Does PtdIns(4,5)P2 concentrate so it can multi-task?

Abstract

Ptdns(4,5)P2 is a minor structural lipid of the plasma membrane (PM), but a master regulator of PM function. Serving either as a substrate for the generation of second messengers, or more commonly as a ligand triggering protein recruitment or activation, it regulates most aspects of PM function. Understanding how this relatively simple biological macromolecule can regulate such a vast array of different functions in parallel, is the key to understanding the biology of the PM as a whole, in both health and disease. In this review, potential mechanisms are discussed that might explain how a lipid can separately regulate so many protein complexes. The focus is on the spatial distribution of the lipid molecules, their metabolism and their interactions. Open questions that still need to be resolved are highlighted, as are potential experimental approaches that might shed light on the mechanisms at play. Moreover, the broader question is raised as to whether PtdIns(4,5)P2 should be thought of as a bona fide signalling molecule or more of a simple lipid cofactor or perhaps both, depending on the context of the particular function in question.

Loss of PTEN promotes formation of signaling-capable clathrin-coated pits

“…Thus, it is possible that the effect of PI(3,4,5)P 3 are due to PI(3,4)P 2 in PTEN-null cells or occur during an acute increase of PI(3,4,5)P 3 . Although PI(3,4,5)P 3 is converted by PTEN to PI(4,5)P 2 , we do not think the effect of PTEN on CCP dynamics is directly related to changes in the PI(4,5)P 2 level because the amount of PI(3,4,5)P 3 is small compared to that of PI(4,5)P 2 (Hammond, 2016). We also do not think the effect of PTEN on CCP dynamics is due to its protein phosphatase activity that has recently been reported to play a role in late endocytic trafficking by dephosphorylation of Rab7 (Shinde and Maddika, 2016).…”

“…Among PIs, phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P 2 ], phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P 2 ] and phosphatidylinositol (3,4,5)-trisphosphate [PI(3,4,5)P 3 ] are found primarily on the plasma membrane. Notably, PI(4,5)P 2 is a master regulator of plasma membrane function, including CCP dynamics regulation and membrane-cytoskeleton interactions (Hammond, 2016). Consequently, lipid-modifying enzymes that are not part of the structural CCP core can also influence CME through modulating PI(4,5)P 2 levels (Zoncu et al, 2007;Mao et al, 2009;Antonescu et al, 2011).…”

Influenza Hemagglutinin Modulates Phosphatidylinositol 4,5-Bisphosphate Membrane Clustering

“…Furthermore, a megapool of unclustered PIP2 (81) would be expected to show examples of freely diffusing PIP2 molecules outside of clusters induced by effectors. Time-dependent spatial visualization of phosphoinositide kinases together with PIP2 and effectors could be quite helpful for testing the possibility of ''selfish PIP2 synthesis'' (81). Distinction between these possibilities could reveal multiple populations of HA and PIP2 (both clustered and unclustered); explain the large variability in cluster properties and the spatial dependence of HA-PIP2 colocalization; and lend support for time-dependent membrane models coupling clustering, confinement, signaling, and cell function.…”

Loss of PTEN promotes formation of signaling-capable clathrin-coated pits

“…Among the PIs, PI(4,5)P 2 , PI(3,4)P 2 , and PI(3,4,5)P 3 are found primarily on the plasma membrane. Notably, PI(4,5)P 2 is a master regulator of plasma membrane function, including CCP dynamics regulation and membrane-cytoskeleton interactions 13 .…”