title: The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3.
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.
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; fcullere@rics.bwh.harvard.edu.
authors.forename: Xavier
authors.initials: X
authors.lastname: Cullere
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Eva
authors.initials: E
authors.lastname: Plovie
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Paul M
authors.initials: PM
authors.lastname: Bennett
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Tanya N
authors.initials: TN
authors.lastname: Mayadas
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000196:embryology / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D055785:Gene Knockdown Techniques; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D029961:Zebrafish Proteins; D048054:Mitogen-Activated Protein Kinase 7; D048748:MAP Kinase Kinase Kinase 3
keywords: MAP kinase; cerebral cavernous malformation; endothelium; expression; signaling