The ERK cascade is a central signaling pathway that regulates a variety of cellular processes including proliferation, differentiation and development. Over the past years, several mechanisms that allow the participation of ERK in so many distinct and even opposing processes have been suggested, including the existence of multiple isoforms in each layer of the ERK cascade. Our group has previously contributed to the understanding of this mechanism by identifying a novel ERK signaling route, composed of the alternatively spliced isoforms MEK1b and ERK1c, that participates in the regulation of Golgi fragmentation during mitosis. Our working hypothesis is that ERK1c has unique functions, which extend the specificity of the ERK cascade in mitosis. Therefore, the objective of this study is to reveal the molecular mechanism by which ERK1c is regulated and induces Golgi fragmentation.
In this study we found that the endogenous ERK1c translocation into the Golgi towards mitosis occurs in several cell lines. Using C-terminal ERK1c mutants, we found that the C terminus of ERK1c is necessary for the Golgi translocation. This region contains a consensus phosphorylation site for CDK1 (Ser343), which is a master regulator of mitosis, and we further found that phosphorylation of this site, is important for ERK1c activation. Therefore our working model suggests that at late G2 phase of the cell cycle, CDK1 phosphorylates ERK1c to induce its translocation to the Golgi. In the Golgi, ERK1c is activated by MEK1b, allowing Golgi fragmentation by further phosophrylation of downstream substrates. The importance of this work is the extension of our knowledge on the signal specificity mechanism of the ERK cascade, as well as on the regulation of Golgi fragmentation during mitosis.