Lipid rafts and caveolae in signaling by growth factor receptors

Abstract

Lipid rafts and caveolae are microdomains of the plasma membrane enriched in sphingolipids and cholesterol, and hence are less fluid than the remainder of the membrane. Caveolae have an invaginated structure, while lipid rafts are flat regions of the membrane. The two types of microdomains have different protein compositions (growth factor receptors and their downstream molecules) suggesting that lipid rafts and caveolae have a role in the regulation of signaling by these receptors. The purpose of this review is to discuss this model, and the implications that it might have regarding a potential role for lipid rafts and caveolae in human cancer. Particular attention will be paid to the epidermal growth factor receptor, for which the largest amount of information is available. It has been proposed that caveolins act as tumor suppressors. The role of lipid rafts is less clear, but they seem to be capable of acting as 'signaling platforms', in which signal initiation and propagation can occur efficiently.

Fig. (1)

Structure of lipid rafts and caveolae. A) Caveolae; B) Lipid Rafts. Caveolin molecules in (A) are shown as hairpin-shaped structures in the inner leaflet; N- and C-termini project into the cytoplasm. GPI-anchored proteins are anchored on the outer leaflet of caveolae and lipid rafts, while signalling molecules such as Src kinase associate with the inner leaflet.

Fig. (2)

The EGFR signalling pathway in lipid rafts. See text for description of the pathway. The PLD shown here is PLD-2, which is activated directly by the EGFR. It must be also emphasised that at least three steps contribute to activation of Akt: (i) binding of PIP₃/PI(3,4)P₂ to its Pleckstrin Homology domain; (ii) phosphorylation on Thr308 by PDK1; and (iii) phosphorylation on Ser473. PLD: phospholipase D; PA: phosphatidic acid; PC: phosphatidylcholine; mTOR: mammalian target of rapamycin; EGFR: epidermal growth factor receptor; FKHR: Forkhead Box, subgroup O, transcription factors; CREB: cAMP response element binding protein; PDK1: 3-phosphoinositide-dependent kinase-1; PI3K: phosphatidylinositol 3-kinase; PIP₂: phosphatidylinositol-4,5-bisphosphate; PI(3,4)P₂: phosphatidylinositol-3,4-bisphosphate; PIP₃: phosphatidylinositol-3,4,5,-trisphosphate; S6K1: ribosomal protein S6 kinase 1.

Fig. (3)

Model for the role of caveolae in cellular transformation. A) In a normal cell, caveolin (hairpin structures) binds and inhibits receptors e.g., the EGFR and components of the MAPK cascade. B) In a transformed cell with low caveolin levels, more growth factor receptors and components of the MAPK cascade are free from the inhibitory effects, and this leads to increased proliferation. For clarity, not all components of the MAPK cascade are shown. Inactive molecules are shown as open ovals, whereas active molecules are depicted as filled ovals; EGF = epidermal growth factor; Erk = extracellular signal-regulated kinase.