Many signals that control the survival, growth and differentiation of cells are initiated by activation of receptor tyrosine kinases on the surface of the cell. Studies of cellular responses to stimuli often focus on the ligands or proteins that perceive the signal, and the protein receptors that carry the signal into the cell to elicit the desired response. However, the composition of the cellular membranes in which those proteins are submerged can also play a direct role in the signaling response. The current study proposes to elucidate how interaction with specific lipids in the membranes of communicating cells affect receptor activation in the TAM family of receptor tyrosine kinases. TAM receptors comprise a unique family of receptor tyrosine kinases activated not by growth factors, but by ligands that are proposed to directly interact with exposed lipids in activating cells. However, the underlying mechanisms that govern lipid induced receptor activation are poorly understood. The proposed research will employ a combination of biochemical and biophysical methods to investigate the molecular details of how lipids may interact with signaling proteins to induce changes that are then converted into an intracellular response. These studies will mechanistically define lipid-mediated TAM receptor activation and provide important insights that may be used for the development of new therapeutics in cancer, viral and autoimmune diseases.
Our Specific Aims address two main questions: (1) What are the requirements for PtdSer stimulation of TAM- dependent phagocytosis? (2) How does binding of PtdSer to the TAM/ligand complex induce activation of the receptor? This work will take place in the laboratory of Dr. Kathryn Ferguson in the supportive and innovative research environment at the new Yale Cancer Biology Institute. The fellow will have access to a wealth of resources at the various departments across the Yale campuses, including several core research facilities and centers that focus on providing tools and training to advance the research of those within the Yale community and beyond.
TAM receptor tyrosine kinases are important regulators of cell survival, cell migration and adhesion, thrombosis and inflammation, but very little is known about how the ligands and receptors organize and interact to elicit desired signaling responses. This proposal uses a combination of biochemical and biophysical approaches to elucidate the molecular details of TAM receptor activation, which is suspected to require a unique interaction of ligand with the membrane lipid, phosphatidylserine. Accomplishment of the aims in this proposal will not only provide mechanistic insights into function in this important kinase family but will also provide information that is critical for the design of new targeted therapies when TAM receptors and their ligands are dysregulated in disease states.
