System output of the MAPK module is spatially regulated.

Signaling via the Raf/MEK/ERK (MAPK) module controls multiple cell functions including proliferation, differentiation and survival. How this single pathway can regulate such diverse cell fates is unknown. Recently, we examined system outputs of the MAPK pathway from different cellular compartments. We observed robust activation of the MAPK cascade from both the plasma membrane and the Golgi. When the MAPK module is localized to plasma membrane nanoclusters corresponding to those occupied by activated H-, N- and K-ras, ERKpp output is digital, with both low and high Raf kinase inputs processed to generate a maximal ERKpp output. In contrast, when the MAPK module is localized to the Golgi, ERKpp output is graded such that Raf kinase input corresponds to ERKpp output. These results clearly demonstrate that different cellular environments available to the MAPK module can fundamentally rewire system output, which in turn may allow this single cascade to direct different cell fate decisions.