Receptor tyrosine kinases are clinically important family of receptors that act as key regulators of a wide range of biological functions. Notably, all RTKs are membrane proteins that share a single-pass transmembrane helix that links and extracellular domain with an intracellular kinase domain. How a single helix promotes the large diversity of signaling processes mediated by RTKs has long been a question of interest, and classically, RTKs are considered to be activated by ligand-induced dimerization. However, in recent years it has become clear that this static view is insufficient to explain the wide diversity RTK mediated signaling and that these signaling mechanisms are much more dynamic than a simple on-or-off mechanism.
Due to their important regulatory roles, receptor tyrosine kinases (RTKs) are common targets in cancer treatments and there are numerous small-molecular inhibitor and monoclonal antibodies targeting RTKs currently used in the clinic. It’s becoming increasingly clear that TAM receptors, like several commonly targeted RTKs, have a role in the development of various cancers and, as such, the development of therapeutics targeting these receptors has become a topic of interest. Working in a collaborative project with teams at UNC, we are using structure to guide the design of various types of therapies that inhibit or degrade TAM receptors.
In a collaborative project with laboratories at Vanderbilt, Fisk and Meharry Medical School, we are working on a project to investigate the role of African American variants of ABCA7 in increased risk for developing Alzheimer’s disease. Alzheimer’s disease is the most common type of dementia and is progressive disease that leads to cognitive decline and for which there is no cure. African Americans have double the prevalence of Alzheimer’s disease when compared to Americans of European descent, but we don’t currently understand the mechanisms for development of the disease that cause this increase in occurrence. Genetic screening has indicated that mutations in the ATP-binding cassette gene, ABCA7, are the strongest indicator for disease development in African Americans, so we are working to investigate the role of ABCA7 variants on the development of Alzheimer’s disease.