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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
The canonical pathway is tightly regulated through negative feedback-regulatory mechanisms at several different levels. First, at the receptor level, increased expression of the cell surface pseudo-receptor BAMBI (BMP and activin membrane-bound inhibitor) that competes with TβRII for ligand binding26,27 suppresses TGF-β/Smad responses. Second, the I-Smads Smad6 and Smad7 compete with R-Smads for their binding to activated TβRI or Smad4 and may also mediate TβRI degradation by recruitment of Smurf ubiquitin ligases28. Third, protein phosphatases dephosphorylate the R-Smad/Smad4 complex29. Fourth, nuclear co-repressors, like Ski and SnoN, bind to the trans-located R-Smad/Co-Smad complex, promoting its degradation via Smurf2 or directly preventing transcription of Smad target genes by recruiting histone deacetylases30.
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.
Genetics of gastric cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
The Smad proteins are a family of proteins that serve as intracellular mediators to regulate TGF-β superfamily signaling. Numerous studies have identified three major classes of Smad proteins: 1) the receptor-regulated Smads (R-Smads) which are direct targets of the TGF-β receptor type I kinase and include Smads1, 2, 3, and 5; 2) the common Smads (Co-Smads: Smad4) which form heteromeric complexes with the R-Smads and propagate the TGF-β mediated signal; and 3) the inhibitory Smads (I-Smads: Smad6 and Smad7) which antagonize TGF-β signaling through the Smad pathway. Mutational inactivation of SMAD2 and SMAD4 has been observed in a high percentage of pancreatic cancers and in 5–10% of colon cancers (Hahn et al., 1996; Riggins et al., 1996; Schutte et al., 1996). Mutations in SMAD4 in stomach cancer occur less frequently and have been demonstrated in approximately 3% of tumors (Powell et al., 1997). Powell et al. identified biallelic inactivation in 1/35 primary gastric carcinomas. One allele was found to carry a nonsense mutation at codon 334, which is predicted to truncate the conserved carboxy-terminal domain of the protein, and the other allele was shown to be missing, using adjacent microsatellite markers (Powell et al., 1997). SMAD2 and SMADS mutations have not been found to date in sporadic gastric carcinomas (Gemma et al., 1998; Shitara et al., 1999). Thus, SMAD mutations appear to play a role in tumor formation in a subset of gastric cancers, but are not as common as TGFBR2 mutations. This finding suggests there are non-Smad TGF-β signaling pathways that play an important role in the tumor suppressor activity of TGFBR2.
Renal fibrosis as a hallmark of diabetic kidney disease: potential role of targeting transforming growth factor-beta (TGF-β) and related molecules
Published in Expert Opinion on Therapeutic Targets, 2022
Jiali Tang, Fang Liu, Mark E. Cooper, Zhonglin Chai
Once released from the latent TGF-β1/LAP/LTBP complex, active TGF-β1, as a ligand, binds to the high affinity receptor, TβRII, on the cell surface (Figure 3). This combination recruits and activates another receptor, TβRI. The activated TβRI then phosphorylates and activates key signaling molecules known as receptor-regulated Smads (R-Smads), such as Smad2/3. The activated R-Smads will bind to Smad4, also known as common-partner Smad (co-Smad), to form a larger complex, which can translocate to the nucleus where they bind to the promoters of target genes to regulate their transcription, such as profibrotic genes encoding collagens, fibronectin, tissue inhibitor of matrix metalloproteinases (TIMP) and α-smooth muscle actin (α-SMA), ultimately leading to myofibroblast activation and matrix accumulation [14,62]. All the focus of TGF-β’s actions has been on profibrotic signaling pathways including Smads 2/3, one should appreciate that there are other Smad molecules such as Smad7, also known as inhibitory Smad (I-Smad), which is a negative regulator of Smad2/3 and indeed inhibits fibrosis [63].
Endostatin in fibrosis and as a potential candidate of anti-fibrotic therapy
Published in Drug Delivery, 2021
Zequn Zhang, Xi Liu, Zhaolong Shen, Jun Quan, Changwei Lin, Xiaorong Li, Gui Hu
Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine, it has the functions of regulating cell proliferation, differentiation, and the production of ECM, and plays an important role in the process of organism development, wound healing, organ fibrosis, tumor generation, and metastasis. Therefore, it has always been a research hotspot in the above fields (Massague et al. 2000; Meng et al. 2016; Stewart et al. 2018). To date, three mammalian isoforms have been identified, TGF-β1, TGF-β2, and TGF-β3 (Yu et al. 2003). On the cellular membrane lies two kinds of serine/threonine kinase-type receptors, which are TGF-β targets. TGF-β signals through a heterologous receptor complex of type I and type II receptors and in most cases transmits the signal via Smads (Xu et al. 2012; Miyazawa & Miyazono 2017). The Smad family includes three categories, receptor-regulated Smads (R-Smad, including Smad1/2/3/5/8), inhibitory Smads (I-Smad, including Smad6/7), and common-mediator Smad (Co-Smad, including Smad4) (Hill 2016). R-Smads are activated by TGF-β receptor I. Smad2 and Smad3 are two main R-Smads phosphorylated by TGF-β receptor I. Phosphorylated R-Smad form heterodimeric complexes with Co-Smad. The complexes then translocate to the nucleus and regulate target gene transcription by binding to specific DNA sequences (Massague & Wotton 2000; Xu et al. 2012).
Infection with enteric pathogens Salmonella typhimurium and Citrobacter rodentium modulate TGF-beta/Smad signaling pathways in the intestine
Published in Gut Microbes, 2018
Yong-Guo Zhang, Megha Singhal, Zhijie Lin, Christopher Manzella, Anoop Kumar, Waddah A. Alrefai, Pradeep K. Dudeja, Seema Saksena, Jun Sun, Ravinder K. Gill
Indeed, TGF-β1signaling is very complex. The ligand TGF-β1 initiates signaling by binding to and bringing together type I (TGF-RI) and type II receptor (TGF-RII) serine/threonine kinases on the cell surface. This allows TGF-RII to phosphorylate the receptor I kinase domain, which then propagates the signal through phosphorylation of the canonical Smad proteins. R-Smads (Smad1, 2, 3, 5, and 8) are directly phosphorylated and activated by the type I receptor kinases and undergo formation of heteromeric complexes with the Co-Smad, Smad4. The activated Smad complexes are translocated into the nucleus and, in conjunction with other nuclear cofactors, regulate the transcription of target genes. The I-Smad, Smad7, keeps a check on TGF-β1 signaling by competing with R-Smads for receptor or Co-Smad interaction and by targeting the receptors for degradation.3,8 Eliminating TGF-β1 or its downstream signaling cascade (Smad2, 3 and 4) leads to inflammatory disease or cancer.9-11 For example, TGF-β-null mice develop systemic inflammation, whereas, transgenic mice expressing a dominant negative TGF-R2 are known to develop severe pulmonary and gut inflammation10,12,13 or tumor formation.14 On the other hand, activation of TGF-β1 signaling pathways leads to tissue repair or remodeling, although excessive signaling can have deleterious consequences such as fibrosis or tumor metastasis.14,15 Whether TGF-β1 signaling is exploited by enteric pathogens to contribute to disease pathogenesis is largely unknown.