Investigation of the function and regulation of ERK3

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DESCRIPTION (provided by applicant): MAPKs like the related cyclin dependent kinases (cdks) are a very important part of the cellular response to mitogenic stimuli, development and environmental stresses. Recently, there has been increasing evidence that ERK3, a member of the MAPK family, may be deregulated in a number of different types of cancer including tobacco associated squamous cell carcinomas. There have been, however, relatively few studies investigating the basic biology of ERK3. Thus, further investigation of ERK3 is warranted not only from a basic science point of view, but also as a potential therapeutic or diagnostic target in the treatment of cancer. Recently, we have discovered that the subcellular localization of ERK3 is temporally regulated during the cell cycle. We therefore propose that further investigation of the function of ERK3 may provide an additional level of understanding of the control of the mammalian cell cycle and ultimately of cancer. This proposal will explore (1) The role of ERK3 in the biology of the Golgi, (2) In the regulation of the cell cycle, and (3) Whether the mitotic kinases PLK and cdc2/cyclin B1 regulate ERK3 in vivo. SiRNA technology combined with confocal microscopy will be used to explore the role of ERK3 in the Golgi. These experiments will specifically address whether ERK3 is involved in the regulation of the fragmentation of the Golgi during mitosis or is required for normal cell cycle progression. To investigate whether PLK or cdc2/cyclin B1 regulate ERK3 in vivo, we will investigate the timing of this association by using a combined biochemical and cell biological approach. These studies will be followed by an in vitro biochemical screen aimed to identify the specific residues or regions of ERK3 targeted by PLK and/or cdc2/cyclin B1. The biological relevance of these domains to ERK3 function in vivo will be assessed by an evaluation of its subcellular localization and effect on the cell cycle.