MAP Kinase Mediated Activation of RSK1 and MK2 Substrate Kinases

Mitogen activated protein kinases (MAPKs) control essential eukaryotic signaling pathways. While much has been learned about MAPK activation, much less is known about substrate recruitment and specificity. MAPK substrates may be other kinases that are crucial to promote a further diversification of the signaling outcomes. Here, we used a variety of molecular and cellular tools to understand the recruitment of two substrate kinases, RSK1 and MK2, to three MAPKs (ERK2, p38α, ERK5). Unexpectedly, we identified that the formation of specific, structurally and functionally distinct heterodimers allows for different signaling outcomes. Furthermore, we show that small molecule inhibitors likely affect the specific quaternary arrangements of kinase heterodimers and thus affect downstream signaling. Overall, our results demonstrate that MAPKs use heterodimer specific strategies to promote different cellular processes that may be exploited in MAPK based drug development.