scholarly journals miR-10b Deficiency Affords Atherosclerosis Resistance

2018 ◽  
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.

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

2007 ◽  
Vol 195 (1) ◽  
pp. 95-103 ◽  
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.

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

2007 ◽  
Vol 178 (2) ◽  
pp. 201-208 ◽  
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.

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.

scholarly journals Transforming Growth Factor-β Induces Formation of a Dithiothreitol-resistant Type I/Type II Receptor Complex in Live Cells

1999 ◽  
Vol 274 (9) ◽  
pp. 5716-5722 ◽  
Author(s):  
Rebecca G. Wells ◽  
Lilach Gilboa ◽  
Yin Sun ◽  
Xuedong Liu ◽  
Yoav I. Henis ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Live Cells ◽  
Type I ◽  
Receptor Complex ◽  
Type Ii

Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin

1994 ◽  
Vol 14 (6) ◽  
pp. 3810-3821
Author(s):  
J Cárcamo ◽  
F M Weis ◽  
F Ventura ◽  
R Wieser ◽  
J L Wrana ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Amino Acid Sequence Identity ◽  
Transforming Growth Factor ◽  
Type I ◽  
Type Ii ◽  
Tgf Beta ◽  
Transcriptional Responses ◽  
Receptor Complexes ◽  
Growth Inhibitory ◽  
Growth Factor Beta

Transforming growth factor beta (TGF-beta) and activin bind to receptor complexes that contain two distantly related transmembrane serine/threonine kinases known as receptor types I and II. The type II receptors determine ligand binding specificity, and each interacts with a distinct repertoire of type I receptors. Here we identify a new type I receptor for activin, ActR-IB, whose kinase domain is nearly identical to that of the recently cloned TGF-beta type I receptor, T beta R-I. ActR-IB has the structural and binding properties of a type I receptor: it binds activin only in the presence of an activin type II receptor and forms a heteromeric noncovalent complex with activin type II receptors. In Mv1Lu lung epithelial cells, ActR-IB and T beta R-I signal a common set of growth-inhibitory and transcriptional responses in association with their corresponding ligands and type II receptors. The transcriptional responses include elevated expression of fibronectin and plasminogen activator inhibitor 1. Although T beta R-I and ActR-IB are nearly identical in their kinase domains (90% amino acid sequence identity), their corresponding type II receptor kinase domains are very different from each other (42% amino acid sequence identity). Therefore, signaling of a specific set of responses by TGF-beta and activin correlates with the presence of similar type I kinases in their complex. Indeed, other TGF-beta and activin type I receptors (TSR-I and ActR-I) whose kinase domains significantly diverge from those of T beta R-I and ActR-IB do not substitute as mediators of these growth-inhibitory and extracellular matrix transcriptional responses. Hence, we conclude that the type I receptor subunits are primary specifiers of signals sent by TGF-beta and activin receptor complexes.

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.

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