(provide by applicant): This proposal concerns the MAP Kinase Erk 2, a critical regulator of multiple cell behaviors, including motility, apoptosis, and proliferation. We will produce novel fluorescent biosensors to study the activation of Erk in individual, living cells. This will be accomplished by developing new, generally applicable methodologies that can report the dynamics of many different protein behaviors in vivo. Erk activation is controlled both spatially and kinetically, but it has not been possible to understand this level of regulation using biochemical techniques applied to cell populations or fixed cells. The much greater spatial and temporal resolution of the new biosensors will enable us to understand how localized, transient activation of Erk generates rapid changes in cell morphology, and how spatio-temporal control is used to activate Erk differently to produce either motility or apoptosis. We will study the roles of upstream molecules in regulating this previously inaccessible mechanism of Erk regulation, focusing on phosphorylation of the focal adhesion protein vinculin, sumoylation of the upstream kinase MEK, and regulation of EGF receptor trafficking. The fundamental processes controlled by Erk, including motility, apoptosis, and proliferation, are critical to normal homeostasis and relevant to many diseases and immune function.
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