Nuclear lipid signalling

Key Points

  • There is strong evidence for the presence of phospholipids inside the nucleus distinct from those that are in the nuclear envelope. The data indicate that these are not in a classic lipid bilayer, but their actual physicochemical form is not clearly understood.

  • Nuclei contain the enzymes necessary to make phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) from phosphatidylinositol, and they also contain at least one isoform of phosphoinositol lipid-specific phospholipase C (the β1 isoform). This can be activated by stimulation of cells with growth factors such as insulin-like growth factor 1 (IGF-1), and the resulting diacylglycerol (DAG) formation can recruit protein kinase C (PKC) to the nucleus.

  • There is also clear evidence for the activation of this PI-PLC pathway at different points of the normal cell cycle. In particular, at G2–M, a pulse of DAG generation from PtdIns(4,5)P2 causes the recruitment of PKCβII to the nucleus, in which its physiological function might be to phosphorylate lamins and thereby regulate nuclear envelope breakdown.

  • Another product of PI-PLC hydrolysis of PtdIns(4,5)P2, inositol-1,4,5-trisphosphate (Ins(1,4,5)P3), might regulate intranuclear calcium levels. It could also function as a precursor of more highly phosphorylated inositol phosphates, which have been suggested to be involved with other nuclear functions, such as messenger RNA export.

  • PtdIns(4,5)P2 might have other intranuclear roles — in particular, a proposed action in the regulation of RNA splicing.

  • Members of the phosphatidylinositol 3-kinase (PI3K) family, which synthesize 3-phosphorylated inositol lipids, have also been reported to be in the nucleus, although their intranuclear functions, if any, are not yet clearly defined.

Abstract

During the past twenty years, evidence has accumulated for the presence of phospholipids within the nuclei of eukaryotic cells. These phospholipids are distinct from those that are obviously present in the nuclear envelope. The best characterized of the intranuclear lipids are the inositol lipids that form the components of a phosphoinositide–phospholipase C cycle. However, exactly as has been discovered in the cytoplasm, this is just part of a complex picture that involves many other lipids and functions.

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Figure 1: The PI-PLC pathway.
Figure 2: The main components of the nucleus.
Figure 3: Regulation of nuclear PI-PLC by growth factors.
Figure 4: The cell cycle.
Figure 5: Synthesis of 3-phosphorylated inositol lipids.

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Acknowledgements

I am grateful to many colleagues, especially those in Cambridge, Amsterdam and Bologna, for helpful discussions and their suggestions, and to the Royal Society for its support.

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DATABASES

InterPro

PH

SH3 domain

LocusLink

DAG kinase

ERK

Ins(1,4,5)P3 receptors

lamins

PIKE

PKC

PI3K

PLC

PLD

PtdIns 4-kinase

type I PtdInsP kinase

type II PtdInsP kinase

Swiss-Prot

diacylglycerol cholinephosphotransferase

inositol polyphosphate multikinase

PTEN

Glossary

BOMBESIN

A strong releaser of gastrin and cholecystokinin that is found in the gut and the brain. It also has a mitogenic action in several cell types.

PLECKSTRIN HOMOLOGY (PH) DOMAIN

A sequence of 100 amino acids that is present in many signalling molecules; some PH domains bind to lipid products of phosphoinositide 3-kinase. Pleckstrin is a protein of unknown function that was identified originally in platelets. It is a principal substrate of protein kinase C.

SPLICEOSOME

A protein–U small nuclear RNA complex that is required for folding of the pre-messenger RNA into the correct conformation for the removal of introns.

SRC-HOMOLOGY-3 (SH3) DOMAIN

A protein sequence of about 50 amino acids that recognizes and binds sequences that are rich in proline.

DOMINANT-NEGATIVE

A defective protein that retains interaction abilities and so distorts or competes with its normal protein counterparts.

CHROMATIN REMODELLING

Dynamic changes of chromatin organization, which are required for optimal execution of processes such as DNA replication, gene transcription, DNA repair or chromosome segregation.

EF-HAND

A graphical description for the structure of a Ca2+-binding motif that was first described in parvalbumin.

HELA CELLS

An established tissue-culture strain of human epidermoid carcinoma cells that contain 70–80 chromosomes per cell. These cells were derived originally from tissue that was taken from a patient named Henrietta Lacks in 1951.

NOCODAZOLE BLOCK

An inhibition of cell-cycle progression that is caused by the effects of the nocodazole microtubule-depolymerizing drug on spindle assembly.

ELUTRIATION

A centrifugal technique (which uses a special elutriation rotor) that separates cells into fractions that are dependent on their size. It can therefore be used to separate cells at different stages of the cell cycle from an asynchronous population.

PHORBOL ESTER

A polycyclic ester that is isolated from croton oil. The most common is phorbol myristol acetate (PMA, also known as 12,13-tetradecanoyl phorbol acetate or TPA). Phorbol esters mimic diacylglycerol, and thereby activate protein kinase C.

BRYOSTATIN

A highly potent activator of protein kinase C that is found in bryozoans.

C2 DOMAIN

(conserved region 2 of protein kinase C). C2 domains are 100 amino-acids long and bind phospholipids and Ca2+ interdependently. They are present in many proteins that are involved in Ca2+ signalling.

PC12 CELLS

A clonal line of rat adrenal pheochromocytoma cells that respond to nerve growth factor and can synthesize, store and secrete catecholamines, much like sympathetic neurons. PC12 cells contain small, clear synaptic-like vesicles and larger, dense core granules.

GUANINE NUCLEOTIDE EXCHANGE FACTOR

A protein that facilitates the exchange of GDP (guanine diphosphate) for GTP (guanine triphosphate) in the nucleotide-binding pocket of a GTP-binding protein.

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Irvine, R. Nuclear lipid signalling. Nat Rev Mol Cell Biol 4, 349–361 (2003). https://doi.org/10.1038/nrm1100

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