ArticleProceedings of the National Academy of Sciences of the United States of America2015
The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 73 citations in OpenAlex.
- Inhibition of MEKK3 Prevents Cerebral Cavernous Malformation Progression Via Restoring Endothelial Integrity and Restricting Microglial Activation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Identification of the adhesion GPCR ADGRL4/ELTD1 as a novel potential prognostic biomarker for cerebral cavernous malformation disease.Molecular medicine (Cambridge, Mass.) · 2026Article
- TIE2 links MEKK3-KLF2/4 and PI3K signaling in cerebral cavernous malformation.The Journal of experimental medicine · 2026Article
- Dual recruitment of two CCM2 molecules to KRIT1 suppresses KLF4 expression.Nature communications · 2026Article
- Structural basis for MEKK2 dimerization and substrate recognition.Nature communications · 2025Article
- Single-cell sequencing insights into the transcriptional landscape of cerebral cavernous malformations.Angiogenesis · 2025Review
- Glomulin and cerebral cavernous malformations 2 protein-like mutations in an extensive blaschkoid glomuvenous malformation with polydactyly.JAAD case reports · 2025Article
- High-throughput differentiation of human blood vessel organoids reveals overlapping and distinct functions of the cerebral cavernous malformation proteins.Angiogenesis · 2025Article
- Compound Heterozygous Loss-of-Function Variants in CCM2L in a Fetus With Tetralogy of Fallot.Molecular genetics & genomic medicine · 2025Article
- Cerebral Cavernous Malformation: From Genetics to Pharmacotherapy.Brain and behavior · 2025Review
- Unraveling hematopoietic stem cell ontogeny through single-cell multi-omics approaches.Frontiers in cell and developmental biology · 2025Review
- HEG1 Protects Against Atherosclerosis by Regulating Stable Flow-Induced KLF2/4 Expression in Endothelial Cells.Circulation · 2024Article
- Hyaluronic acid turnover controls the severity of cerebral cavernous malformations in bioengineered human micro-vessels.APL bioengineering · 2024Article
- Article
- Clonal Expansion in Cardiovascular Pathology.JACC. Basic to translational science · 2024Review
- Plasma metabolites with mechanistic and clinical links to the neurovascular disease cavernous angioma.Communications medicine · 2023Article
- KRIT1: A Traffic Warden at the Busy Crossroads Between Redox Signaling and the Pathogenesis of Cerebral Cavernous Malformation Disease.Antioxidants & redox signaling · 2023Review
- Review
- Article
- Is Location Everything? Regulation of the Endothelial CCM Signaling Complex.Frontiers in cardiovascular medicine · 2022Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Three genes, CCM1, CCM2, and CCM3, interact genetically and biochemically and are mutated in cerebral cavernous malformations (CCM). A recently described member of this CCM family of proteins, CCM2-like (CCM2L), has high homology to CCM2. Here we show that its relative expression in different tissues differs from that of CCM2 and, unlike CCM2, the expression of CCM2L in endothelial cells is regulated by density, flow, and statins. In vitro, both CCM2L and CCM2 bind MEKK3 in a complex with CCM1. Both CCM2L and CCM2 interfere with MEKK3 activation and its ability to phosphorylate MEK5, a downstream target. The in vivo relevance of this regulation was investigated in zebrafish. A knockdown of ccm2l and ccm2 in zebrafish leads to a more severe "big heart" and circulation defects compared with loss of function of ccm2 alone, and also leads to substantial body axis abnormalities. Silencing of mekk3 rescues the big heart and body axis phenotype, suggesting cross-talk between the CCM proteins and MEKK3 in vivo. In endothelial cells, CCM2 deletion leads to activation of ERK5 and a transcriptional program that are downstream of MEKK3. These findings suggest that CCM2L and CCM2 cooperate to regulate the activity of MEKK3.
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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.