TGF‐β signaling: A recap of SMAD‐independent and SMAD‐dependent pathways

Aashaq, Sabreena; Batool, Asiya; Mir, Shabir Ahmad; Beigh, Mushtaq A.; Andrabi, Khurshid Iqbal; Shah, Zaffar Amin

doi:10.1002/jcp.30529

Cited by 95 publications

(46 citation statements)

References 299 publications

(471 reference statements)

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“…There was a division among the researchers, some believed that TGF-β could be tumour promoter, and some ended up saying that it has a role in tumour suppression. Dysregulation of TGF-β signaling hijacks the complexes of biological functions that plays critical role in developmental processes and tumorigenesis, thus emerges as a promising signaling pathway to be targeted for the anticancer drug development at preclinical and clinical stages ( Aashaq et al, 2021 ). TGF-β signaling pathway has a decisive and dual role in the human cancer progression.…”

Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within

et al. 2022

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A ubiquitously expressed cytokine, transforming growth factor-beta (TGF-β) plays a significant role in various ongoing cellular mechanisms. The gain or loss-of-function of TGF-β and its downstream mediators could lead to a plethora of diseases includes tumorigenesis. Specifically, at the early onset of malignancy TGF-β act as tumour suppressor and plays a key role in clearing malignant cells by reducing the cellular proliferation and differentiation thus triggers the process of apoptosis. Subsequently, TGF-β at an advanced stage of malignancy promotes tumorigenesis by augmenting cellular transformation, epithelial-mesenchymal-transition invasion, and metastasis. Besides playing the dual roles, depending upon the stage of malignancy, TGF-β also regulates cell fate through immune and stroma components. This oscillatory role of TGF-β to fight against cancer or act as a traitor to collaborate and crosstalk with other tumorigenic signaling pathways and its betrayal within the cell depends upon the cellular context. Therefore, the current review highlights and understands the dual role of TGF-β under different cellular conditions and its crosstalk with other signaling pathways in modulating cell fate.

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Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within

et al. 2022

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“…Then, seven genes, including BMP2, GSTA1, GSTA3, BST1, S100A9, TTR, and GATM, were identified as the targets of the YSHS granule in the treatment of ADR-induced FSGS by Real-time PCR analysis. Among these validated targets of YSHS, BMP2 belongs to the TGF-β superfamily, has a similar ligand structure, similar receptor-binding proteins, and similar downstream signaling cascades to TGF-β1 ( Aashaq et al, 2022 ). Many researches demonstrated that BMP2 plays an important role in the occurrence, development, and outcome of renal interstitial fibrosis ( Yang et al, 2009 ; Yang et al, 2011 ; Simone et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Yi-Shen-Hua-Shi Granule Alleviates Adriamycin-Induced Glomerular Fibrosis by Suppressing the BMP2/Smad Signaling Pathway

Tan

Si²,

Yu³

et al. 2022

Front. Pharmacol.

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Focal segmental glomerulosclerosis (FSGS) is a common clinical condition with manifestations of nephrotic syndrome and fibrosis of the glomeruli and interstitium. Yi-Shen-Hua-Shi (YSHS) granule has been shown to have a good effect in alleviating nephrotic syndrome (NS) in clinical and in animal models of FSGS, but whether it can alleviate renal fibrosis in FSGS and its mechanism and targets are not clear. In this study, we explored the anti-fibrotic effect and the targets of the YSHS granule in an adriamycin (ADR)-induced FSGS model and found that the YSHS granule significantly improved the renal function of ADR-induced FSGS model mice and also significantly reduced the deposition of collagen fibers and the expression of mesenchymal cell markers FN, vimentin, and α-SMA in the glomeruli of ADR-induced FSGS mice, suggesting that the YSHS granule inhibited the fibrosis of sclerotic glomeruli. Subsequently, a network pharmacology-based approach was used to identify the potential targets of the YSHS granule for the alleviation of glomerulosclerosis in FSGS, and the results showed that the YSHS granule down-regulated the expressions of BMP2, GSTA1, GATS3, BST1, and S100A9 and up-regulated the expressions of TTR and GATM in ADR-induced FSGS model mice. We also proved that the YSHS granule inhibited the fibrosis in the glomeruli of ADR-induced FSGS model mice through the suppression of the BMP2/Smad signaling pathway.

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“…SMADs play an important role as transducers of cellular responses after TGF-β receptor engagement 11 . To address the role of these transcription factors inTGF-β-triggered EMT, we isolated endometrial epithelial cells from tamoxifen-inducible double SMAD2/3 knock-out mice (Cre:ER +/− ;SMAD2 f/f ;SMAD3 f/f ).…”

Section: Loss Of Cell Polarity Caused By Absence Of Ecm Impairs Tgf-β...mentioning

confidence: 99%

“…The SMAD family consists of nine members, which form 3 subfamilies: receptor-activated (R-)SMADs (SMAD1, SMAD2, SMAD3, SMAD5, SMAD8 and SMAD9), a single common-mediator (Co-)SMAD (SMAD4) and two inhibitory (I-)SMADs (SMAD6 and SMAD7). TGF-β also induces non-SMAD pathways, including mitogen-activated protein kinase (MAPK), phosphoinositide-3kinase (PI3K) and Rho GTPases 11 .…”

Section: Introductionmentioning

confidence: 99%

Lack of extracellular matrix switches TGF-β-induced apoptosis of endometrial cells to Epithelial-to-Mesenchymal transition through AKT, ERK and SMAD2/3-depdendent mechanisms

Ruiz-Mitjana

Navaridas

Vidal-Sabanés

et al. 2022

Preprint

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The extracellular matrix and the correct establishment of epithelial cell polarity plays a critical role in epithelial cell homeostasis and cell polarity. In addition, loss of tissue structure is a hallmark of carcinogenesis. In this study, we have addressed the role of extracellular matrix in the cellular responses to TGF- β. It is well known that TGF-β is a double-edged sword: it acts as a tumor suppressor in normal epithelial cells, but conversely has tumor-promoting effects in tumoral cells. However, the factors that determine cellular outcome in response to TGF-β remain controversial. Here, we have demonstrated that the lack of extracellular matrix and consequent loss of cell polarity inhibits TGF-β-induced apoptosis, observed when endometrial epithelial cells are polarized in presence of extracellular matrix. Rather, in absence of extracellular matrix, TGF-β-treated endometrial epithelial cells display features of epithelial-to-mesenchymal transition. We have also investigated the molecular mechanism of such a switch in cellular response. On the one hand, we found that the lack of Matrigel results in increased AKT signaling which is sufficient to inhibit TGF-β-induced apoptosis. On the other hand, we demonstrate that TGF-β-induced epithelial-to-mesenchymal transition requires ERK and SMAD2/3 activation. In summary, we demonstrate that loss of cell polarity changes the pro-apoptotic function of TGF-β to tumor-associated phenotype such as epithelial-to-mesenchymal transition. These results may be important for understanding the dual role of TGF- β in normal versus tumoral cells.

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TGF‐β signaling: A recap of SMAD‐independent and SMAD‐dependent pathways

Cited by 95 publications

References 299 publications

Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within

Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within

Yi-Shen-Hua-Shi Granule Alleviates Adriamycin-Induced Glomerular Fibrosis by Suppressing the BMP2/Smad Signaling Pathway

Lack of extracellular matrix switches TGF-β-induced apoptosis of endometrial cells to Epithelial-to-Mesenchymal transition through AKT, ERK and SMAD2/3-depdendent mechanisms

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