Local PIP₂ signals: When, where, and how?

PIP₂ is a minor phospholipid that modulates multiple cellular processes. However, its abundance by mass, like diacylglycerol, is still 20 to 100 times greater than the master phospholipid second messenger, PIP ₃. Therefore, it is a case-by-case question whether PIP₂ is acting more like GTP, in being a cofactor in regulatory processes, or whether it is being used as a true second messenger. Analysis of signaling mechanisms in primary cells is essential to answer this question, as overexpression studies will naturally generate false positives. In connection with the possible messenger function of PIP₂, a second question arises as to how and if PIP₂ metabolism and signaling may be limited in space. This review summarizes succinctly the notable cases in which PIP₂ is proposed to function in a localized way and the different mechanistic models that may allow it to function locally. In general, drastic restrictions of PIP₂ diffusion are required. It is speculated that molecular PIP₂ signaling may be possible in the absence of PIP₂ gradients via ternary complexes between PIP₂ and two protein partners. That PIP₂ synthesis and hydrolysis might be locally dependent on protein-protein interactions, and direct lipid "hand-off" is suggested by multiple results.