CCM2 is a scaffold protein that plays a crucial role in cerebral cavernous malformation (CCM) signaling, which regulates heart and vessel formation and integrity 1. The protein functions as a key component of a three-protein complex with CCM1/KRIT1 and CCM3/PDCD10, where loss-of-function mutations in any of these genes cause familial autosomal dominant CCMs 1. CCM2 directly binds to MEKK3 (MAP3K3), and disruption of this interaction leads to pathogenic gain of MEKK3 signaling and increased expression of transcription factors KLF2 and KLF4 in endothelial cells 2. This aberrant signaling cascade drives CCM lesion formation through multiple mechanisms, including increased endothelial nitric oxide production, astrocyte VEGF synthesis, and blood-brain barrier dysfunction 3. Disease-causing CCM2 mutations specifically abrogate the MEKK3 interaction without affecting CCM complex formation, demonstrating the critical importance of this scaffold function 2. Familial CCMs due to CCM2 mutations account for approximately 20% of inherited cases, typically presenting with multiple lesions and symptoms including seizures, cerebral hemorrhage, and focal neurological deficits 4. The CCM signaling pathway has also been implicated in coronary artery disease risk, highlighting broader cardiovascular functions 5.