Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes.
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.
Casar
Berta
B
Departamento de Biología Molecular, Facultad de Medicina, Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas-IDICAN-Universidad de Cantabria, Santander, 39011 Cantabria, Spain.
Pinto
Adán
A
Crespo
Piero
P
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism*; D019281:Dimerization; D048049:Extracellular Signal-Regulated MAP Kinases / Q000737:chemistry / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
D003598:Cytoskeletal Proteins; D034741:RNA, Small Interfering; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D054513:Group IV Phospholipases A2