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Human Molecular Genetics Advance Access originally published online on July 21, 2005
Human Molecular Genetics 2005 14(17):2521-2531; doi:10.1093/hmg/ddi256
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis

Jon S. Zawistowski1,{dagger}, Lisa Stalheim2,{dagger}, Mark T. Uhlik2, Amy N. Abell2, Brooke B. Ancrile1, Gary L. Johnson2 and Douglas A. Marchuk1,*

1Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA and 2Department of Pharmacology and the Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, USA

* To whom correspondence should be addressed. Tel:+1 9196843290; Fax:+1 9196819193; Email: march004{at}mc.duke.edu

Received April 28, 2005; Accepted July 14, 2005

Cerebral cavernous malformations (CCMs) are sporadically acquired or inherited vascular lesions of the central nervous system consisting of clusters of dilated thin-walled blood vessels that predispose individuals to seizures and stroke. Familial CCM is caused by mutations in KRIT1 (CCM1) or in malcavernin (CCM2), the murine ortholog of which was concurrently characterized as osmosensing scaffold for MEKK3 (OSM). The roles of the CCM proteins in the pathogenesis of the disorder remain largely unknown. Here, we use co-immunoprecipitation, fluorescence resonance energy transfer and subcellular localization strategies to show that the CCM1 gene product, KRIT1, interacts with the CCM2 gene product, malcavernin/OSM. Analogous to the established interactions of CCM1 and ß1 integrin with ICAP1, the CCM1/CCM2 association is dependent upon the phosphotyrosine binding (PTB) domain of CCM2. A familial CCM2 missense mutation abrogates the CCM1/CCM2 interaction, suggesting that loss of this interaction may be critical in CCM pathogenesis. CCM2 and ICAP1 bound to CCM1 via their respective PTB domains differentially influence the subcellular localization of CCM1. Furthermore, we expand upon the established involvement of CCM2 in the p38 mitogen-activated protein kinase signaling module by demonstrating that CCM1 associates with CCM2 and MEKK3 in a ternary complex. These data indicate that the genetic heterogeneity observed in familial CCM may reflect mutation of different molecular members of a coordinated signaling complex.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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