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Familial Pancreatic Cancer
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The SMAD4 (SMAD family member 4) gene on chromosome 18q21.2 spans 56.6 kb and encodes a 552 aa, 60 kDa protein (SMAD4) that is a member of the Smad family of signal transduction proteins. SMAD4 forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which, upon phosphorylation and activation by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling, take part in the regulation of target gene transcription. SMAD4 inactivation disrupts TGF-β signaling and results in tumorigenesis and metastatic recurrence of pancreatic cancer (60% of cases) as well as juvenile polyposis syndrome.
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.
Systemic sclerosis
Published in Rajan Madhok, Hilary Capell, The Year in Rheumatic Disorders Volume 4, 2004
INTERPRETATION. Protein and messenger RNA (mRNA) levels of SMAD3 (a substrate for activated TGF-pRI) were increased in most scleroderma fibroblasts, but not those of SMAD4 (the common signalling partner for SMAD2 and SMAD3) or of SMAD7 (which is inhibitory). When intracellular expression of SMAD proteins was examined in the presence and absence of TGF-p, TGF-p repressed expression of SMAD3 mRNA in both control and SSc fibroblasts, suggesting that the elevated steady-state levels of SMAD3 seen in some SSc fibroblasts cannot be attributed to failure of a SMAD3-related negative feedback mechanism. In the absence of exogenous TGF-p, SMAD3 and 4 had a predominantly cytoplasmic localization in control fibroblasts, whereas they showed elevated nuclear localization in SSc fibroblasts. Also, the levels and nuclear localization of phosphorylated SMAD2/3 were increased in SSc fibroblasts (in the absence of TGF-p), suggesting activation of the SMAD pathway. TGF-p blockade failed to correct the subcellular localization of SMAD in SSc fibroblasts. This suggests that the increased nuclear localization of SMADs is due to alterations downstream of the TGF-p receptors and is therefore ligand-independent. Thus, abnormalities in SMAD signalling may contribute to the abnormal SSc fibroblast phenotype and therefore to fibrosis.
Glaucoma – ‘A Stiff Eye in a Stiff Body’
Published in Current Eye Research, 2023
Sarah Powell, Mustapha Irnaten, Colm O’Brien
There are a number of pro-fibrotic molecules upregulated in glaucoma, including CTGF,75,82 TGF-ß, the matricellular protein TSP-1 and secreted protein acidic and rich in cysteine.47,75,83 TGFß, a pro-fibrotic cytokine84 is an important regulator of ECM synthesis and propagates ECM remodeling by activating Smad proteins (members of the signal transducer family) following its binding to serine/threonine kinase receptors.84 Smad protein activation results in their translocation to the nucleus where they subsequently function to regulate gene transcription.85,86 TGFß signaling can, of course, also be activated by pathways independent of Smad, in response to the binding of ligands. These non-canonical signaling pathways include MAPK, Rho-like GTPase, phosphatidylinositol-3-kinase and Ak strain transforming pathways.87,88 Several studies89,90 have demonstrated that TGFß plays an important role in wound healing processes in the eye. There is considerable evidence demonstrating that TGFß is overexpressed in the TM and LC regions as well as the aqueous humor of glaucoma patients, thereby suggesting a role for TGFß as a fundamental driver for the pathological deposition of ECM seen in glaucomatous eyes.91,92 TGFß inhibition is an attractive treatment therapy for many diseases such as glaucoma93 and may have implications for the management of glaucoma in the future.
Baicalin protects against renal interstitial fibrosis in mice by inhibiting the TGF-β/Smad signalling pathway
Published in Pharmaceutical Biology, 2022
Hui Wang, Qingtao Jiang, Lizhu Zhang
Activation of TGF-β/Smad exerts a vital effect on the progression of RIF (Chen L et al. 2018). Smad proteins act as intracellular signalling mediators of TGF-β. Therefore, the protein expression of Smad2, and Smad3, and the levels of phosphorylation of Smad2 and Smad3, as well as TGF-β, were investigated by western blotting. The results showed that compared with the sham group, the UUO group showed obviously increased levels of phosphorylated Smad2 and Smad3. In addition, the UUO group exhibited higher levels of TGF-β protein expression. Baicalin treatment decreased the activated phosphorylation of Smad2 (79.4% decrease) and Smad3 (75.4% decrease) in a dose-dependent manner. Similarly, the levels of TGF-β protein expression were reduced (66.3% decrease) with baicalin treatment in a dose-dependent manner. These findings indicate that baicalin inhibited the activation of the TGF-β/Smad pathway (Figure 4(A,B)).
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.