From genetic data and structures to drug development: New approaches to target Eph receptors

Abstract The Eph receptors are the largest receptor tyrosine kinase (RTK) group. The Ephs and their ephrin ligands are expressed in many tissues during development and in the adult organism and play important roles in diverse processes, including neuronal development, vasculogenesis, cell migration, immunity, tumor progression, and metastasis (Klein, 2012; Wilkinson, 2014; Darling and Lamb, 2019; [1] , [2] , [3] ). Understanding the molecular mechanisms of Eph/ephrin signaling requires detailed characterization of the interactions between Ephs and ephrins in health and disease, and of how these interactions promote initiation of downstream signaling (Nikolov et al., 2013; Pasquale, 2008; Kania and Klein, 2016; [4] , [5] , [6] ). In this chapter we review current genomics, structural, molecular, and cellular biology studies aimed at understanding the molecular mechanisms of Eph-mediated signaling. We discuss the roles of Ephs and ephrins in tumor progression, metastasis, and development of therapeutic treatments. We focus on Eph-mediated signaling in tumor cells and discuss how mutations altering specific Eph receptor molecular surfaces can lead to pro-malignant misregulation of signaling. The rapidly expanding patient-derived DNA sequence databases have made it possible to use Eph/ephrin structural information to identify disease-causing (missense) mutations that alter Eph molecular surface regions affecting specific protein-protein interfaces and interactions. Such mutations can cause changes in ligand binding, kinase activation, or Eph clustering, ultimately leading to impaired signaling properties. In this chapter we argue that by studying the role of the different protein-protein interactions and interfaces in healthy tissues and in diseases, including cancer, novel and valuable drug candidates and therapeutic strategies can be developed.