Smad linker region phosphorylation is a signalling pathway in its own right and not only a modulator of canonical TGF-β signalling

Kamato, Danielle; Hang, Bich; Osman, Narin; Ross, Benjamin P.; Mohamed, Raafat; Xu, Suowen; Little, Peter J.

doi:10.1007/s00018-019-03266-3

Cited by 39 publications

(38 citation statements)

References 58 publications

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“…In mammals, there are eight SMAD proteins, which are sub-divided into three types: Receptor-regulated SMADs (R-SMADs), common-mediator SMADs and inhibitory SMADs (4)(5)(6). SMADs can recognize and bind several sequence-specific and context-dependent transcriptional regulation factors, such as FoxH1, Sp1, YY1 and p53, which have been found to participate in various biological processes, including cell proliferation, apoptosis, differentiation, as well as tumor progression and immune regulation processes (7)(8)(9). The majority of signaling pathways regulated by SMADs, such as TGF-β/SMAD, BMP/SMAD, ERK/MAPK, JAK/STAT and Wnt/β-catenin, are deregulated in various human malignant carcinomas, including lung carcinoma, malignant melanoma, colorectal cancer, kidney cancer, breast cancer, ovarian cancer and prostate cancer (10)(11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

SMAD‑6, ‑7 and ‑9 are potential molecular biomarkers for the prognosis in human lung cancer

Pan

Zhou

et al. 2020

Oncol Lett

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SMADs, a family of proteins that function as signal transducers and transcriptional regulators to regulate various signaling pathways, including the transforming growth factor-β signaling pathway, are similar to the mothers against decapentaplegic family of genes and the sma gene family in Caenorhabditis elegans. SMADs generate context-dependent modulation by interacting with various sequence-specific transcription factors, such as E2F4/5, c-Fos, GATA3, YY1 and SRF, which have been found to serve a key role in lung carcinoma oncogenesis and progression. However, the prognostic values of the eight SMADs in lung cancer have not been fully understood. In the present study, the expression levels and survival data of SMADs in patients with lung carcinoma from the Oncomine, Gene Expression Profiling Interactive Analysis, Kaplan-Meier plotter and cBioPortal databases were downloaded and analyzed. It was found that the mRNA expression levels of SMAD-6,-7 and-9 were decreased in lung adenocarcinoma and squamous cell carcinoma compared with that in adjacent normal tissues, while there was no significant difference in SMADs 1-5. Survival analysis revealed that not only were low transcriptional levels of SMAD-6,-7 and-9 associated with low overall survival but they also had prognostic role for progression-free survival and post-progression survival (P<0.05) in patients with lung carcinoma. In conclusion, the present study demonstrated that SMAD-6,-7 and-9 are potential biomarkers for the prognosis of patients with lung carcinoma.

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Section: Introductionmentioning

confidence: 99%

SMAD‑6, ‑7 and ‑9 are potential molecular biomarkers for the prognosis in human lung cancer

Pan

Zhou

et al. 2020

Oncol Lett

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“…In this study, also the relevance for chondrocytes was established. Joint inflammation during OA development will result in kinase and phosphatase activation that could (de-)phosphorylate the SMAD linker region independent of the C-terminal phosphorylation, including the S204 and S213 site [ 85 ]. We showed that the (de)-phosphorylation of these linker sites led to a disturbance of the TGF-β signaling pathway in cartilage, which is of great importance for chondrocyte homeostasis maintenance.…”

Section: Discussionmentioning

confidence: 99%

Osteoarthritis-Related Inflammation Blocks TGF-β’s Protective Effect on Chondrocyte Hypertrophy via (de)Phosphorylation of the SMAD2/3 Linker Region

Thielen

Neefjes

Wiegertjes

et al. 2021

IJMS

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Osteoarthritis (OA) is a degenerative joint disease characterized by irreversible cartilage damage, inflammation and altered chondrocyte phenotype. Transforming growth factor-β (TGF-β) signaling via SMAD2/3 is crucial for blocking hypertrophy. The post-translational modifications of these SMAD proteins in the linker domain regulate their function and these can be triggered by inflammation through the activation of kinases or phosphatases. Therefore, we investigated if OA-related inflammation affects TGF-β signaling via SMAD2/3 linker-modifications in chondrocytes. We found that both Interleukin (IL)-1β and OA-synovium conditioned medium negated SMAD2/3 transcriptional activity in chondrocytes. This inhibition of TGF-β signaling was enhanced if SMAD3 could not be phosphorylated on Ser213 in the linker region and the inhibition by IL-1β was less if the SMAD3 linker could not be phosphorylated at Ser204. Our study shows evidence that inflammation inhibits SMAD2/3 signaling in chondrocytes via SMAD linker (de)-phosphorylation. The involvement of linker region modifications may represent a new therapeutic target for OA.

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“…In a genome-wide study, GPCR transactivation dependent signalling accounted for approximately 50 per cent of the total genes regulated by thrombin [26]. TGF-β plays a major role in mammalian homeostasis and is implicated in a diverse set of developmental disorders and diseases, including cancer, brosis, auto-immune and cardiovascular diseases [70,71] including a potent stimulator of PAI-1 expression [17,72]. To have a functional understanding of TLR transactivation of the TGFBR1 we measured the expression of PAI-1.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Acting Via Toll Like Receptor 4 Transactivates The TGF-β Receptor in Vascular Smooth Muscle cells

Afroz

Kumarapperuma

Raafat

et al. 2021

Preprint

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Toll-like receptors (TLRs) recognise pathogen‑associated molecular patterns, which allow the detection of microbial infection by host cells. Bacterial derived toxin lipopolysaccharide activates TLR4 and leads to the activation of the Smad2 transcription factor. The phosphorylation of the Smad2 transcription factor is the result of the activation of the transforming growth factor-β receptor 1 (TGFBR1). Therefore, we sought to investigate LPS via TLR4 mediated Smad2C phosphorylation dependent on the (trans)activation of the TGFBR1. The invitro used human aortic vascular smooth muscle cells (HA-VSMCs) to assess the implications of TLR4 (trans)activation of the TGFBR1 in vascular pathophysiology. We show that LPS mediated Smad2 carboxy-terminal phosphorylation is inhibited in the presence of TGFBR1 inhibitor SB431542 in HA-VSMCs. Treatment with MyD88 and TRIF pathways antagonists does not affect LPS mediated phosphorylation of Smad2C; however, LPS mediated Smad2 phosphorylation was inhibited in the presence of MMP inhibitor, GM6001 and unaffected in the presence of ROCK inhibitor Y27632. LPS via transactivation of the TGFBR1 stimulates PAI-1 mRNA expression. TLRs are first in line to respond to exogenous invading substances and endogenous molecules; our findings characterise a novel signalling pathway in the context of cell biology. Identifying TLR transactivation of the TGFBR1 may provide future insight into the detrimental implications of pathogens in pathophysiology.

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Smad linker region phosphorylation is a signalling pathway in its own right and not only a modulator of canonical TGF-β signalling

Cited by 39 publications

References 58 publications

SMAD‑6, ‑7 and ‑9 are potential molecular biomarkers for the prognosis in human lung cancer

SMAD‑6, ‑7 and ‑9 are potential molecular biomarkers for the prognosis in human lung cancer

Osteoarthritis-Related Inflammation Blocks TGF-β’s Protective Effect on Chondrocyte Hypertrophy via (de)Phosphorylation of the SMAD2/3 Linker Region

Lipopolysaccharide Acting Via Toll Like Receptor 4 Transactivates The TGF-β Receptor in Vascular Smooth Muscle cells

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