Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases

Abstract

Receptor tyrosine kinases (RTKs) orchestrate embryonic development and tissue homeostasis by controlling key cellular processes like growth and proliferation. Consequently, the vast majority of the 58 RTKs in humans are linked to cancer or metabolic disorders. For instance, RTKs represent known oncogenic drivers (such as EGFR in non-small cell lung cancer), contribute to cancer hallmarks (such as VEGFR in pro-tumor angiogenesis), and mediate resistance to therapeutics or hormones (such as the Insulin Receptor in diabetes). Classically, RTKs transduce signals through various modes of ligand-induced receptor dimerization and subsequent tyrosine kinase-mediated signaling; however, ~10% of all metazoan RTKs are pseudokinases—that is, they lack the capability to catalyze phosphotransfer. Our objective is to ascertain how RTK pseudokinases relay extracellular cues without kinase activity and whether they can be targeted therapeutically. Using structural, biophysical, and cell signaling approaches, we investigated this class of RTKs to shed light on potential non-catalytic signaling mechanisms. We identified structural elements conserved between the pseudokinases and their kinase relatives, found their pseudokinase domains to be conformationally dynamic, and uncovered a putative route to drugging these receptors via “conformational disrupting” small molecules. Our findings suggest that RTK pseudokinases could serve as viable drug targets and set the scene for future dissection of signaling pathways that have long been considered enigmatic.