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, PIP3. 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.