Physical and Functional Interactome Atlas of Human Receptor Tyrosine Kinases

Much of cell-to-cell communication is facilitated via cell surface receptor tyrosine kinases (RTKs). These proteins phosphorylate their downstream cytoplasmic substrates in response to stimuli such as growth factors. Despite their central role, the functions for many RTKs are still poorly understood. To resolve the lack of systematic knowledge, we used three complementary methods to map the molecular context and substrate profiles of RTKs. We utilized AP-MS to characterize stable binding partners and RTK protein complexes, BioID to identify transient and proximal interactions, and an in-vitro kinase assay to identify substrates for RTKs. To identify how the kinase interactions are dependent on kinase activity, we also used kinase-deficient mutants. Our established data represents the first comprehensive, systemic mapping of RTK interactions and substrates. The resource adds information to the well-studied RTKs, offers insights into the function of the less-studied receptor tyrosine kinases, and highlights RTK-RTK interactions and shared signaling pathways.