Cells respond to and interact with their environments through their plasma membrane (PM), thus the PM is a critical interface for cell physiology. The proteins in the PM provide the basis for these physiological responses, so cells have elaborate mechanisms to regulate which proteins are found in specific cellular domains. Temporal control is also important, in order to effect rapid or sustained changes, as needed. One very important mechanism for controlling the composition of the PM is endocytosis, a pathway for the selective removal of membrane proteins and lipids. Endocytosis is also important for bringing essential nutrients into the cell and for retrieving intracellular proteins that are transiently incorporated into the PM. Adaptor proteins select specific membrane cargo for internalization. Scaffolding proteins are thought to promote efficiency of the process by coordinating cargo collection with formation of the endocytic structure and ultimately, separation of the endocytic vesicle. Adaptors and scaffolds must be regulated in order to turn on and off as needed. In this application, I propose a model in which the Actin Regulating Kinase (ARK) family of protein kinases regulates a cycle of interactions between adaptors and scaffolds. Additionally, we have evidence for two related scaffolds that may mediate cargo collection in parallel. Differential regulation of these two scaffolding complexes could provide cells with an ability to respond to a variety of extracellular and intracellular cues. Understanding the mechanisms of this fundamental cell regulatory pathway has widespread application. Many viruses and pathogens gain entry into cells via endocytosis. Cancer cells can sometimes proliferate due to an overabundance of signaling receptors that have not been properly internalized. Gene therapy strategies look to use endocytosis as a way to deliver the active compounds into the cell. ? ?
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