Paper detail

Dependence of MAPK mediated signaling on Erk isoforms and differences in nuclear shuttling

The mitogen activated protein kinase (MAPK) family of proteins is involved in regulating cellular fate activities such as proliferation, differentiation and apoptosis. Their fundamental importance has attracted considerable attention on different aspects of the MAPK signaling dynamics; this is particularly true for the Erk/Mek system, which has become the canonical example for MAPK signaling systems. Erk exists in many different isoforms, of which the most widely studied are Erk1 and Erk2. Until recently, these two kinases were considered equivalent as they differ only subtly at the sequence level; however, these isoforms exhibit radically different trafficking between cytoplasm and nucleus. 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. We are especially interested in understanding why two such similar proteins should co-exist in the same organism, as their functional roles appear to be different. Our models elucidate some of the factors governing the interplay between processes and the Erk1/2 localization in different cellular compartments, including competition between isoforms. This methodology is applicable to a wide range of systems, such as activation cascades, where translocation of species occurs via signal pathways. Furthermore, our work may motivate additional emphasis for considering potentially different roles for isoforms that differ subtly at the sequence level.