Session 7: Membrane pathophysiology and disease
What roles do lipid rafts and alternative trafficking play in cancer?
Jeff Wrana
Many theories regarding lipid-raft size, biogenesis, stability and function have been floated around in the literature. In addition, raft-dependent endocytosis has been noted for several cell-surface receptors, suggesting that partitioning and trafficking via these pathways can yield different endocytic compartments of distinct membrane and protein composition. Lipid rafts have been proposed to serve as important platforms for assembling cell-signalling networks, and disturbance of lipid rafts can dramatically alter the function of these networks. How signalling networks are assembled in rafts, and indeed whether lipid and protein constituents might cooperate in assembling distinct raft-protein signalling platforms that regulate specific biological outputs, is unknown.
How partitioning of signalling receptors and their downstream effectors between rafts and non-raft membranes occurs, and how this affects signalling-network organization and activity in cancer cells, is a largely unexplored area. Furthermore, as raft-dependent trafficking has been associated with internalization and down-regulation of transmembrane proteins, including signalling receptors, interference with these activities could also have a profound influence on the manner of cancer-cell response to extracellular cues. For example, regulation of transforming growth factor-β (TGFβ) receptors, which is mediated by a raft-dependent trafficking route, is profoundly altered in tumours. This may be related to expression of the raft constituent caveolin, which is strongly down-regulated in cancer cells. How altered trafficking and partitioning of proteins that are constituents of rafts is altered in cancer, how this contributes to disease progression, and whether this might be an effective therapeutic target, are therefore crucial questions.
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