Related Experiment Video

Updated: Aug 21, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

RASA1 deficiency aggravates the lesion burden of cerebral cavernous malformations via the Ras/Raf/MAPK pathway

Yuwen Wang1,2, Ziyu Xiong1,2, Qile Ye3

  • 1Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.

Iscience
|August 20, 2026
PubMed

Insights

RASA1 deficiency worsens cerebral cavernous malformations (CCMs) by activating the Ras/Raf/MAPK pathway, increasing endothelial proliferation, and altering cell metabolism. Ras inhibition offers a potential therapeutic strategy for these vascular lesions.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Cerebral cavernous malformations (CCMs) are cerebrovascular lesions linked to genetic factors impacting endothelial cells.
  • Endothelial signaling pathways, particularly Ras signaling, are implicated in CCM development.

Purpose of the Study:

  • To investigate the role of RASA1 deficiency in modifying CCM progression.
  • To elucidate the molecular mechanisms by which RASA1 affects endothelial cells in CCMs.
  • To evaluate the therapeutic potential of targeting Ras signaling in CCMs.

Main Methods:

  • Bioinformatic analyses
  • hCMEC/D3 endothelial cell models (knockdown and rescue)
  • Seahorse metabolic profiling
  • Ras-GTP pull-down assays
  • PDCD10-deficient mouse model with endothelial Rasa1 knockdown

Main Results:

  • RASA1 deficiency promoted endothelial proliferation and reduced ZO-1 expression.
  • Metabolic profiling revealed a shift from oxidative phosphorylation to glycolysis.
  • Ras/Raf/MAPK signaling pathway was activated by RASA1 deficiency.
  • In vitro and in vivo studies showed that RASA1 rescue or Ras inhibition (RMC-7977) partially reversed abnormalities and reduced lesion severity.

Conclusions:

  • RASA1 deficiency exacerbates CCM-like pathology via Ras/Raf/MAPK pathway activation.
  • Targeting the Ras pathway presents a potential therapeutic avenue for specific CCM subtypes.
  • Further research into Ras-targeted strategies for genetically defined CCMs is warranted.
Keywords:
RASA1Ras/Raf/MAPK pathwaymetabolic reprogrammingsporadic cerebral cavernous malformationsvascular endothelial proliferation

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