Atypical MAP Kinase Signal Transduction

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Project Summary: MAP kinases (MAPKs) are regulatory components of many signal transduction pathways that impact eukaryotic cell growth, differentiation, and movement. Relatively little is known about the function and regulation of atypical MAPKs (represented by MAPK15/Erk8 in mammals) found only in eukaryotes that have cell motility. Atypical MAPKs are not activated by conventional MAPK kinases and the external signals that trigger activation are not known except in the amoeba Dictyostelium, a model organism for chemotactic movement and development. We have found that the Dictyostelium atypical MAPK, Erk2, is essential for chemotactic movement to multiple signals. In our previously funded research we also discovered that Erk2 phosphorylates specific residues of a GATA transcription factor, GtaC, resulting in the translocation of this factor from the nucleus to the cytoplasm in response to at least two chemotactic signals that promote different cell fates. We have also demonstrated that Erk2 kinase activity is not required for activation in vivo indicating that an unconventional MAPK kinase regulates atypical MAPKs rather than autophosphorylation. The proposed research will investigate if Erk2 promotes different cell fates through the differentially modification of GtaC or through the regulation of other transcription factors. We will use a GFP tagged GtaC to map Erk2 docking sites and compare these to docking sites of other groups of MAPKs. We will also use co-immunoprecipitations, mass spectrometry, and genetic analysis to identify proteins that associate and function with Erk2 in signaling pathways and identify proteins that directly regulate Erk2 activation. The results of this project are expected to identify specific mechanisms of atypical MAPK regulation and function and uncover roles for atypical MAPK signaling in chemotactic movement and cell fate determination that can guide the research of MAPKs in other organisms such as mammals.