Related Experiment Video

Updated: Nov 5, 2025

Monitoring Activation of the Antiviral Pattern Recognition Receptors RIG-I And PKR By Limited Protease Digestion and Native PAGE
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Monitoring Activation of the Antiviral Pattern Recognition Receptors RIG-I And PKR By Limited Protease Digestion and Native PAGE

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Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation

Anassuya Ramachandran1, Merima Mehić1, Laabiah Wasim2

  • 1Developmental Signalling Laboratory, The Francis Crick Institute, London, UK.

The EMBO Journal
|May 18, 2021
PubMed

Insights

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) share ACVR1 mutations. The R206H mutation causes auto-activation via receptor clustering, disrupting SMAD1/5 signaling in these diseases.

Area of Science:

  • Molecular biology
  • Cell signaling
  • Genetics

Background:

  • Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are severe diseases.
  • Both FOP and DIPG are linked to mutations in ACVR1, a TGF-β family type I receptor.
  • The ACVR1R206H mutation is common in both FOP and DIPG, but the mechanism of aberrant signaling is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which the ACVR1R206H mutation triggers aberrant SMAD1/5 signaling.
  • To investigate the role of Activin A in ACVR1 activation in FOP and DIPG.

Main Methods:

  • Utilized optogenetics and live-imaging techniques.
  • Investigated Activin A-mediated SMAD1/5 phosphorylation.
  • Examined ACVR1 activation mechanisms in wild-type and mutant forms.

Main Results:

  • ACVR1 is crucial for Activin A-mediated SMAD1/5 phosphorylation.
  • Wild-type ACVR1 is activated by ACVR1B/C, while ACVR1R206H auto-activates via Activin A-induced receptor clustering.
  • Activin A-induced receptor clustering requires ACVR2A/B.

Conclusions:

  • The ACVR1R206H mutation leads to aberrant signaling through Activin A-dependent auto-activation.
  • This study provides molecular insights into the pathogenesis of FOP and DIPG by linking genetic mutations to disrupted signaling pathways.
Keywords:
ACVR1R206HActivin ADIPGFOPreceptor clustering

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