Inositol lipid phosphatases in membrane trafficking and human disease

Abstract

The specific interaction of phosphoinositides with proteins is critical for a plethora of cellular processes, including cytoskeleton remodelling, mitogenic signalling, ion channel regulation and membrane traffic. The spatiotemporal restriction of different phosphoinositide species helps to define compartments within the cell, and this is particularly important for membrane trafficking within both the secretory and endocytic pathways. Phosphoinositide homoeostasis is tightly regulated by a large number of inositol kinases and phosphatases, which respectively phosphorylate and dephosphorylate distinct phosphoinositide species. Many of these enzymes have been implicated in regulating membrane trafficking and, accordingly, their dysregulation has been linked to a number of human diseases. In the present review, we focus on the inositol phosphatases, concentrating on their roles in membrane trafficking and the human diseases with which they have been associated.

Emerging roles of PtdIns(4,5)P2 – beyond the plasma membrane

“…Local PIPKIγi5 and PtdIns(4,5)P 2 effectors, such as SNX5, SNX6 and LAPTM4B, as well as inward budding of the limiting membrane during intraluminal sorting, might all contribute to the establishment of local PtdIns(4,5)P 2 microdomains at endosomal surface. To ensure a dynamic turnover of PtdIns(4,5)P 2 microdomains, endosomal phosphoinositide phosphatases, such as OCRL1 and Sac2, might also be involved (Hsu et al, 2015;Nakatsu et al, 2015;Billcliff and Lowe, 2014). However, if the generation of PtdIns(4,5)P 2 by PIPKs is spatially coordinated with PtdIns(4,5)P 2 effectors, then PtdIns(4,5)P 2 could be channeled to the effector without requiring a PtdIns(4,5)P 2 microdomain.…”

SHIP2 controls plasma membrane PI(4,5)P2 thereby participating in the control of cell migration in 1321 N1 glioblastoma cells

“…There are ten different enzymes that often catalyze the dephosphorylation of both phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] and [PI(3,4,5)P3] at the 5-position, although it is not always clear whether or not both lipids are modified in intact cells. Despite some sequence identity in their catalytic sites, it appears that inositol polyphosphate 5-phosphatases are not redundant in intact cells and mutations of several members of this family have been found to be associated with very specific human diseases such as the Lowe syndrome, Dent disease and Joubert syndrome (Balla, 2013;Billcliff and Lowe, 2014;Pirruccello and De Camilli, 2012;Staiano et al, 2015). Recent data have clearly shown the tumor regulatory role of the inositol polyphosphate 5-phosphatases in different type of cancers such as glioblastoma (Kim et al, 2014).…”

Panta rhei an der Plasmamembran: Phosphoinositlipide in der Endozytose

“…Diese wiederum stellen ein geeignetes Substrat für die Dynamin-vermittelte Abschnürung des endozytotischen Vesikels von der Plasmamembran dar [3,9]. Schließlich erfolgt zusammen mit der explosionsartigen Selbstassemblierung von Dynamin die vollständige Hydrolyse von PI(4,5)P 2 zu PI(4)P durch die Aktivität der 5-Phosphatasen Synaptojanin und OCRL [7] und damit eine Konversion der PI-Identität der internalisierten Membran von PI(4,5)P 2 zu PI(3,4)P 2 . Es ist durchaus möglich, dass diese PI-Konversion auch den Trigger für die von Hsc70 und Auxilin katalysierte uncoating-Reaktion darstellt, die eine Voraussetzung für die nachfolgende Fusion der endozytierten Vesikel mit PI(3)P-positiven Endosomen darstellt.…”