My research concerns the mechanisms, evolution and structures of the molecular assemblies that carry out cellular signal transduction and DNA replication. My laboratory uses biochemical, biophysical, structural and cell biological analyses to elucidate mechanisms, as well as deep-mutagenesis methods and computer simulations to understand the effects of mutations. My laboratory has provided the structural framework for understanding the mechanisms underlying high-speed processive DNA replication, by determining the structures of sliding clamps, clamp loaders, and DNA polymerases. In the area of signal transduction, breakthroughs from my lab have included determining the auto-inhibited structures of several tyrosine kinases, including that of the kinase ZAP-70 and elucidating the mechanism of ZAP-70 activation by its upstream regulators, a crucial step in T cell receptor signaling, and the regulatory mechanism of Btk, a kinase important in B cell signaling. My laboratory has provided a fundamental understanding of the structure and regulation of several other signaling proteins, including the Src kinases, the epidermal growth factor receptor, the Ras activator SOS, and CaMKII. Our insights have helped understand how the misregulation of these enzymes is often coupled to cancer and immune diseases and has implications for the development of kinase-targeted drugs to treat these diseases.