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.


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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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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SH3 domain


DAG kinase


Ins(1,4,5)P3 receptors







PtdIns 4-kinase

type I PtdInsP kinase

type II PtdInsP kinase


diacylglycerol cholinephosphotransferase

inositol polyphosphate multikinase




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


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


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


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.


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


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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).

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