The Structural Basis of TAM Receptor Oligomerizarion and Co-receptor Interactions

TAM receptors are receptor tyrosine kinases with important regulatory roles in cells. These receptors are essential to maintaining cellular homeostasis through the clearance of apoptotic cells and through control of inflammatory and immune responses. Linked to their important regulatory roles, dysregulation of TAM receptors is implicated in numerous disease states including cardiovascular disease, hereditary blindness, autoimmune disorders, chronic inflammation and cancer. While there is growing interest in TAM receptors as therapeutic targets, their multiple roles in homeostatic processes create challenges for developing therapeutic strategies. Understanding TAM receptor activation mechanisms is important for further investigation of the potential development of targeted therapies. While these receptors are commonly believed to be activated through classical receptor-induced dimerization, my preliminary work presents the first in-depth study of the biochemistry and suggests that this simplified view may not be applicable to TAM receptors. Importantly, to fully understand how TAMs are activated, I intend to utilize a combination of structural, biophysical and biochemical approaches to investigate TAM oligomerization and cross-talk with other receptors. These studies will guide the development of informed theories of TAM receptor activation and provide important insights that may be used for the development of new therapeutics in cancer and autoimmune diseases.