Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewNuclear PI(4,5)P2: A new place for an old signal
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
References (85)
- et al.
Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes
J. Biol. Chem.
(1999) - et al.
A differential location of phosphoinositide kinases, diacylglycerol kinase, and phospholipase C in the nuclear matrix
J. Biol. Chem.
(1992) - et al.
Type I phosphatidylinositol-4-phosphate 5-kinases synthesize the novel lipids phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 5-phosphate
J. Biol. Chem.
(1998) - et al.
Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules
J. Biol. Chem.
(1997) - et al.
Nuclear phospholipase C and signaling
Biochim. Biophys. Acta
(2001) - et al.
Phospholipases in the nucleus
Semin. Cell Dev. Biol.
(1997) - et al.
Phospholipid signalling in the nucleus. Een DAG uit het leven van de inositide signalering in de nucleus
Biochim. Biophys. Acta
(1998) - et al.
SHIP-2 and PTEN are expressed and active in vascular smooth muscle cell nuclei, but only SHIP-2 is associated with nuclear speckles
J. Biol. Chem.
(2003) - et al.
Characterization of a G protein-activated phosphoinositide 3-kinase in vascular smooth muscle cell nuclei
J. Biol. Chem.
(2001) - et al.
Agonists cause nuclear translocation of phosphatidylinositol 3-kinase gamma. A Gbetagamma-dependent pathway that requires the p110gamma amino terminus
J. Biol. Chem.
(1999)
Evidence that a phosphatidylinositol 3,4,5-trisphosphate-binding protein can function in nucleus
J. Biol. Chem.
Rapid changes in phospholipid metabolism in the nuclei of Swiss 3T3 cells induced by treatment of the cells with insulin-like growth factor I
Biochem. Biophys. Res. Commun.
The localization of sites containing nascent RNA and splicing factors
Exp. Cell Res.
Reversible disassembly of transcription domains in lymphocyte nuclei during inhibition of RNA synthesis by DRB
Biol. Cell
Phosphatidylinositol 3-kinase c2alpha contains a nuclear localization sequence and associates with nuclear speckles
J. Biol. Chem.
Diacylglycerol kinase-theta is localized in the speckle domains of the nucleus
Exp. Cell Res.
Composition and metabolism of lipids within repressed and active chromatin of interphase lymphocytes
Biochim. Biophys. Acta
DNA–lipid interactions in vitro and in vivo
Bioelectrochemistry
Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling
Cell
Involvement of actin-related proteins in ATP-dependent chromatin remodeling
Mol. Cell
Type I PIPkinases interact with and are regulated by the retinoblastoma susceptibility gene product-pRB
Curr. Biol.
The PHD finger: implications for chromatin-mediated transcriptional regulation
Trends Biochem. Sci.
The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor
Cell
Different HATS of the ING1 gene family
Trends Cell Biol.
Insulin selectively stimulates nuclear phosphoinositide-specific phospholipase C (PI-PLC) beta1 activity through a mitogen-activated protein (MAP) kinase-dependent serine phosphorylation
FEBS Lett.
Protein kinase C alpha -mediated negative feedback regulation is responsible for the termination of insulin-like growth factor I-induced activation of nuclear phospholipase C beta1 in Swiss 3T3 cells
J. Biol. Chem.
An SH3 domain is required for the mitogenic activity of microinjected phospholipase C-gamma 1
FEBS Lett.
Nucleophosmin/B23, a nuclear PI(3,4,5)P(3) receptor, mediates the antiapoptotic actions of NGF by inhibiting CAD
Mol. Cell
Nuclear phosphatidylinositols decrease during S-phase of the cell cycle in HeLa cells
J. Biol. Chem.
A role for nuclear phosphatidylinositol-specific phospholipase C in the G2/M phase transition
J. Biol. Chem.
Nuclear phospholipase C-beta1b activation during G2/M and late G1 phase in nocodazole-synchronized HL-60 cells
Biochim. Biophys. Acta
A role for nuclear phospholipase Cbeta 1 in cell cycle control
J. Biol. Chem.
Searching for a function for nuclear actin
Trends Cell Biol.
Association of actin with the nuclear matrix from bovine lymphocytes
Exp. Cell Res.
Phosphoinositide signalling in nuclei of Friend cells: DMSO-induced differentiation reduces the association of phosphatidylinositol-transfer protein with the nucleus
Biochem. Biophys. Res. Commun.
Phosphatidylinositol phosphate kinases put PI4,5P(2) in its place
J. Membr. Biol.
Nuclear phosphoinositide kinases and inositol phospholipids
J. Cell. Biochem.
Nuclear lipid signaling
Sci. STKE
Nuclear lipid signalling
Nat. Rev., Mol. Cell Biol.
Nuclear inositol lipid metabolism: more than just second messenger generation?
J. Cell. Biochem.
A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate
Nature
Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing pre-mRNA processing factors
Mol. Biol. Cell
Cited by (0)
- 1
These authors contributed equally to the manuscript.