This MIRA proposal addresses two important avenues of discovery made by our laboratory. In Part 1, we will examine the mechanism of allosteric activation by phosphorylation of the MAP kinase, ERK2. This project advances the protein kinase field, by showing how protein motions underlie the catalytic activation of ERK2 and how this impacts the action of high affinity inhibitors. In Part 2, we will examine the mechanisms controlling the assembly and function of a rear-polarized cellular complex, named the WRAMP structure. The WRAMP structure advances the field of cell motility, as a new mechanism that controls the persistence of directional cell migration and the direction of cell movement. The projects are unified by their dissection of molecular mechanisms that control dynamics in cell signaling. This occurs at a microscopic level by the molecular motions of protein kinases and at a macroscopic level by the assembly of cellular protein-organelle complexes.
The proposed research is relevant to public health because it dissects the mechanisms of action of molecules that go awry in cancer and other human diseases. The work in this proposal will examine previously unrecognized molecular processes which are central to the regulation of human cells. Detailed knowledge of these processes will provide information that can be used to develop new therapeutics to treat cancer and other diseases.