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Transforming Growth Factor-β/Smad Signaling in Myocardial Disease
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Claudio Humeres, Nikolaos G. Frangogiannis
Very little is known regarding the potential role of Smad1 signaling in the regulation of fibroblast phenotype in response to TGF-β. Surprisingly, in a mouse model of scleroderma-like fibrosis due to forced expression of ALK5, activation of a fibrogenic transcriptional program was found to be dependent on Smad1 and Erk1/2, and not on Smad2/365, suggesting that an ALK1/Smad1 pathway may be critically involved in certain fibrotic conditions. However, the role of Smad1 signaling in the activation of cardiac fibroblasts remains unknown.
Molecular Pathways Regulating the Geometric Induction of Bone Formation
Published in Ugo Ripamonti, The Geometric Induction of Bone Formation, 2020
Members of the TGF-β superfamily, which includes the BMPs, are responsible for proliferation and differentiation of bone progenitors and the TGF-β isoforms are master regulators of mesenchymal cell fate and are involved in controlling early osteoblast differentiation (reviewed in Grafe et al. 2018). To transduce their signal, TGF-β ligands require two classes of serine/threonine kinase receptors, TGF-β receptor type I (TβRI), or ALK-5, and TGF-β receptor type II (TβRII) (Shi and Massagué 2003). The classical intracellular signalling pathway downstream of the receptors involves the Smad pathway (Feng and Derynck 2005). The Smads are composed of a group of receptor-regulated Smads (R-Smads), Smad1, 2, 3, 5 and 8, the inhibitory Smads (Smad6 and 7), and the common mediator Smad (co-Smad), Smad 4. Intracellular signalling initiates when TβRI phosphorylates R-Smads and the activated R-Smads heterodimerize with Smad-4, followed by translocation of the entire complex to the nucleus to drive transcriptional responses (Ross and Hill 2008).
TGF-β signaling in testicular development, spermatogenesis, and infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Poonam Mehta, Meghali Joshi, Rajender Singh
For transmission of a signal from the cell surface to the intracellular compartments, transcription factors, i.e., SMADs, play important roles. Ligand receptor–mediated phosphorylation of SMAD proteins present in the cytosol translocate them to the nucleus for regulating target gene transcription (8,10). The term SMAD was coined after identification of human SMAD1, which shared sequence similarity with Sma and Mad proteins (11). There are eight SMAD proteins encoded by the human genome, which are further classified into three classes, based on their function (8,10): R-SMADs (receptor-activated SMADs): Act as substrates for TGF-β receptors and include SMAD1, SMAD2, SMAD3, SMAD5, SMAD8. BMP ligands via its receptors activate SMADs 1, 5, 8, and activins, nodal and TGF-βs activate SMAD2 and SMAD3.Co-SMADs (common mediator SMADs): Partners for R-SMADs and make transcriptionally active complex. SMAD4 is the only Co-SMAD known.I-SMADs (inhibitory SMADs): Negative regulation of signaling and includes SMAD6 and SMAD7.
A review of BMP and Wnt signaling pathway in the pathogenesis of pulmonary arterial hypertension
Published in Clinical and Experimental Hypertension, 2022
Zhihong Xin, Junfu Wang, Susu Li, Chao Sun, Wan Jiang, Qian Xin, Jue Wang, Tonggnag Qi, Kailin Li, Zhaohua Zhang, Yun Luan
The induction of inhibitor of DNA binding (ID) protein expression by BMP contributes to its proangiogenic response. Regulation of Id proteins by BMPs, with relevance to PAH, plays a main role in the smooth muscle cell function. The ID family of transcription factors, especially ID1 and ID3 as important functional targets of BMP signaling, is potently regulated by BMP signaling in PASMCs and might play a complementary and partially redundant role in regulating cell cycling in vascular and other tissues (12). The ID family of transcription factors as important functional targets of BMP signaling, with relevance to PAH, both ID1 and ID3, were downregulated in the lungs along with BMPR2 in MCT rats (22). BMP antagonists, such as gremlin and noggin, are potentially important mediators of vascular changes in hypoxic pulmonary hypertension and have been implicated to play a key role in the pathophysiology of pulmonary arterial hypertension (23,24). Downregulation of BMP/Smad signaling by antagonists binding directly to BMP molecules leads to a reduction in the Smad1/5/8 pathway and to a concomitant increase in the Smad2/3 pathway. The balance between TGF-β1 and BMP signaling also plays an important role in pulmonary fibrosis and TGF-β1 and BMP signal through a heteromeric cell surface serine/threonine kinase complex, resulting in the receptor-mediated phosphorylation and activation of Smad2/3 or Smad1/5/8 (BMPs) transcription factors and alterations in gene transcription (25).
