Schematic model showing the CD59 signal transduction mediated by the transbilayer raft phase, which recruits lipid-anchored signaling molecules at the ligated, stabilized CD59 cluster domains in the PM outer leaflet, inducing enhanced interactions of recruited molecules. (A) First, the ligand binding triggers the conformational changes of CD59, which in turn induce CD59 clustering, creating stable CD59 cluster signaling rafts. If GM1 is clustered closely, then stable GM1 cluster rafts will be produced. (B) Then, the transbilayer raft phase is induced by the CD59 cluster raft by involving molecules in the inner leaflet, recruiting cholesterol and molecules with saturated alkyl chains (left) and also excluding molecules with unsaturated alkyl chains. An as yet unknown TM protein(s) X, which has affinities to raft domains, might also be recruited to the transbilayer raft phase (right; recruitment of X could be enhanced by specific protein–protein interactions with the ligated CD59 exoplasmic protein domain). (C) Finally, cytoplasmic lipid-anchored signaling molecules, such as H-Ras and Lyn, are recruited to the transbilayer raft phase in the inner leaflet by the raft–lipid interaction (left). This could be enhanced by the protein–protein interaction with the TM protein X (right). Although the residency times of the inner-leaflet signaling molecules beneath the CD59 cluster may be limited, because many molecules will be recruited there one molecule after another, interactions of two or more species of cytoplasmic signaling molecules will occur efficiently beneath the CD59 cluster raft. This way, the transbilayer raft phase induced by the stabilized CD59 cluster raft would function as an important signaling platform.