Role of Dynamin in the Regulation of Signaling by the erbB Family of Receptor Tyrosine Kinases

摘要

Improper regulation of the level and duration of activated erbB family growth factor receptors at the cell surface can lead to uncontrolled cell proliferation and transformation. The GTPase dynamin is a regulator both of transport of receptors to the plasma membrane and down-regulation of receptors via receptor-mediated endocytosis (RME). The localization of specific dynamin isoforms led us to hypothesize that different dynamin isotypes are involved in the distinct processes of vesicle budding from the TGN and receptor-mediated endocytosis from the plasma membrane. This proposal outlines a study of the role of different dynamin isoforms in cellular trafficking to define which members of the dynamin family are involved in up-versus down-regulation of erbB receptors. The analysis of these hypotheses is still on going. I also hypothesized that the pleckstrin homology (PH) domain of dynamin is essential for dynamin targeting. My studies indicate that this is not the case, and that the PH domain may instead be directly involved in vesicle scission. PH domains have characteristics that suggest they will be good targets for small molecule drugs, so understanding the role of the PH domain in dynamin function should allow for modulating dynamin activity to control the level of erbB-mediated signaling.