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. Author manuscript; available in PMC: 2015 Feb 1.
Published in final edited form as: Int J Biochem Cell Biol. 2013 Dec 11;47:118–148. doi: 10.1016/j.biocel.2013.11.021

Fig. 4. Alternative models for Ccm protein function in vascular development and integrity.

Fig. 4

(A) Based on the evidence discussed in the text, we propose a model in which Ccm3/GCKIII has overlapping functions with Ccm1/Ccm2. This model is consistent with the common function of these proteins in vascular development and integrity, the fact that Ccm3, Ccm2, and Ccm1 form a complex together, and the differences reported for Ccm3 versus Ccm1 and Ccm2 in CCM mouse models, zebrafish, and human CCM. The arrow from Ccm3 to Ccm2/Ccm1 indicates that Ccm3 functions together with these proteins, not necessarily upstream of them, while the arrow from Ccm3 directly to vascular development and integrity represents a Ccm2/Ccm1-independent pathway. (B) In an alternative model, Ccm3/GCKIII acts only through a distinct pathway from Ccm1 and Ccm2 in vascular development and in promoting vascular integrity (for examples, see (Chan et al., 2011, Yoruk et al., 2012)). (C) In a third model, Ccm3/GCKIII signals together with Ccm1/Ccm2 in a common pathway in vascular development and in promoting vascular integrity (for example, see (Zheng et al., 2010)). Each of these models is consistent with mutation in any one of CCM genes leading to development of CCM, but the first model is the most compatible with existing data.