Structural basis for receptor-regulated SMAD recognition by MAN1

Miyazono, Ken-ichi; Ohno, Yosuke; Wada, Haruki; Ito, Tomoko; Fukatsu, Yui; Kurisaki, Akira; Asashima, Makoto

doi:10.1093/nar/gky925

Cited by 17 publications

(20 citation statements)

References 53 publications

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“…21 Recombinant human mothers against decapentaplegic homolog 4 (Smad4) can form complexes with other activated Smads (Smad1/5/8); the resulting heterodimers complex with diverse transcription factors (coactivators or corepressors) to regulate gene expression in the nucleus. 22,23 Furthermore, the Smad4 protein pathway has been found to enhance osteoblast differentiation. Smad4 is the only common Smad involved in BMP2 signaling.…”

Section: Introductionmentioning

confidence: 99%

<p>The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway</p>

Zhang¹,

Liu²,

Wang³

et al. 2020

IJN

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Background: In recent years, nanomaterials have been increasingly developed and applied in the field of bone tissue engineering. However, there are few studies on the induction of bone regeneration by tantalum nanoparticles (Ta NPs) and no reports on the effects of Ta NPs on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanisms. The main purpose of this study was to investigate the effects of Ta NPs on bone regeneration and BMSC osteogenic differentiation and the underlying mechanisms. Materials and Methods: The effects of Ta NPs on bone regeneration were evaluated in an animal experiment, and the effects of Ta NPs on osteogenic differentiation of BMSCs and the underlying mechanisms were evaluated in cell experiments. In the animal experiment, hematoxylin-eosin (HE) staining and hard-tissue section analysis showed that Ta NPs promoted bone regeneration, and immunohistochemistry revealed elevated expression of BMP2 and Smad4 in cells cultured with Ta NPs. Results: The results of the cell experiments showed that Ta NPs promoted BMSC proliferation, alkaline phosphatase (ALP) activity, BMP2 secretion and extracellular matrix (ECM) mineralization, and the expression of related osteogenic genes and proteins (especially BMP2, Smad4 and Runx2) was upregulated under culture with Ta NPs. Smad4 expression, ALP activity, ECM mineralization, and osteogenesis-related gene and protein expression decreased after inhibiting Smad4. Conclusion: These data suggest that Ta NPs have an osteogenic effect and induce bone regeneration by activating the BMP2/Smad4/Runx2 signaling pathway, which in turn causes BMSCs to undergo osteogenic differentiation. This study provides insight into the molecular mechanisms underlying the effects of Ta NPs in bone regeneration.

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Section: Introductionmentioning

confidence: 99%

<p>The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway</p>

Zhang¹,

Liu²,

Wang³

et al. 2020

IJN

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“…MAN1 engages the MH2 domain through interactions with a-helix 2 of the bundle motif and multiple b-strands in the b-sandwich including the L3 loop. 151 Further diversity in Smad binding was shown by the same group, who published the structure of the Smad interacting domain of FoxH1 in complex with the MH2 domain of Smad3. 150 These structures highlight that interactions can occur through different binding epitopes, demonstrating the complexity of these Smad protein mechanism (Figure 5 In 1998, the structure of the MH1 domain of Smad3 bound to DNA depicted the first structure of a MH1 domain.…”

Section: Smad Protein Structuresmentioning

confidence: 97%

Structural biology of the TGFβ family

Goebel

Hart

McCoy

et al. 2019

Exp Biol Med (Maywood)

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The transforming growth factor beta (TGFβ) signaling pathway orchestrates a wide breadth of biological processes, ranging from bone development to reproduction. Given this, there has been a surge of interest from the drug development industry to modulate the pathway – at several points. This review discusses and provides additional context for several layers of the TGFβ signaling pathway from a structural biology viewpoint. The combination of structural techniques coupled with biophysical studies has provided a foundational knowledge of the molecular mechanisms governing this high impact, ubiquitous pathway, underlying many of the current therapeutic pursuits. This work seeks to consolidate TGFβ-related structural knowledge and educate other researchers of the apparent gaps that still prove elusive. We aim to highlight the importance of these structures and provide the contextual information to understand the contribution to the field, with the hope of advancing the discussion and exploration of the TGFβ signaling pathway. Impact statement The transforming growth factor beta (TGFβ) signaling pathway is a multifacetted and highly regulated pathway, forming the underpinnings of a large range of biological processes. Here, we review and consolidate the key steps in TGFβ signaling using literature rooted in structural and biophysical techniques, with a focus on molecular mechanisms and gaps in knowledge. From extracellular regulation to ligand–receptor interactions and intracellular activation cascades, we hope to provide an introductory base for understanding the TGFβ pathway as a whole.

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“…However, in constrast, Smad1 and Smad5 have also been indicated to probably contribute to the diverse roles in the embryogenesis and hematopoiesis 42 - 43 . It has been further elucidated that Smad1/5 activity might be affected and controlled by the different ligand stimulations and different membrane receptors and/or intracellular signaling proteins associations 44 . Thus, these findings might support our results about distinct roles of Smad1 and Smad5 in DAPT-treated glioma cells, but their exact mechanisms still need more clear examination.…”

Section: Discussionmentioning

confidence: 99%

γ-secretase inhibitors, DAPT and RO4929097, promote the migration of Human Glioma Cells via Smad5-downregulated E-cadherin Expression

et al. 2021

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Malignant gliomas are a type of central nervous system cancer with extremely high mortality rates in humans. γ-secretase has been becoming a potential target for cancer therapy, including glioma, because of the involvement of its enzymatic activity in regulating the proliferation and metastasis of cancer cells. In this study, we attempted to determine whether γ-secretase activity regulates E-cadherin to affect glioma cell migration. The human glioma cell lines, including LN18 and LN229, and the γ-secretase inhibitors, including N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) and RO4929097, were used in this study. It was shown that γ-secretase activity inhibition by DAPT and RO4929097 could promote LN18 and LN229 glioma cell migration via downregulating E-cadherin mRNA and protein expressions, but not via affecting E-cadherin protein processing. In addition, γ-secretase activity inhibition was regulated by bone morphogenetic proteins-independent Smad5 activation in glioma cells. Moreover, endogenous Smad1 in glioma cells was found to play an important role in regulating E-cadherin expression and subsequent cell migration but did not affect DAPT-stimulated effects. These results help further elucidate the molecular mechanisms of γ-secretase activity regulation involved in controlling glioma cell malignancy. Information about a potential role for Smad1/5 activity upregulation and subsequent E-cadherin downregulation during inhibition of γ-secretase activity in the development of gliomas is therefore relevant for future research.

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Structural basis for receptor-regulated SMAD recognition by MAN1

Cited by 17 publications

References 53 publications

<p>The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway</p>

<p>The Role of Tantalum Nanoparticles in Bone Regeneration Involves the BMP2/Smad4/Runx2 Signaling Pathway</p>

Structural biology of the TGFβ family

γ-secretase inhibitors, DAPT and RO4929097, promote the migration of Human Glioma Cells via Smad5-downregulated E-cadherin Expression

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