PtdIns5P: News and views of its appearance, disappearance and deeds

Abstract

Accumulated evidence indicates that PtdIns5P, one of the seven phosphoinositides, found now to be constitutively present in yeast, plants and metazoa, serves as a signaling molecule to modulate pleiotropic cellular functions in both the nucleus and the cytoplasm. The enzymatic routes in biogenesis of basal PtdIns5P have remained incompletely understood. The role for candidate kinase PIKfyve that is principally involved in PtdIns(3,5)P2 production, has been questioned. In this review article we scrutinize the past obstacles that prevented the definitive implication of PIKfyve in PtdIns5P biosynthesis from PtdIns and focus on the recent pharmacological and genetic advancements that now make this conclusion well supported. We further summarize our current knowledge of the diverse stimuli modulating PtdIns5P levels, binding partners and regulated cellular process, with particular reference to the available mechanistic insights for the relevant signaling pathways.

Class III PI 3-kinase is the main source of PtdIns3P substrate and membrane recruitment signal for PIKfyve constitutive function in podocyte endomembrane homeostasis

“…Consistent with the failure of PIKfyve membrane recruitment under localized depletion of PtdIns3P, a step critical for formation of productive complex of PIKfyve with its protein partners and, hence, activation of PIKfyve lipid kinase (1,46), we observed similar reduction in both PIKfyve lipid products PtdIns5P and PtdIns(3,5)P 2 (Fig. 4).…”

“…The ramification of the lost PIKfyve endosome localization is a commensurate reduction of PtdIns5P production (Fig. 4), a finding consistent with direct PIKfyve-catalyzed synthesis of PtdIns5P (46,54). The concomitant PtdIns5P diminution suggests that the cytosolic PIKfyve fails to gain access to the PtdIns substrate on membranes and/or form a productive heterooligomeric complex (PAS complex) with the two partner proteins, i.e., the scaffolding regulator ArPIKfyve and the antagonistic PtdIns(3,5)P 2 phosphatase Sac3 (1,37,55).…”

“…Both membrane recruitment and the PAS complex formation are crucial steps for PIKfyve activity, as evidenced by the inability of the dominant-negative kinase-deficient point mutant PIKfyve K1831 to trigger the vacuolation phenotype if incapacitated for PtdIns3P binding or ArPIKfyve-Sac3 association through truncated mutations in the FYVE domain or ArPIKfyve-Sac3 interaction sites, respectively (9,56). Concordantly, gene disruption of ArPIKfyve or Sac3 impairs PtdIns5P synthesis, further reinforcing the prerequisite of intact PAS complex in PIKfyve-catalyzed PtdIns5P production [reviewed in (46,54)].…”

cdc-Like/Dual-Specificity Tyrosine Phosphorylation–Regulated Kinases Inhibitor Leucettine L41 Induces mTOR-Dependent Autophagy: Implication for Alzheimer’s Disease

“…5C, L41 is able to reduce recombinant PIKfyve in vitro activity for PtdIns(3,5)P 2 synthesis (IC 50 5 3.3 mM). We also verified the effect of L41 on PtdIns5P generation with adenovirally produced PIKfyve and native PtdIns substrate preparation (Shisheva, 2013), which data demonstrated that both PtdIns5P and PtdIns(3,5)P 2 synthesis were similarly inhibited, with an IC 50 value of 0.7-1 mM (data not shown). These data suggest that the synergy observed upon CLK siRNA and L41 treatment could result from PIKfyve inhibition.…”

TOM1 is a PI5P effector involved in the regulation of endosomal maturation

“…In the nucleus, in response to stress signaling (Jones et al, 2006), PI5P acts as a regulator of chromatin organization and gene expression though its interaction with the PHD (plant homeodomain) domaincontaining protein ING2 (Gozani et al, 2003). Outside the nucleus, PI5P has been shown to be implicated in the regulation of membrane dynamics and trafficking (Shisheva, 2013;Viaud et al, 2014a). In this context, three potential pathways lead to an increase in the amount of PI5P: one involves the direct phosphorylation of phosphatidylinositol by the 5-kinase PIKfyve, the second involves a PI3P-PI(3,5)P 2 -PI5P route with the concerted action of the PIKfyve and the 3-phosphatases of the myotubularin family (Viaud et al, 2014a) and the third uses PI(4,5)P 2 as a source of PI5P.…”