Competition between type I activin and BMP receptors for binding to ACVR2A regulates signaling to distinct Smad pathways

Szilágyi, Szabina Szófia; Amsalem-Zafran, Ayelet R.; Shapira, Keren E.; Ehrlich, Marcelo; Henis, Yoav I.

doi:10.1186/s12915-022-01252-z

Cited by 16 publications

(70 citation statements)

References 88 publications

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“…Surprisingly, Acvr2a KD upregulated both Hepcidin and Id1 (Figure S5B,C). Since ACVR2A can form nonsignaling complexes with type I receptors in the absence of ligands, 17 we hypothesize that its silencing activates the BMP‐SMAD pathway by releasing ALK2 and/or ALK3 and making them available for the formation of active receptor complexes, likely with BMPR2. Upon FKBP12 sequestration by TAC, Hepcidin (Figures 1A and S6A) and Id1 (Figures 1B and S6B) upregulation was preserved in Bmpr2 ‐silenced cells but abolished in Acvr2a ‐silenced mHCs.…”

Section: Resultsmentioning

confidence: 99%

Section: Fkbp12 Silencing In Primary Mhcs Impairs Tac-mediated Hepcid...mentioning

confidence: 99%

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FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes

Pettinato,

Dulja,

Colucci

et al. 2023

American J Hematol

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The expression of the iron regulatory hormone hepcidin in hepatocytes is regulated by the BMP-SMAD pathway through the type I receptors ALK2 and ALK3, the type II receptors ACVR2A and BMPR2, and the ligands BMP2 and BMP6. We previously identified the immunophilin FKBP12 as a new hepcidin inhibitor that acts by blocking ALK2. Both the physiologic ALK2 ligand BMP6 and the immunosuppressive drug Tacrolimus (TAC) displace FKBP12 from ALK2 and activate the signaling. However, the molecular mechanism whereby FKBP12 regulates BMP-SMAD pathway activity and thus hepcidin expression remains unclear. Here, we show that FKBP12 acts by modulating BMP receptor interactions and ligand responsiveness. We first demonstrate that in primary murine hepatocytes TAC regulates hepcidin expression exclusively via FKBP12. Downregulation of the BMP receptors reveals that ALK2, to a lesser extent ALK3, and ACVR2A are required for hepcidin upregulation in response to both BMP6 and TAC. Mechanistically, TAC and BMP6 increase ALK2 homooligomerization and ALK2-ALK3 hetero-oligomerization and the interaction between ALK2 and the type II receptors. By acting on the same receptors, TAC and BMP6 cooperate in BMP pathway activation and hepcidin expression both in vitro and in vivo. Interestingly, the activation state of ALK3 modulates its interaction with FKBP12, which may explain the cell-specific activity of FKBP12. Overall, our results identify the mechanism whereby FKBP12 regulates the BMP-SMAD pathway and Mariateresa Pettinato and Alessandro Dulja are considered as co-first authors.

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Section: Resultsmentioning

confidence: 99%

Section: Fkbp12 Silencing In Primary Mhcs Impairs Tac-mediated Hepcid...mentioning

confidence: 99%

FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes

Pettinato,

Dulja,

Colucci

et al. 2023

American J Hematol

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“…GPCRs from the same GPCR families and, less frequently, different families can bind the same ligands due to similar structure and electrostatic properties of the ligand binding pockets (Dankwah et al, 2022). Not only does a receptor binding to a different ligand propagate different responses, but it can also create competition between receptors for a finite pool of ligands (Antebi et al, 2017; Szilágyi et al, 2022).…”

Section: Crosstalk: Merging Signals To Develop a Full Picture Of The ...mentioning

confidence: 99%

How cells sense and integrate information from different sources

Ullo

Case

2023

WIREs Mechanisms of Disease

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Cell signaling is a fundamental cellular process that enables cells to sense and respond to information in their surroundings. At the molecular level, signaling is primarily carried out by transmembrane protein receptors that can initiate complex downstream signal transduction cascades to alter cellular behavior. In the human body, different cells can be exposed to a wide variety of environmental conditions, and cells express diverse classes of receptors capable of sensing and integrating different signals. Furthermore, different receptors and signaling pathways can crosstalk with each other to calibrate the cellular response. Crosstalk occurs through multiple mechanisms at different levels of signaling pathways. In this review, we discuss how cells sense and integrate different chemical, mechanical, and spatial signals as well as the mechanisms of crosstalk between pathways.To illustrate these concepts, we use a few well-studied signaling pathways, including receptor tyrosine kinases and integrin receptors. Finally, we discuss the implications of dysregulated cellular sensing on driving diseases such as cancer.

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“…Phosphorylated ACVR1 phosphorylates the intracellular effector protein SMAD2/SMAD3, which forms a complex with SMAD4. The SMAD2/SMAD3/ SMAD4 complex is transported into the nucleus to activate or inhibit the transcription of different target genes, [19][20][21][22][23] modulating the behavior of colon cancer. To further explore the underlying mechanism, the interaction between the activin A/ACVR2A axis and SMAD2 or SMAD3 was examined.…”

Section: Activin A/acvr2a Axis Inhibits Colon Cancer Cell Metastasis ...mentioning

confidence: 99%

Activin A/ACVR2A axis inhibits epithelial‐to‐mesenchymal transition in colon cancer by activating SMAD2

Zhang

Ruan

Chen

et al. 2023

Molecular Carcinogenesis

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Colorectal cancer is one of the most common malignancies worldwide. Liver metastasis is the major direct cause of colorectal cancer‐related deaths. Although radical resection is the most effective treatment for colorectal cancer liver metastasis, several patients are not eligible for surgery. Therefore, there is a need to develop novel treatments based on the understanding of the biological mechanisms underlying liver metastasis in colorectal cancer. This study demonstrated that activin A/ACVR2A inhibits colon cancer cell migration and invasion, as well as suppresses the epithelial‐to‐mesenchymal transition of mouse colon cancer cells. This finding has been further validated in animal experiments. Mechanistic studies revealed that activin A binds to Smad2 (instead of Smad3) and activates its transcription. Analysis of the paired clinical samples further confirmed that the expression levels of ACVR2A and SMAD2 were the highest in adjacent healthy tissues, followed by primary colon cancer tissues and liver metastasis tissues, suggesting that ACVR2A downregulation may promote colon cancer metastasis. Bioinformatics analysis and clinical studies demonstrated that ACVR2A downregulation was significantly associated with liver metastasis and poor disease‐free and progression‐free survival of patients with colon cancer. These results suggest that the activin A/ACVR2A axis promotes colon cancer metastasis by selectively activating SMAD2. Thus, targeting ACVR2A is a potential novel therapeutic strategy to prevent colon cancer metastasis.

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Competition between type I activin and BMP receptors for binding to ACVR2A regulates signaling to distinct Smad pathways

Cited by 16 publications

References 88 publications

FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes

FKBP12 inhibits hepcidin expression by modulating BMP receptors interaction and ligand responsiveness in hepatocytes

How cells sense and integrate information from different sources

Activin A/ACVR2A axis inhibits epithelial‐to‐mesenchymal transition in colon cancer by activating SMAD2

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