Cerebral cavernous malformations (CCMs) are relatively common vascular malformations that cause stroke and seizure in mid-life. Human genetic studies have identified 3 CCM disease genes that encode intracellular adaptors, KRIT1 (CCM1), CCM2, and PDCD10 (CCM3). Genetic studies in fish and mice and biochemical studies have demonstrated that CCM proteins interact with each other and with the endothelial receptor HEG during cardiovascular development. Human CCMs exhibit defective endothelial junctions and the CCM pathway is required in endothelial cells during cardiovascular development, but the downstream signals by which CCM proteins regulate cardiovascular function are not known. Our preliminary studies have identified two new downstream arms of the CCM pathway. First, we find that CCM3 coupling to the GCK-III family of Sterile 20-like serine/threonine kinases (STKs) that includes MST4, STK24 and STK25 is required for cardiovascular development in vivo and regulates RHO activity in endothelial cells in vitro. Second, we have identified a novel, endothelial- specific CCM2 homologue, CCM2L, that binds CCM1 and HEG but does not bind CCM3. Preliminary studies reveal that CCM2L is a strong activator of MEKK3, an endothelial MAPK required for mouse cardiovascular development. CCM2L-deficient mice exhibit strong genetic interaction with HEG, demonstrating participation by this novel protein in the CCM signaling pathway. We propose that CCM signaling regulates endothelial cell function through two distinct downstream pathways, a CCM3-STK pathway required for cell junctions and a CCM2L-MEKK3 pathway that regulates transcription. Defining the molecular components and functional roles of these novel downstream pathways will reveal how CCM signaling participates in cardiovascular development and human vascular disease.

Public Health Relevance

Cerebral cavernous malformations (CCMs) are relatively common vascular malformations that cause stroke and seizure in mid-life. Defining the molecular components and functional roles of these novel downstream pathways will reveal how CCM signaling participates in cardiovascular development and human vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102138-04
Application #
8515509
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Charette, Marc F
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$502,827
Indirect Cost
$188,560
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zheng, Xiangjian; Riant, Florence; Bergametti, Fran├žoise et al. (2014) Cerebral cavernous malformations arise independent of the heart of glass receptor. Stroke 45:1505-9