Editors' ChoiceMAPK Signaling

What Are Dimers Good For?

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Science Signaling  09 Sep 2008:
Vol. 1, Issue 36, pp. ec315
DOI: 10.1126/scisignal.136ec315

Extracellular signal-regulated kinase 1 (ERK1) and ERK2 are members of the mitogen-activated protein kinase (MAPK) family of serine/threonine kinases. They are activated in response to many stimuli, including those leading to cellular proliferation. Once activated, ERKs form homodimers, but the importance of dimer formation to their function is poorly understood. Scaffold proteins such as KSR1 act as assembly points for components of the MAPK pathway, thus providing temporal and spatial regulation of ERK signaling. Casar et al. investigated whether ERK dimer formation had an impact on scaffold protein use or substrate targeting. From experiments with wild-type and mutant forms of ERK2 in cells in which epidermal growth factor (EGF)-stimulated, ERK2-mediated activation of cytosolic phospholipase A2 (cPLA2) was monitored, the authors showed that EGF stimulated the assembly of complexes containing KSR1, cPLA2, and ERK2 dimers. The formation of ERK2 dimers was necessary for the recruitment of cPLA2 to KSR1 and to other scaffold proteins. Although scaffold protein–specific small inhibitory RNAs (siRNAs) blocked ERK2-mediated activation of cPLA2, they had no effect on the activation of the transcription factor Elk1, a nuclear substrate of ERK2. Immunofluorescence studies of EGF-stimulated cells showed that monomeric, but not dimeric, ERKs accumulated in the nucleus, whereas dimeric ERKs were mostly cytoplasmic. Injection of nude mice with tumor cells expressing a dimerization-defective ERK2 mutant resulted in delayed tumor formation and smaller tumor size compared with that in mice that received control tumor cells. These data suggest that ERK dimers interact with scaffold proteins to target cytoplasmic, but not nuclear, targets and that disruption of ERK dimer formation may have potential in antitumor therapies.

B. Casar, A. Pinto, P. Crespo, Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes. Mol. Cell 31, 708-721 (2008). [PubMed]

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