TAM Receptors Cells

Understanding the structural basis for TAM receptor activation

TAMreceptors Final Cells

This image represents the TAM ligand: receptor dimer that is often portrayed in the literature compared to the more complex view suggested by various independent studies. Understanding which, if either, of these models is more accurate is a major goal of the lab.

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.

To better understand the structural basis of RTK signaling, my lab is currently focused on studying TAM (Tyro3, Axl and Mer) receptors. TAMs are a clinically important and mechanistically understudied RTK subfamily whose activation appears to involve not only ligand but also interactions with the membrane lipid, phosphatidylserine. These non growth-factor associated receptors have a vital role in maintaining cellular homeostasis through the clearance of apoptotic cells and control of inflammatory and immune responses and, because of this, dysregulation of TAM receptors is implicated in numerous disease states. Having a role in multiple diseases is a hallmark of cell surface receptor tyrosine kinases, and our limited understanding of how these receptors are differentially regulated severely limits our ability to truly understand the activation process or to develop better targeted therapies. How TAM receptors are activated by different mechanisms and how the various activation mechanisms toggle signaling output is an important basic question that my lab aims to address through structural, biochemical, and cellular studies.

Tyro3 Kinase domain model

Structure-guided design for targeting of receptor tyrosine kinases

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.

IMG 4095

Utilizing structural biology to develop new approaches to precision medicine in Alzheimer’s disease

IMG 4095 800In 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.

This project, which includes structural biology, microscopy, and translational teams, will attempt not only to combine our expertise toward an increased understanding the role that ABCA7 plays Alzheimer’s, but also aims to involve leaders within the African American community in the decision-making process. We are working to develop a Community Action Board to promote science education and ensure that everyone understands the proposed project at all stages.