhance SIK-mediated receptor degradation. Loss of endogenous SIK results in enhanced gene responses of the fibrotic and cytostatic programs of TGFβ. We thus identify in SIK a negative regulator that controls TGFβ receptor turnover and physiological signaling.

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