Frequency and amplitude control of cortical oscillations by phosphoinositide waves

Abstract

Rhythmicity is prevalent in the cortical dynamics of diverse single and multicellular systems. Current models of cortical oscillations focus primarily on cytoskeleton-based feedbacks, but information on signals upstream of the actin cytoskeleton is limited. In addition, inhibitory mechanisms--especially local inhibitory mechanisms, which ensure proper spatial and kinetic controls of activation--are not well understood. Here, we identified two phosphoinositide phosphatases, synaptojanin 2 and SHIP1, that function in periodic traveling waves of rat basophilic leukemia (RBL) mast cells. The local, phase-shifted activation of lipid phosphatases generates sequential waves of phosphoinositides. By acutely perturbing phosphoinositide composition using optogenetic methods, we showed that pulses of PtdIns(4,5)P2 regulate the amplitude of cyclic membrane waves while PtdIns(3,4)P2 sets the frequency. Collectively, these data suggest that the spatiotemporal dynamics of lipid metabolism have a key role in governing cortical oscillations and reveal how phosphatidylinositol 3-kinases (PI3K) activity could be frequency-encoded by a phosphatase-dependent inhibitory reaction.

Excitable Signal Transduction Networks in Directed Cell Migration

“…In some cases, the similar phase relationships among various components has been documented. In mast cells, for example, F-actin zones correspond to troughs in PIP2 waves (Xiong et al, 2016). It remains to be determined whether these dynamic events are displayed by a few cell types under specific conditions or whether they are an unrecognized general feature of migrating cells and perhaps play further roles in cell physiology.…”

Progress and perspectives in signal transduction, actin dynamics, and movement at the cell and tissue level: lessons fromDictyostelium

“…There is strong evidence that phospholipid signalling is an integral part of this actin oscillator with a positive feedback loop in which F-actin activates PI3K. PI3K-dependent production of PIP3 phosphoinositides, integral constituents of the cell membrane, can in turn stimulate further F-actin production through Rac, which activates NPFs of Arp2/3 [47,48]. Khamviwath et al [24] have proposed a continuum model for actin waves based on a large number of molecular details of actin network dynamics and the PI3K pathway ( figure 7).…”

Clathrin Assembly Defines the Onset and Geometry of Cortical Patterning

“…We previously showed that SHIP1, a PIP3 5-phosphatase is a molecular marker for the refractory phase of FBP17 waves (Xiong et al, 2016). To determine whether the difference in time of the clathrin onset was determined by the length of the refractory phase in the previous cycle, we imaged SHIP1 together with clathrin.…”

“…For cortical actin waves, molecular players that act upstream of actin, including Rho family GTPases and their activating lipid second messengers have been heavily investigated. These include Rac and phosphatidylinositol-3,4,5-trisphosphate (PIP3) in HL-60 neutrophils (Weiner et al, 2007), Rho in Xenopus eggs and starfish oocytes (Bement et al, 2015), PIP3 and phosphoinositide-3-kinase (PI3K) in Dictyostelium discoideum (Arai et al, 2010), and Cdc42 and PI3K in RBL-2H3 mast cells (Xiong et al, 2016). Because waves of Rho GTPase activation usually precedes actin waves and inactivation of these Rho GTPases could abolish actin waves, activation of Rho GTPases has been suggested to be involved in wave nucleation.…”

“…A more recently identified group of actin-regulatory proteins involved in cortical waves is Fer/CIP4, Bin, amphiphysin, and Rvs (F-BAR) proteins of the Toca family, including FBP17, CIP4, and Toca-1 (Wu et al, 2013; Xiong et al, 2016). In mast cells, receptor activation by multivalent antigen leads to pronounced dynamic accumulation of F-BAR proteins and the formation of traveling waves.…”