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

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.

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

Blood ◽

10.1182/blood.v95.11.3371.011k37_3371_3379 ◽

2000 ◽

Vol 95 (11) ◽

pp. 3371-3379 ◽

Cited By ~ 1

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.

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

Journal of Biological Chemistry ◽

10.1074/jbc.m106176200 ◽

2001 ◽

Vol 276 (50) ◽

pp. 46707-46713 ◽

Cited By ~ 264

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.

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

Cells ◽

10.3390/cells10082070 ◽

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.

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Activin receptor-like kinase-2 inhibits activin signaling by blocking the binding of activin to its type II receptor

Journal of Endocrinology ◽

10.1677/joe-07-0281 ◽

2007 ◽

Vol 195 (1) ◽

pp. 95-103 ◽

Cited By ~ 19

Author(s):

Nina Renlund ◽

Francis H O’Neill ◽

LiHua Zhang ◽

Yisrael Sidis ◽

Jose Teixeira

Keyword(s):

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Underlying Mechanism ◽

Luciferase Reporter ◽

Type I ◽

Type Ii ◽

Activin Receptor ◽

Activin Signaling ◽

Endogenous Expression ◽

Receptor Like Kinase

Activin receptor-like kinase-2 (Alk2) has been shown to be a promiscuous type I receptor for the transforming growth factor β (TGFβ) family of growth and differentiation factors, such as activin, bone morphogenetic proteins, and Müllerian inhibiting substance (MIS). We have studied the putative role of Alk2 in activin signaling using MA-10 cells, a mouse transformed Leydig cell line, in which endogenous expression of cytochrome P450 c17 hydroxylase/C17–20 lyase mRNA is inhibited by both MIS and activin A. Overexpression of Alk2 in MA-10 cells inhibited the activation of the activin-responsive CAGA-luciferase reporter and, conversely, transfection of siRNA for Alk2 increased the response. In contrast, overexpression of the MIS type II receptor in MA-10 cells increased the activin-mediated induction of CAGA-luciferase approximately fivefold, which we hypothesized occurs by MIS type II receptor sequestering endogenous Alk2. Binding experiments with 125I-labeled activin show that the underlying mechanism of Alk2-mediated inhibition of activin signaling involves Alk2 blocking the access of activin to its type II receptor, which we show can bind Alk2 in the absence of ligand. These results show that the complement of other type I receptors in addition to the ligand-specific type I receptor can provide an important mechanism for modulating cell-specific responses to members of the TGFβ family.

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Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs.

Molecular and Cellular Biology ◽

10.1128/mcb.15.7.3479 ◽

1995 ◽

Vol 15 (7) ◽

pp. 3479-3486 ◽

Cited By ~ 399

Author(s):

F Liu ◽

F Ventura ◽

J Doody ◽

J Massagué

Keyword(s):

Transforming Growth Factor Beta ◽

Mammalian Cells ◽

Transforming Growth Factor ◽

Transcriptional Response ◽

Family Type ◽

Type I ◽

Type Ii ◽

Receptor System ◽

Bone Morphogenic Proteins ◽

Bmp Receptors

Bone morphogenic proteins (BMPs) are universal regulators of animal development. We report the identification and cloning of the BMP type II receptor (BMPR-II), a missing component of this receptor system in vertebrates. BMPR-II is a transmembrane serine/threonine kinase that binds BMP-2 and BMP-7 in association with multiple type I receptors, including BMPR-IA/Brk1, BMPR-IB, and ActR-I, which is also an activin type I receptor. Cloning of BMPR-II resulted from a strong interaction of its cytoplasmic domain with diverse transforming growth factor beta family type I receptor cytoplasmic domains in a yeast two-hybrid system. In mammalian cells, however, the interaction of BMPR-II is restricted to BMP type I receptors and is ligand dependent. BMPR-II binds BMP-2 and -7 on its own, but binding is enhanced by coexpression of type I BMP receptors. BMP-2 and BMP-7 can induce a transcriptional response when added to cells coexpressing ActR-I and BMPR-II but not to cells expressing either receptor alone. The kinase activity of both receptors is essential for signaling. Thus, despite their ability to bind to type I and II receptors receptors separately, BMPs appear to require the cooperation of these two receptors for optimal binding and for signal transduction. The combinatorial nature of these receptors and their capacity to crosstalk with the activin receptor system may underlie the multifunctional nature of their ligands.

