Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes

Abstract

Signals transmitted by ERK MAP kinases regulate the functions of multiple substrates present in the nucleus and in the cytoplasm. ERK signals are optimized by scaffold proteins that modulate their intensity and spatial fidelity. Once phosphorylated, ERKs dimerize, but how dimerization impacts on the activation of the different pools of substrates and whether it affects scaffolds functions as spatial regulators are unknown aspects of ERK signaling. Here we demonstrate that scaffolds and ERK dimers are essential for the activation of cytoplasmic but not nuclear substrates. Dimerization is critical for connecting the scaffolded ERK complex to cognate cytoplasmic substrates. Contrarily, nuclear substrates associate to ERK monomers. Furthermore, we show that preventing ERK dimerization is sufficient for attenuating cellular proliferation, transformation, and tumor development. Our results disclose a functional relationship between scaffold proteins and ERK dimers and identify dimerization as a key determinant of the spatial specificity of ERK signals. © 2008 Elsevier Inc. All rights reserved.The P.C. lab is supported by grants BFU2005-00777 and GEN2003-20239-C06-03 from the Spanish Ministry of Education and by GROWTHSTOP (LSHC CT-2006-037731) and SIMAP (IST-2004-027265) projects from the EU VI Framework Program and Red Temática de Investigación Cooperativa en Cáncer (RTICC) (RD06/0020/0105), Spanish Ministry of Health.Peer Reviewe