Robustness of MAPK signalling at various expression levels of Erk1/2.

Franziska Witzel, Charite, Berlin, Germany

Franziska Witzel, Raphaela Fritsche-Guenther, Anja Sieber, Ricarda Herr, Nadine Lehmann, Sandra Braun, Tilman Brummer, Christine Sers and Nils Blüthgen

Cell fate decisions like proliferation, differentiation or migration involve the activation of the MAPK signalling pathway that engages Erk. The pathway consists of a cascade of kinases that activate each other by phosphorylation. It is known that the expression of the proteins involved varies strongly between cells, posing the question of how the pathway is able to transmit information in a quantitative and reproducible manner despite varying expression levels of the kinases. Intuitively, the phosphorylated form of a kinase should be positively correlated with the total level of the kinase. In contrast, we have found that the steady state level of phosphorylated Erk was robust against perturbations of Erk protein level in a panel of human cell lines. Although different motifs of the pathway structure might entail robustness, a single negative feedback from Erk to Raf-1 was found to provide the observed stability. During transient pathway activation, maximal Erk activity correlated with the total amount of Erk, however, the width of the activity pulse remained constant and induction of gene expression downstream of Erk was unaffected. Taken together our theoretical and experimental analysis suggests that Erk activation is robust to fluctuating levels of Erk and insensitive to Erk overexpression.