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Nodal signalling and apoptosis

Reproduction ◽

10.1530/rep-07-0053 ◽

2007 ◽

Vol 133 (5) ◽

pp. 847-853 ◽

Cited By ~ 31

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.

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Expression of Transforming Growth Factor-β Type I and Type II Receptors Is Altered in Rat Lungs Undergoing Bleomycin-Induced Pulmonary Fibrosis

Experimental and Molecular Pathology ◽

10.1006/exmp.2000.2319 ◽

2000 ◽

Vol 69 (2) ◽

pp. 67-78 ◽

Cited By ~ 16

Author(s):

Yun Zhao ◽

Deepti U. Shah

Keyword(s):

Growth Factor ◽

Pulmonary Fibrosis ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Type I ◽

Type Ii ◽

Rat Lungs

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The disintegrin and metalloproteinase ADAM12 contributes to TGF-β signaling through interaction with the type II receptor

The Journal of Cell Biology ◽

10.1083/jcb.200612046 ◽

2007 ◽

Vol 178 (2) ◽

pp. 201-208 ◽

Cited By ~ 85

Author(s):

Azeddine Atfi ◽

Emmanuelle Dumont ◽

Frédéric Colland ◽

Dominique Bonnier ◽

Annie L'Helgoualc'h ◽

...

Keyword(s):

Transcriptional Activation ◽

Target Genes ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Type I ◽

Type Ii ◽

Transmembrane Receptors ◽

Smad Proteins ◽

Early Endosomes ◽

A Disintegrin And Metalloproteinase

Transforming growth factor-β (TGF-β) regulates a wide variety of biological processes through two types of Ser/Thr transmembrane receptors: the TGF-β type I receptor and the TGF-β type II receptor (TβRII). Upon ligand binding, TGF-β type I receptor activated by TβRII propagates signals to Smad proteins, which mediate the activation of TGF-β target genes. In this study, we identify ADAM12 (a disintegrin and metalloproteinase 12) as a component of the TGF-β signaling pathway that acts through association with TβRII. We found that ADAM12 functions by a mechanism independent of its protease activity to facilitate the activation of TGF-β signaling, including the phosphorylation of Smad2, association of Smad2 with Smad4, and transcriptional activation. Furthermore, ADAM12 induces the accumulation of TβRII in early endosomal vesicles and stabilizes the TβRII protein presumably by suppressing the association of TβRII with Smad7. These results define ADAM12 as a new partner of TβRII that facilitates its trafficking to early endosomes in which activation of the Smad pathway is initiated.

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miR-10b Deficiency Affords Atherosclerosis Resistance

10.1101/248641 ◽

2018 ◽

Cited By ~ 1

Author(s):

Masako Nakahara ◽

Norihiko Kobayashi ◽

Masako Oka ◽

Kenta Nakano ◽

Tadashi Okamura ◽

...

Keyword(s):

Transforming Growth Factor ◽

Vascular Endothelial Cells ◽

Transforming Growth Factor Β ◽

Experimental Atherosclerosis ◽

High Cholesterol Diet ◽

Type I ◽

Type Ii ◽

Protein Signaling ◽

Leading Role ◽

Growth Inhibitory

AbstractHuman vascular endothelial cells (ECs) are categorized into two groups; pro-stenotic (Type-I) and anti-stenotic (Type-II) ECs, and one of the master genes for a stress-induced “Type-II-to-Type-I” degeneration is Regulator of G-protein signaling 5 (RGS5). Here we show that miR-10b is a crucial downstream mediator in RGS5-dependent degeneration. We also demonstrated the miR-10bhigh Type-I EC exosome has a trans effect which suppresses anti-proliferative abilities of Type-II ECs. Moreover, we found miR-10b-deficient mice showed a resistance to experimental atherosclerosis, where high-fat-high-cholesterol-diet-fed mice were subjected to partial carotid ligation. Furthermore, we determined the key target of miR-10b was Latent transforming growth factor-β binding protein 1 (LTBP1), which is a regulator of TGF-β signaling. Compatible with a commonly accepted view that TGF-β creates the major growth-inhibitory signal against vascular smooth muscle cells, TGF-β inhibitor treatments abolished anti-proliferative functions of Type-II ECs. Therefore, RGS5/miR-10b/LTBP1/TGF-β axis plays a leading role in quality control of ECs.

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