Phosphatidylinositol 4-kinase IIβ negatively regulates invadopodia formation and suppresses an invasive cellular phenotype

Abstract

The PI4KIIs play important roles in membrane trafficking through the production of PI(4)P. This study reveals a novel function of PI4KIIβ in regulating invadopodia formation and illustrates the importance of maintaining specific pools of trans-Golgi network–endosomal PI(4)P.

The Many Roles of Type II Phosphatidylinositol 4‐Kinases in Membrane Trafficking: New Tricks for Old Dogs

“…The biosynthesis of PtdIns4 P by different PI4K isoforms can occur in metabolically separate pools . Connecting each of these pools to a particular PI4KII activity in the absence of effective inhibitors has been challenging; however, the Balla laboratory has adopted and developed techniques to acutely manipulate PIs in different organelles by the inducible targeting of PI phosphatases .…”

“…B) PI4KIIβ is partially cytosolic and is dynamically palmitoylated in response to growth factors and expression of constitutively active Rac, which both lead to PM recruitment. PI4KIIβ synthesises a pool of PtdIns4 P that colocalises with TGN46 (green). At the TGN, PI4KIIβ is responsible for recruitment of the clathrin adaptor AP‐1 .…”

“…In the case of PI4KIIβ/AP‐1, this depends on the biosynthetic activity of PI4KIIβ; whereas, with PI4KIIα/AP‐3, despite having a requirement for both kinase activity and an intact dileucine motif, evidence supporting a direct role for PtdIns4 P in AP‐3 recruitment has been elusive. However, the PI4KII isoforms synthesize spatially separate pools of PtdIns4 P in the TGN‐endosomal system (Figure ) and a pool of PtdIns4 P is required for AP‐3 cargo trafficking, arguing that both PI4K‐adaptor systems are dependent on PtdIns4 P . In summary, it is clear that PI4KII isoforms operate in different post‐TGN trafficking pathways by utilizing distinct PI4KII‐dependent clathrin adaptor systems, and that the PI4KIIα/AP‐3 and PI4KIIβ/AP‐1 complexes exhibit a similar reciprocal relationship between location and function.…”

“…The functions of PtdIns4 P have also expanded into a much broader subcellular distribution than previously envisaged. Discrete pools of PtdIns4 P outside of the Golgi are now recognized on early (EE) and sorting endosomes (SEs), late endosomes (LEs), at the plasma membrane (PM) and even on different subdomains of the trans‐Golgi network (TGN)‐endosomal system (Figure ). The PI4KIIα and PI4KIIβ enzymes have also been detected at the PM and in endosomal compartments containing PtdIns4 P .…”

“…Discrete PI4K activities are responsible for this distribution and it is known that PI4KIIIα is a major PtdIns4 P biosynthetic activity at the PM (yellow). PI4KIIIβ produces a pool in the Golgi apparatus (magenta), whereas PI4KIIα and PI4KIIβ produce PtdIns4 P on separate domains of the TGN (red and green, respectively) . PI4KIIα is also responsible for pools of PtdIns4 P on RE, SE, LE, and Apg membranes (blue) that are likely to be dynamically regulated.…”