Caracterización molecular y funcional de la MAP kinasa ERK5

ERK5 is a new member of the MAP kinase family of protein kinases. ERK5 and its activator MEK5 take part of a new signal transduction pathway that is activated by growth factors and in response to cellular stresses. The MEK5-ERK5 pathway seems to play an important role in neuronal cells, since it is activated in response to neuronal survival factors (neurotrophins) or in response to oxidative stress (involved in ischemia and reperfusion injury of the brain). A role of MEK5-ERK5 in vasculogenesis, angiogenesis and in several processes of carcinogenesis has also been described. However, the precise role that this pathway palys in such biological processes has not been assessed, mainly due to the fact that only few substrates have been identified so far. The aim of this project is to carry out a dissection of this signalling pathway through the following objectives: \b *To study the regulation of MEK5-ERK5 pathway by its interacting proteins (recently identified in our laboratory using the TAP methodology) *To identify new ERK5 substrates *To study how ERK5 works. Characterization of the putetive \i docking sites\i0 . Development of peptide inhibitors.\b0 Oreviously, we have observed in our laboratory a dramatic decrease on ERK5 protein levels after subjecting cultures of primary cortical neurons to \i in vitro\i0 ischemia. We have also observed that ERK5 is an \i in vitro\i0 substrate of the calpain protease. Now, an important objective of this project is to carry out a detailed characterization of this degradation, as well as \b to study the neuroprotective role of ERK5 on the ischemia-mediated injury of cultured neuronal cells.\b0