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Page 16 of 23 Padarti et al. Vessel Plus 2018;2:21 I http://dx.doi.org/10.20517/2574-1209.2018.34

Interactome

CSC signalome
Integrin signaling Notch signaling KLF4/KLF2 signaling VEGF signaling MAPK signaling TLR4 signaling

CSC vasculome
EC angiogenesis Morphology/integrity Apoptosis Exocytosis Autophagy
EC vasculogenesis
Gonadogenesis
ROS and oxidative damage

Figure 1. The cellular roles of the CSC complex. The schematic diagram summarizes the known CSC interaction protein partners
(interactome), defined CSC-modulated signaling pathways (signalome), and distinct molecular and cellular functions of CSC complex
(vasculome) with our current understanding of CSC cellular functions. CCM: cerebral cavernous malformations; CSC: CCM signaling
complex; EC: endothelial cells

CCM3 mRNA 3’UTR was found to be able to bind to Mir-103, a microRNA that was found to be associated
with prostate cancer. This microRNA was found to be down-regulated in prostate cancer. Furthermore,
in vivo studies showed that up-regulation of Mir-103 restored cells to senescence. The in vitro studies of cell
culture showed that Mir-103 plays an important role for G1/S cellular checkpoint. When Mir-103 binds to
CCM3 mRNA, it targets the CCM3 transcript for degradation. The decreased expression of CCM3 in the
cell leads to increased apoptosis. Further, overexpression Mir-103 in normal cells resulted in increased
apoptosis. Likewise, down-regulation of CCM3 observed in a prostate cancer cell line resulted in increased
apoptosis , suggesting that CCM3 may play a role as oncogene or tumor suppressor (depending on cell
[176]
signaling), in the tumorigenesis.
In summary, CCM proteins form a signaling complex (CSC) that have been demonstrated to play major
roles in the regulation of multiple cell structures and signaling mechanisms involved in fundamental
physiological and biogenic functions, as well as in cell responses to various environmental stressors. We
have detailed these recent findings in the review, with a diagrammatic summary of major functions of CSC
in three categories: interactome, signalome, and vasculome [Figure 1].