Protein phosphorylation represents a rapid and reversible post-translational regulation that enables a fast control of protein activation that play key roles in cell signaling. For instance, Mitogen Activated Protein Kinase (MAPK) pathways are activated upon sequential phosphorylations, resulting in phosphorylation of cytosol and nuclear targets. We focus here on MAPK ERK1/2 signaling that accounts for diverse cellular responses such as cell cycle progression, proliferation, differentiation, senescence, migration, formation of GAP junctions, cell adhesion, cell motility, survival and apoptosis. We review the role of protein phosphorylation in MAPK ERK1/2 activation, in its regulation in time and space and how its dysregulation can lead to tumorigenesis.