Regulation of ERK1/2 by the pseudophosphatase STYX: implications for cell migration and epithelial-mesenchymal transition.

Hesso Farhan, Biotechnology Institute Thurgau, Switzerland

Veronika Reiterer, Dirk Fey, Alexander Krämer, Walter Kolch, Boris Kholodenko, Hesso Farhan

Fully one tenth of the human phosphatome is composed of pseudophosphatases, which harbor mutations in conserved domains, predicting to render these proteins enzymatically inactive. The pseudophosphatase STYX belongs to the family of dual-specificity phosphatases, which are known to regulate various MAPKs. Using mathematical modeling together with biochemical and cell biological experiments, we identify STYX as a nuclear anchor for ERK1/2. By affecting the nucleo-cytoplasmic shuttling of ERK1/2, STYX regulates spatio-temporal signaling by these MAPKs. We employed fluorescence resonance energy transfer (FRET)-based probes and found that STYX regulates ERK1/2 oscillation and affects the fraction of ERK1/2 in the “on-phase”. STYX also affects the biological outcome of ERK1/2 signaling. Using PC12 cell differentiation as a model, we found that STYX regulates ERK-dependent cell fate decisions. Moreover, STYX modulated the ability of cancer cells to undergo epithelial-mesenchymal transition (EMT) and regulated E-cadherin levels in an ERK-dependent manner. In accordance with a potential role in cancer, we find that STYX is overexpressed in breast cancer compared to the matched healthy tissue. Altogether our work highlights STYX as a regulator of ERK1/2 signaling and suggests that this mode of regulation might be disrupted in tumors, making STYX a new, previously unappreciated drug target.