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Local PIP2 signals: when, where, and how?

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Abstract

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.

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Acknowledgments

I express my deep gratitude to all past and present members of this laboratory who contributed importantly to the perspectives outlined here. They include David P. Cash, Anthony Collins, Satoshi Matsuoka, Siyi Feng, Tong M. Kang, Mei-Jung Lin, Alp Yarandanakul, Chengcheng Shen, Tzu-Ming Wang, and Vincenzo Larrici. I thank Dr. Vytas A. Bankaitis (Univeristy of North Carolina) for generous provision of phosphatidylinositol transfer protein and Erwin Neher and Jakob Sorenson (MPI, Goettingen) for critical discussion. This work was supported by NIH-HL067942 and HL5132312.

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Hilgemann, D.W. Local PIP2 signals: when, where, and how?. Pflugers Arch - Eur J Physiol 455, 55–67 (2007). https://doi.org/10.1007/s00424-007-0280-9

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