The role in cell signaling of ERK1 and ERK2 MAP kinases is not redundant. We have previously demonstrated that ERK1 ablation results in abnormal signaling responses, producing not only an up regulation of ERK2 activity in the brain but also a significant growth advantage in proliferating cells. Based on our initial results we originally proposed that ERK1 can be seen as a partial agonist to ERK2 by negatively regulating the interaction with signaling partners. Despite the fact that the overall sequence identity between the two kinases is very high, an unique N-terminal stretch is exclusively present in ERK1. We found that this domain is responsible for the functional difference between these two MAP kinases. In fact, anchoring the N-terminal domain of ERK1 to ERK2 (ERK2>1) confers ERK1-like signaling properties to ERK2 while its removal from ERK1 (1>2) converts the protein into a ERK2-like kinase. In culture cells, overexpression of ERK1 and ERK2>1 reduces cell growth and increases apoptosis, while overexpression of ERK2 and ERK1>2 induces an increase in cell growth and seems to protect from apoptosis. In addition, knockdown of ERK1 by shRNA and shRNAmir technologies results in an increase in cell growth and reduces apoptosis, while ERK2 knockdown induces a decrease in the cell growth and increased apoptosis. Furthermore, we sought evidence that by changing the ERK1/ERK2 ratio in the brain we could affect neuronal cell signaling and behavioral responses. Analysis of dendritic harborisation demonstrates that while ERK2 overexpressing and ERK1 knockdown mice show an increase density of spines, overexpression of ERK1 does just the opposite. These morphological changes in neurons lead to altered behavioral responses. Altogether these results confirm that ERK1 and ERK2 play distinct roles in signaling by differentially contribute to a fine tuning of cellular responses both in proliferating cells and in post mitotic neurons.