Mathematical modeling reveals the functional implications of the different nuclear shuttling rates of Erk1 and Erk2.

The mitogen-activated protein kinase (MAPK) family of proteins is involved in regulating cellular fates such as proliferation, differentiation and apoptosis. In particular, the dynamics of the Erk/Mek system, which has become the canonical example for MAPK signaling systems, have attracted considerable attention. Erk is encoded by two genes, Erk1 and Erk2, that until recently had been considered equivalent as they differ only subtly at the sequence level. However, these proteins exhibit radically different trafficking between cytoplasm and nucleus and this fact may have functional implications. Here we use spatially resolved data on Erk1/2 to develop and analyze spatio-temporal models of these cascades, and we discuss how sensitivity analysis can be used to discriminate between mechanisms. Our models elucidate some of the factors governing the interplay between signaling processes and the Erk1/2 localization in different cellular compartments, including competition between Erk1 and Erk2. Our approach is applicable to a wide range of signaling systems, such as activation cascades, where translocation of molecules occurs. Our study provides a first model of Erk1 and Erk2 activation and their nuclear shuttling dynamics, revealing a role in the regulation of the efficiency of nuclear signaling.