Fig. 2.

Function of PH and C2 membrane targeting domains in the recruitment and activation of signaling proteins on target membrane surfaces (Corbalan-Garcia et al., 2007; Leonard and Hurley, 2011; Newton, 2009; Lemmon, 2008; Cho, 2001; Nalefski and Falke, 1996). First, a 2° messenger signal triggers the recruitment of the signaling protein targeting domain from the cytoplasm to the bilayer surface: many PH domains are recruited to the plasma membrane by a PI(3,4,5)P₃ (PIP₃) lipid signal, while the C2 domains of classical protein kinase C isoforms (cPKCs) are activated by Ca²⁺ binding and then dock to PS and PI(4,5)P₂ (PIP₂) on the plasma membrane. Second, the signaling domain of each recruited protein is activated by its proximity on the membrane surface to membrane-associated protein and/or lipid molecules that serve as effectors or substrates. At the leading edge membrane, PIP₃ and Ca²⁺ both recruit signaling proteins and establish a signaling network on the bilayer surface. Lateral, 2-dimensional diffusion on the bilayer is required for the signaling proteins to encounter and bind their signaling partners, and for the resulting membrane-bound products to diffuse away. Thus, the lipid bilayer serves as a 2-dimensional platform for the assembly of the dynamic signaling circuit, and for the diffusion of its many components during signaling reactions.