Understanding the phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks):  A way of PIPping cancer to the post?


Year:

Session type:

Daniel Fitzgerald1, Nullin Divecha1
1The Paterson Institute for Cancer Research, Manchester, United Kingdom

Background

Phosphoinositides (PIs) are a family of lipids composed of phosphorylated derivatives of phosphatidylinositol (PtdIns).  Whilst the PIs constitute only a minor fraction of the total phospholipid content, they are important components in a plethora of cellular signalling pathways, with phoshatidylinositol-4,5-bisphosphate (PIP2) being the most well known player.  As PIP2 is the substrate for the PI-3 kinase and Phospholipase C signalling pathways, both of which are upregulated in a number of cancers, understanding the control of it’s production is key to elucidating these cancer phenotypes. Equally, determining how to modulate PIP2 synthesise may be beneficial as a cancer therapeutic.

Method

The enzymatic production of PIP2 is predominantly mediated through the PIP5Ks, of which there are three isoforms (?, ?, and ?) in mammalian cells.  The localisation of these proteins within the cell has not been fully resolved, and it is now widely recognised that most proteins are guided to their active sites by multiple targeting factors.  In fact, the existence of these multiple factors allows a greater level of complexity within the cell, with co-incidence detection mechanisms ensuring specificity during distinct signalling events.

Results

In order to address the localisation (as well as the underlying factors that control it), of these proteins under various conditions, fluorescently tagged versions of the wild-type and point mutant PIP5Ks proteins have been utilised in conjunction with live microscopy.  Observations from this investigation demonstrate there is not only a difference between the resting location of the PIP5K isoforms, but also that the response of these proteins to different cellular treatments are distinct.

Conclusion

In addition, the data indicates that it is not likely to be simple electrostatic switches, or binding to regulatory proteins alone that control the targeting of the PIP5Ks, but that more complex modulation exists.