The surface of a cell contains a large number of receptors, the purpose of which is to perceive extracellular stimuli and initiate the appropriate intracellular response. In the context of a multicellular organism, it is particularly important that the appropriate cells respond to extracellular stimuli as needed. While some cell types are constantly multiplying, others do so for a limited period and subsequently cease. Failure to appropriately terminate the cellular response to growth factors leads to deregulated multiplication, a hallmark of tumorigenesis. One mechanism that the cell utilizes to modulate its response to growth factors is to simply remove growth factor receptors from the cell surface, rendering them insensitive to the factor. Signaling through activated receptor-agonist complexes is terminated by internalization from the cell surface and subsequent destruction within the hydrolytic lysosome, a process referred to as "receptor downregulation." The delivery of these activated receptors to the lysosome for degradation is the result of a sorting decision that occurs at a late endosomal compartment during the formation of multivesicular bodies.
We are interested in the molecular mechanisms that control the intracellular trafficking of activated receptors. By utilizing the model organism yeast, we have identified both cis-acting signals that identify cargo for inclusion into MVBs, and a number of gene products required receptor downregulation. Thus far, all genes have mammalian orthologs, indicating that this process is highly conserved. Our goal is to use the yeast system to dissect the molecular mechanism of receptor downregulation.