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Review
. 2009 Aug:24:231-44.
doi: 10.1152/physiol.00014.2009.

Phosphoinositide signaling: new tools and insights

Tamas Balla  1 , Zsofia Szentpetery, Yeun Ju Kim
Affiliations
Review

Phosphoinositide signaling: new tools and insights

Tamas Balla et al. Physiology (Bethesda). 2009 Aug.

Abstract

Phosphoinositides constitute only a small fraction of cellular phospholipids, yet their importance in the regulation of cellular functions can hardly be overstated. The rapid metabolic response of phosphoinositides after stimulation of certain cell surface receptors was the first indication that these lipids could serve as regulatory molecules. These early observations opened research areas that ultimately clarified the plasma membrane role of phosphoinositides in Ca(2+) signaling. However, research of the last 10 years has revealed a much broader range of processes dependent on phosphoinositides. These lipids control organelle biology by regulating vesicular trafficking, and they modulate lipid distribution and metabolism more generally via their close relationship with lipid transfer proteins. Phosphoinositides also regulate ion channels, pumps, and transporters as well as both endocytic and exocytic processes. The significance of phosphoinositides found within the nucleus is still poorly understood, and a whole new research concerns the highly phosphorylated inositols that also appear to control multiple nuclear processes. The expansion of research and interest in phosphoinositides naturally created a demand for new approaches to determine where, within the cell, these lipids exert their effects. Imaging of phosphoinositide dynamics within live cells has become a standard cell biological method. These new tools not only helped us localize phosphoinositides within the cell but also taught us how tightly phosphoinositide control can be linked with distinct effector protein complexes. The recent progress allows us to understand the underlying causes of certain human diseases and design new strategies for therapeutic interventions.

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Figures

Figure 1
Figure 1
Phosphoinositides regulate multiple membrane-associated molecular events. (A) Signaling from the inner leaflet of the plasma membrane is the best documented and known function of PtdIns(4,5)P2 and PtdIns(3,4,5)P3. PtdIns(4,5)P2 serves both as a precursor for PLC-generated messengers such as Ins(1,4,5)P3 and diacylglycerol, and an activator of other phospholiases, such as PLD. PtdIns(4,5)P2 is also converted to PtdIns(3,4,5)P3 by PI 3-kinases. This lipid recruits and activates several important protein kinases such as Akt/PKB, Btk and some PKC isoforms. (B) Phosphoinositides also regulate the activity of a number of ion channels and transporters thereby controlling ion distribution and gradients. (C) Phosphoinositides not only help hydrophilic and charged molecules (such as ions) to cross the hydrophobic membranes, but as increasingly being recognized, they also help hydrophobic molecules to traverse the aqueous phase separating the membranes. The lipid transfer proteins may carry their cargo to farther distances within the cell, but more likely they work within functional contact zones formed by adjacent membranes without moving too far from these membranes. Such functional zones exist between the ER and the Golgi, the ER and the mitochondria and the ER and the PM. Phosphoinositides probably also regulate the flipase and flopase proteins that help move certain lipids between the inner and the outer leaflet of membranes. (D) Phosphoinositides control the budding and fission process between membranes and hence are critical regulators of vesicular trafficking. Intriguingly the steady state phosphorylation state of phosphoinositides increases as one moves from the nuclear envelope/ER (very little if any phsophorylated PtdIns) toward the PM which has most of the PtdIns(4,5)P2 and PtdIns(3,4,5)P3. The role of phosphoinositides in these locations is to recruit adaptor proteins and to work together with the small GTP binding proteins often regulating their nucleotide exchange factors or GAP proteins.
Figure 2
Figure 2
Coincidence detection in phosphoinositide signaling. (A) Phosphoinositide recognition and its activation of downstream signals is often contingent upon simultaneous engagement with the active, GTP-bound from of small G nucleotide binding proteins. For example, PtdIns4P-mediated signals usually require activated Arf1, while PtdIns3P is linked with the Rab5 and possibly other Rab proteins. PtdIns(3,4,5)P3 function is often closely associated with the Rac and Ras proteins while PtdIns(4,5)P2 is with that of Arf6. This listing, however, is incomplete and will be greatly extended by future research. (B) Phosphoinositide signaling can be compartmentalized to the extent that the phosphoinositide is channeled to a particular effector molecule. In this arrangement the associated kinase and phosphatase enzyme provides the specificity and the specificity of inositide binding of the effector is not crucial to the process.
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