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.
Highlights
The ‘fluid mosaic’ model envisions the plasma membrane to contain proteins floating freely in a uniform ‘sea’ of lipid
Wu et al [56] localised TrkA to low buoyant density fractions lacking caveolin, suggesting that it is present in rafts, and Huang et al [137] demonstrated that 40% of TrkA and 60% of p75 neurotrophin receptor (p75NTR) in 3T3-TrkA-p75 cells was present in the caveolae/raft fraction. p75NTR co-immunoprecipitated with caveolin either with or without nerve growth factor (NGF) treatment; the co-immunoprecipitation of TrkA with caveolin could not be demonstrated
This is due in part to the use of methods which do not completely isolate lipid rafts and caveolae, and the use of methods such as cholesterol depletion, which can give unreliable results
Summary
The ‘fluid mosaic’ model envisions the plasma membrane to contain proteins floating freely in a uniform ‘sea’ of lipid. From lipid rafts, and found the PDGFR to be associated with these domains, along with molecules known to act downstream of the receptor, such as PLC, PI3K and nonreceptor tyrosine kinases They used confocal immunofluorescence microscopy to show that PDGF treatment caused tyrosine phosphorylation of proteins in caveolae, both in cell culture and in intact rat lungs. Antibodies to the PDGFR precipitated membranes containing the EGFR and vice versa, suggesting that the two receptors are present in the same microdomains This is supported by the fact that Matveev and Smart [96] showed that pretreatment of Swiss 3T3 cells with either EGF or PDGF for 60 minutes caused sequestration of the receptor for the other ligand, preventing ligand binding and activation. Both of the above studies suggest that membrane microdomains are involved in FGF signalling and activation of Grb and FRS2
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