ArticleNature2016
Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling.
Article in Nature, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 208 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
208 citing papers in PubMed, 1 synthesis or guideline pooled it, 313 citations in OpenAlex.
- Molecular Pathways and Circulating Biomarkers in Cerebral Cavernous Malformations-A Systematic Review.International journal of molecular sciences · 2026Pooled it
- Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial.Neurosurgery · 2019Trial
- Structure-based discovery of acridone alkaloids as disruptors of the HEG1-KRIT1 protein-protein interaction in cerebral cavernous malformation signaling.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Cerebral cavernous malformations: epidemiology, molecular pathogenesis, diagnosis and therapy.Molecular biomedicine · 2026Review
- Inhibition of MEKK3 Prevents Cerebral Cavernous Malformation Progression Via Restoring Endothelial Integrity and Restricting Microglial Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- c-KIT expands the tool kit for treating arteriovenous malformation.The Journal of clinical investigation · 2026Article
- Loss of Smad4 drives vascular malformations via c-KIT-dependent high-fluid shear stress mimicry.The Journal of clinical investigation · 2026Article
- From Somatic Driver to Molecular Therapy in Retinal, Choroidal and Periocular Vascular Disease: Mosaicism, Targetable Pathways and Ocular Toxicity.International journal of molecular sciences · 2026Review
- Article
- Article
- Oxygenated 9H-carbazole-3-carbaldehyde scaffolds as cerebral cavernous malformation-relevant protein-protein interaction disruptors of the HEG1-KRIT1 interface.Journal of computer-aided molecular design · 2026Article
- Endothelial estrogen receptor alpha (ESR1) regulates cerebral cavernous malformation pathogenesis via MEKK3-KLF signaling pathway.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026Article
- Rapamycin Partially Reverts Cavernoma Endothelial Cell Phenotype and, When Combined With Lapatinib, Ameliorates Chronic Lesions.Journal of cellular and molecular medicine · 2026Article
- Human stem cell models in cerebral cavernous malformations.Stem cell research & therapy · 2026Review
- Metal-dependent regulated cell death: Molecular architecture and translational frontiers.iMeta · 2026Review
- TIE2 links MEKK3-KLF2/4 and PI3K signaling in cerebral cavernous malformation.The Journal of experimental medicine · 2026Article
- Knockin expression of human ADAMTS5 impairs cardiovascular development and aggravates cerebral cavernous malformations in mice.Disease models & mechanisms · 2026Article
- MEKK3 bridges gut-brain communication and cerebral cavernous malformation pathogenesis.Cell death discovery · 2026Review
- Lycium barbarum polysaccharide inhibits Hcy-induced vascular smooth muscle cells migration and invasion via upregulation of KLF4.Scientific reports · 2026Article
- Dual recruitment of two CCM2 molecules to KRIT1 suppresses KLF4 expression.Nature communications · 2026Article
148 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
16 authors at 6 institutions in 4 countries.
Funding
Abstract
Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.