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Adipose Tissue (Adipokinome), Skeletal Muscle (Myokinome), and Liver (Hepatokinome) as Endocrine Regulators During Exercise
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Logan K. Townsend, Greg L. McKie, Hesham Shamshoum, David C. Wright
Transforming growth factor β2 (TGFβ2) is a TGFβ receptor ligand and one of three mammalian TGFβ isoforms encoded by TGFβ genes (59). TGFβ2 is involved in a number of physiological functions, including the suppression of T-cell generation and proliferation, as well as the regulation of glucose and fatty acid metabolism (128, 137). TGFβ signal transduction relies primarily on SMAD proteins, ubiquitous intracellular transcription factors, to initiate the expression of target genes in the nucleus. Given that the TGFβ family of proteins plays an important role in cellular development, it is not surprising that impairments in the TGFβ signalling pathway are commonly associated with a number of diseased states (138).
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.
SMAD4 protein is decreased in the dorsolateral prefrontal and anterior cingulate cortices in schizophrenia
Published in The World Journal of Biological Psychiatry, 2021
Andrew S. Gibbons, Daniel Hoyer, Brian Dean
TGFB1 is part of a larger superfamily of proteins that mediate their signal transduction through the mothers against decapentaplegic (SMAD)-family proteins (Kingsley 1994; Figure 1). TGFB-superfamily signalling involves the phosphorylation of receptor-regulated SMADs (R-SMAD) by the membrane-bound TGFB receptors. Members of the R-SMAD protein family interact with the TGFB-superfamily receptors in a receptor-specific manner, such that TGFB1 signal transduction is mediated by the R-SMADS SMAD2 and SMAD3. Once phosphorylated, the R-SMAD then binds to the common partner SMAD (Co-SMAD) SMAD4, facilitating the transport of the R-SMAD:CoSMAD complex to the nucleus where it regulates gene transcription (Ross and Hill 2008). As the sole Co-SMAD, SMAD4 forms complexes with all R-SMAD proteins, mediating not just TGFB1 signalling, but all SMAD-pathway signalling of the TGFB superfamily. Notably, our micro array study in BA46 showed that levels of SMAD4 mRNA (Fold change to control = 0.8; p = .01) were lower in subjects with schizophrenia whilst SMAD2 mRNA showed a trend to being lower in those with the disorder (Fold change to control = 0.80; p = .04) (Narayan et al. 2008). These changes were not detected in our later study of gene expression in BA 9, BA 10 or BA 33 (Scarr et al. 2018a), raising the possibility that changes in SMAD mRNA in BA46 are cortical-region specific. Given the critical role of SMAD 4 in a number of signalling pathways (see below), our data suggested changes in SMAD4, and possibly SMAD2, expression could be affecting the functioning of BA46 in subjects with schizophrenia.
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).
Inevitable role of TGF-β1 in progression of nonalcoholic fatty liver disease
Published in Journal of Receptors and Signal Transduction, 2020
Bhagyalakshmi Nair, Lekshmi R. Nath
TGF-β1 is a multi-functional and pleiotropic polypeptide cytokine involved in various categories of cellular events like cell proliferation, cellular migration, apoptosis or cell death. To elicit the activity of TGF-β1 on adjacent and neighboring cells, TGF-β1 binds to transmembrane type I and type II receptors [28]. Initially, the active TGF-β1 emancipated from the large latent complex binds to TGF-β1I receptor which recruits and auto-phosphorylate the TGF-β1 receptor. Both type of receptors and TGF-β1 polypeptide forms a heteromeric complex. During the production of heteromeric complex, Activins (ALK-1 and ALK-5) are formed. These activins are mainly receptor kinases expressed in different types of cells. Binding of TGF-β1 to its specific transmembrane receptors activate certain SMAD dependent and SMAD independent canonical and non-canonical pathways respectively. SMAD’s are structurally similar proteins characterized into three different families namely R-SAMD, Co-SMAD and I-SMAD. SMAD 2 and SMAD 3 proteins of R-SMAD family are activated through phosphorylation by ALK-5. The activated SMAD 2 and SMAD 3 proteins forms complex with the Co-SMAD family protein and translocate into nucleus for TGF-β mediated fibrogenic responses [29]. Apart from SMAD dependent pathways, TGF-β1 also exerts fibrogenic responses through non-canonical SMAD independent pathways. SMAD-independent pathways are mediated by different set of proteins namely, MAPK, JNK, ERK, PI3/Aktetc (Figure 3).