Role of Dynamic 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 via over-stimulation of mitogenic signaling cascades. The large GTPase dynamin is a key regulator both of transport of receptors to the plasma membrane after receptor biosynthesis and down-regulation of receptors via receptor-mediated endocytosis (RME), during which it is involved in the scission of endocytic vesicles. Disruption of RME has been shown to render the epidermal growth factor receptor (erbB1) oncogenic (1), illustrating the importance of proper attenuation of signaling by down- regulation. This proposal addresses the mechanistic role of the pleckstrin homology (PR) domain in dynamin function, which may provide a pharmacologic target for modulating dynamin activity. The PR domain binds phosphatidylinositol (4,5) bisphosphate (PI(4,5)P(sub 2)) at the plasma membrane (PM), but the role of this binding is not yet understood. The experiments detailed below address whether PI(4,5)P(sub 2) binding is involved in targeting of dynamin to the PM, or whether phosphoinositide binding instead plays a more physical role in the scission of endocytic vesicles, and therefore receptor downregulation.