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.
