Review
Nuclear PI(4,5)P2: A new place for an old signal

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Abstract

Over the last decades, evidence has accumulated suggesting that there is a distinct nuclear phosphatidylinositol pathway. One of the best examined nuclear lipid pathways is the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI4,5P2) by PLC resulting in activation of nuclear PKC and production of inositol polyphosphates. However, there is a growing number of data that phosphoinositides are not only precursor for soluble inositol phosphates and diacylglycerol, instead they can act as second messengers themselves. They have been implicated to play a role in different important nuclear signaling events such as cell cycle progression, apoptosis, chromatin remodeling, transcriptional regulation and mRNA processing. This review focuses on the role of specifically PI4,5P2 in the nucleus as a second messenger as well as a precursor for PI3,4,5P3, inositol polyphosphates and diacylglycerol.

Introduction

Phosphoinositides are ubiquitous signaling phospholipids that perform a diverse array of tasks in eukaryotic cells. In the “canonical” phosphoinositide cycle, extracellular stimuli trigger the metabolism of phosphoinositides by several classes of kinases, phosphatases and phospholipases. The coordinated activity of these enzymes at discrete subcellular locations provides tight regulation of effector proteins whose activities are modulated by specific phosphoinositide species. Cellular processes regulated by phosphoinositides include vesicular trafficking, migration, endocytosis and actin polymerization, to name just a few [1]. Over the past few decades, it has become increasingly clear that not only does a nuclear phosphoinositide cycle also exist in eukaryotic cells, but also that its regulation is independent of the cytosolic pathway. The identification of an autonomous nuclear phosphoinositide cycle suggests that these phospholipids modulate nuclear processes, and to date phospholipids metabolism has been implicated in nuclear processes ranging from transcription and pre-mRNA splicing to growth, proliferation and cell cycle regulation [2], [3], [4], [5].

There is an extensive collection of literature pertaining to nuclear phosphoinositides and phosphoinositide-modifying enzymes, yet, as with many other nuclear processes, our understanding of how phosphoinositides function within the nucleus is still far from complete. This point is illustrated by the following observation: in the cytosol there is substantial evidence that the phosphoinoisitides are located in membrane compartments, whereas in the nucleus there is no evidence that PI(4,5)P2 or any other phosphoinositide is located within a membrane. This single observation suggests the paradigm shifting nature of the nuclear phosphoinositide signaling pathway. In this review, we will discuss the nuclear functions ascribed to and modulated by the metabolism of PI(4,5)P2.

Section snippets

The nuclear phosphoinositide cycle

Phosphatidylinositol (PI) can be phosphorylated at the 3′, 4′ and 5′ position of the inositol ring by a variety of kinases resulting in all possible combinations of phosphatidylinositol phosphates. These phosphate residues in turn can be utilized by phosphatases to complete the cycle and even increase the number of different phosphatidylinositol phosphates isomers. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is the predominant regulatory molecule in the cytosolic phosphoinositide cycle.

PI(4,5)P2 in gene expression

Phosphoinositides and enzymes involved in their metabolism have been shown to exist in the nucleus as described above. This suggests that phosphoinositides may play a role in regulating nuclear signaling processes, but even now, there is little mechanistic data defining how phosphoinositides may regulate nuclear events. There is emerging evidence for a role of phosphoinositides in gene expression, specifically mRNA processing and chromatin remodeling.

Nuclear PI(4,5)P2 metabolism in mitogenesis and cell cycle progression

The nuclear and cytoplasmic phosphoinositide cycles function independently of each other, yet the mechanisms of phosphoinositide signaling share common themes. Nuclear PI(4,5)P2 can directly modulate the activities of PI(4,5)P2-binding proteins, or can be further phosphorylated by phosphoinositide 3-kinase (PI3K) or hydrolyzed by phosphoinositide-specific phospholipases C (PI-PLCs). Over the past decade it has become increasingly apparent that nuclear PI(4,5)P2 metabolism modulates mitogenesis

Summary

It is clear from the current literature that PI(4,5)P2 metabolism plays essential roles in a number of nuclear processes ranging from chromatin remodeling and pre-mRNA splicing to growth and proliferation as summarized in Fig. 3. Despite the accumulation of data about the nuclear phosphoinositide cycle, there are still more questions raised than answered. For example, why are there two different pathways leading to nuclear PI(4,5)P2 production, what are the downstream events following PI(4,5)P2

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