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Membrane-associated signaling proteins targeting

Membrane-associated signaling proteins typically function correctly only when targeted to a specific cellular membrane compartment, and often only when targeted to specific domains within this membrane compartment. Our research interests are focused on understanding two important aspects of the targeting, and hence the function, of proteins involved in signal transduction at the plasma membrane:

1. Understanding the organization and function of the specialized membrane microdomains known as 'lipid rafts'. These domains, found within the plasma and certain other membranes of mammalian cells, exhibit a physical organization and composition distinct from those of non-'raft' regions of the membrane and serve distinct functions as well, notably in membrane signal transduction and in sorting of membrane proteins (and lipids) during intracellular membrane trafficking. We are currently working to define better the structural features of membrane-associated molecules that govern their ability to associate with rafts, and to assess how varying the organization and distribution of rafts modulates signal transduction at the plasma membrane in mammalian cells.
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2. Elucidating the mechanisms of targeting of lipidated signaling proteins to their correct subcellular destinations. Our current interests in this area are focused on two classes of protooncogenic lipid-modified signaling proteins: the farnesylated ras small G-proteins and N/S-acylated proteins such as the src-homologous intracellular tyrosine kinases. Our objectives are to understand how these proteins are targeted to their correct membrane (and submembrane) destinations, and to identify enzymes or receptors involved in their targeting as potential sites for pharmacological intervention (e.g., to block the oncogenic actions of mutationally activated forms of these proteins).