Events

Decoding pathogenic signaling from the molecular to the cellular scale

Our lab is driven by two overarching questions: (1) What are the molecular principles underlying the faithful transmission of information in mammalian cells? (2) How do mutations in cell signaling proteins disrupt signal transduction and lead to human diseases? We ask these questions in the context of two enzyme families, protein tyrosine kinases and protein tyrosine phosphatases. We focus on these enzymes because of their biomedical importance – many are dysregulated in diseases and are therapeutic targets – and because they are superb model systems to study allostery and molecular recognition. Over the past few years, we have developed and implemented a suite of innovative approaches that are yielding new insights into kinase- and phosphatase-mediated cell signaling and the effects of disease-associated mutations. These methods include deep mutational scanning to simultaneously characterize the activities of thousands of mutant enzymes, high-throughput peptide display assays to profile molecular recognition, and chemical approaches to map transient protein-protein interactions in cells. In this talk, I will discuss how we are applying these approaches to probe sequence-structure-function relationships in SHP2, a phosphatase associated with cancer and developmental disorders. I will describe how our methods are revealing unexpected mechanisms by which perturbations to SHP2 structure, dynamics, and molecular recognition drive aberrant cell signaling.