Differential expression of BMP/SMAD signaling and ovarian-associated genes in the granulosa cells of FecB introgressed GMM sheep
Published in Systems Biology in Reproductive Medicine, 2020
Satish Kumar, Pradeep Kumar Rajput, Sangharatna V. Bahire, Basanti Jyotsana, Vijay Kumar, Davendra Kumar
It is well known that the BMP factors (ligands) act through the two sub-types of receptors with serine/threonine kinase activity. Seven type I receptors and five type II serine/threonine kinase receptors have been reported (Attisano and Wrana 1996). Activin receptor-like kinase 1 (Alk1 or ACVRL1), Alk2 (ACVR1), Alk3 (BMPR1A), Alk4 (ACVR1B), Alk5 (TGFβR1), Alk6 (BMPR1B), and Alk7 (ACVR1C) act as type 1 receptors, whereas BMP receptor 2 (BMPRII), Activin receptor 2 (ActR2), Activin receptor 2A/Activin receptor 2B (ActR2A/2B), and TGFβ receptor 2 (TGFβRII) are the type 2 receptors (Kaivo-oja et al. 2006; Loomans and Andl 2016). Out of seven type 1 receptors, three receptors bind and interact with BMP ligands; BMPR1A, BMPR1B, and ActR1A (Horbelt et al. 2012). Out of five type 2 receptors, three receptors are known to interact with BMP ligands; BMPRII, ActR2A, and ActR2B (Wang et al. 2014). These BMP factors interact with hetero-tetrameric complexes of type 1 and type 2 receptors. Type 2 receptor phosphorylates the type 1 receptor. Once phosphorylated, the type 1 receptor phosphorylates one of the receptor-regulated intracellular signaling SMAD proteins (either SMAD1, -5 and -8). Hence, the phosphorylated BMP receptor-regulated SMADs hetero-dimerizes with common SMAD4 and translocate into the nucleus, where these hetero-complexes act as a transcriptional activator to regulate the expression of the target genes (Massagué 1998, 2000; Souza et al. 2004). Interaction of the BMP, TGFβ, and GDF ligands to their respective receptors have been mentioned in Figure 1A-C.
Baohuoside-I suppresses cell proliferation and migration by up-regulating miR-144 in melanoma
Published in Pharmaceutical Biology, 2018
Next, we further pursued the pathological role of miR-144 through identification of its candidate target. Based on the bioinformatics prediction, we confirmed SMAD1 as novel target of miR-144 in this setting. SMAD1 belongs to the SMAD family, which are signal transducers and transcriptional modulators that mediate multiple signalling pathway. SMAD1-mediated signalling cue from bone morphogenetic proteins (BMPs) ligand, which was subsequently phosphorylated and formed complex with SMAD4 as functional transcription regulator (Liu et al. 1996). SMAD1 pathway is involved in diverse biological processes such as cell growth, apoptosis, morphogenesis, development and immune modulation. The activation of ACVR2/SMAD1/SMAD4 played fundamental role in autocrine bone morphogenetic protein-9 mediated ovarian cancer cell proliferation (Herrera et al. 2009). The SMAD1 induction by BMP signalling, along with up-regulation of MMP-2 was critical for pancreatic cancer invasiveness (Gordon et al. 2009). In line with these notions that SMAD1 functioned as oncogene involving in promotion of cancer cell growth and invasion, we have unambiguously demonstrated that expression of SMAD1 was significantly suppressed in response to baohuoside-I treatment, which exclusively depended on miR-144 up-regulation. Moreover, our xenograft mice manifested optimal response to baohuoside-I administration, which highlighted the potential of clinical application of the natural chemical.