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Fig. 4. General principles of regulation by phosphoinositides. (A) Phosphorylation and dephosphorylation cycles control signaling cascades either directly (i) by phosphorylation of proteins, or indirectly (ii) by altering the phosphorylation state of GDP/GTP bound to GTP-binding proteins. Phosphorylation of membrane inositides (iii) offers a unique regulatory feature in that the phosphate acceptor molecule is membrane bound and can be phosphorylated in multiple ways. The phosphorylated lipid species interacts with proteins that recognise the lipid. It thereby contributes to the recruitment of these proteins to the membrane and probably also evokes conformational changes that affect their functions. (B) Phosphoinositides can control several kinds of signaling processes. Many proteins that contain phosphoinositide-recognition domains assume an inactive conformation (E_inactive) in the cytosol in which the inositide-binding site is masked by intramolecular or inter-molecular interactions. Production of the appropriate phosphoinositide (PtdIns(x,y)P_n+1) recruits the protein to the membrane, and specificity is imparted through interaction with integral (I) or peripheral (P) membrane proteins. The complex can remain active at the membrane and recruit additional proteins, such as actin or clathrin or, after modification, the protein can return to the cytosol in an activated (i.e. phosphorylated) form (E_active). The localization of both the lipid kinase and phosphatases that act on phosphoinositide adds to the precise control of individual effectors.

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