Lipid rafts and signal transduction

Abstract

Signal transduction is initiated by complex protein–protein interactions between ligands, receptors and kinases, to name only a few. It is now becoming clear that lipid micro-environments on the cell surface — known as lipid rafts — also take part in this process. Lipid rafts containing a given set of proteins can change their size and composition in response to intra- or extracellular stimuli. This favours specific protein–protein interactions, resulting in the activation of signalling cascades.

Key Points

  • Lipid rafts consist of dynamic assemblies of cholesterol and sphingolipids in the exoplasmic leaflet of the lipid bilayer.

  • Lipid rafts can include or exclude proteins selectively, and the raft affinity of a given protein can be modulated by intra- or extracellular stimuli.

  • They are too small to be seen by standard microscope techniques. It is also not possible to isolate lipid rafts in their native state. Detergent-resistant membranes, containing clusters of many rafts, can be isolated by extraction with Triton X-100 or other detergents on ice.

  • Raft association of proteins can be assayed by manipulating the lipid composition of rafts. If cholesterol or sphingolipids are depleted from membranes, lipid rafts are dissociated, and previously associated proteins are no longer in rafts.

  • There is great confusion in the nomenclature for lipid rafts, and Table 2 proposes a new nomenclature.

    Table 2 Raft nomenclature
  • Rafts are involved in signal transduction. Crosslinking of signalling receptors increases their affinity for rafts. Partitioning of receptors into rafts results in a new micro-environment, where their phosphorylation state can be modified by local kinases and phosphatases, modulating downstream signalling.

  • Raft clustering could also be involved in signal transduction. Several rafts coalesce, resulting in amplification of the signal.

  • Some examples for such raft-dependent signalling processes are IgE signalling during the allergic response, T-cell activation and GDNF signalling.

  • Rafts are also necessary for Hedgehog signalling during development but the mechanism is very different. Hedgehog is a membrane-bound ligand and needs to be released from its cell of origin so it can signal to cells several layers away. It can be released from the cell when it is anchored in rafts through its cholesterol moiety.

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Figure 1: Initial signalling events in rafts for a | IgE receptor (FcɛRI)- and b | T-cell antigen receptor (TCR)-mediated signalling.
Figure 2: Models of how signalling could be initiated through raft(s).

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Acknowledgements

We thank D. Brown, R. Parton, T. Harder and T. Kurzchalia for critical reading of this manuscript. C. Ibáñez provided helpful discussions on GDNF signalling.

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DATABASE LINKS

Src kinase

caveolin

IgE

FcɛRI

Lyn

Syk

ZAP-70

PLCγ

LAT

TCR

CD3

Fyn

Vav

Grb2

Lck

GDNF

RET

Ras

Raf

ERK

Hedgehog

Patched

Smoothened

Dispatched

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Lipids

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EXOPLASMIC LEAFLET

Lipid layer facing the extracellular space.

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Transport of macromolecules across a cell, consisting of endocytosis of a macromolecule at one side of a monolayer and exocytosis at the other side.

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The surface of an epithelial cell that faces the lumen.

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The surface of an epithelial cell that adjoins underlying tissue.

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The surface of a neuron that surrounds the cell body and dendrites.

BIOSYNTHETIC PATHWAY

Secretory or membrane proteins are inserted into the endoplasmic reticulum. They are then transported through the Golgi to the trans-Golgi network, where they are sorted to their final destination.

ENDOCYTIC PATHWAY

Macromolecules are endocytosed at the plasma membrane. They first arrive in early endosomes, then late endosomes, and finally lysosomes where they are degraded by hydrolases. Recycling back to the plasma membrane from early endosomes also occurs.

SUCROSE GRADIENT CENTRIFUGATION

Allows separation of cellular membranes according to their size and/or density by centrifugation.

GANGLIOSIDES

Anionic glycosphingolipids that carry, in addition to other sugar residues, one or more sialic acid residues.

MAST CELL

A type of leukocyte, of the granulocyte subclass.

BASOPHIL

Polymorphonuclear phagocytic leukocyte of the myeloid series.

METHYL-β-CYCLODEXTRIN

Carbohydrate molecule with a pocket for binding cholesterol.

MAJOR HISTOCOMPATIBILITY COMPLEX

A complex of genetic loci, occurring in higher vertebrates, encoding a family of cellular antigens that help the immune system to recognize self from non-self.

ANTIGEN-PRESENTING CELL

A cell, most often a macrophage or dendritic cell, that presents an antigen to activate a T cell.

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Simons, K., Toomre, D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1, 31–39 (2000). https://doi.org/10.1038/35036052

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