MAPK Signaling

Not Just for Translation

Science Signaling  20 Dec 2011:
Vol. 4, Issue 204, pp. ec355
DOI: 10.1126/scisignal.4204ec355

Eukaryotic translation initiation factor 3 (eIF3) is a multisubunit complex that participates in protein translation. Xu et al. report that subunit a of this complex, eIF3a, is a binding partner for proteins of the mitogen-activated protein kinase (MAPK) pathway. eIF3a was identified in a proteomic screen for proteins that interacted with the scaffolding protein β-arrestin2. Knockdown of either β-arrestin2 or eIF3a increased the peak of extracellular signal–regulated kinase (ERK) activity as well as extended the duration of its activity in HEK293 cells stimulated with epidermal growth factor (EGF). Coimmunoprecipitation experiments revealed that eIF3a interacted with the adaptor SHC and the MAPKKK Raf-1 but not with Raf-B. Overexpression of β-arrestin2 enhanced the interaction between Raf-1 and eIF3a, and in β-arrestin1 and -2 knockout cells, this interaction was largely undetectable. Stimulation of cells with EGF triggered the dose-dependent dissociation of eIF3a from Raf-1. Analysis of the phosphorylation state of Raf-1 showed that the fraction of Raf-1 that coimmunoprecipitated with eIF3a after EGF stimulation was phosphorylated at an inhibitory phosphorylation site and thus was inactive when bound to eIF3a. Cells in which eIF3a was down-regulated with siRNA showed increased basal abundance of c-Fos, which is encoded by a gene that is stimulated in response to ERK signaling, and also showed enhanced stimulation of the accumulation of c-Fos in response to EGF. In PC12 cells (a pheochromocytoma cell line that can be induced to differentiate or proliferate in response to ERK signaling), knockdown of eIF3a enhanced EGF and nerve growth factor–induced ERK activity and increased the abundance of transcripts encoding proteins associated with neuronal differentiation. Whether these effects of eIF3a are solely due to its role as an inhibitor of Raf-1 or whether they are also mediated through its role in the eukaryotic translation initiation complex remains to be established.

T.-R. Xu, R.-F. Lu, D. Romano, A. Pitt, M. D. Houslay, G. Milligan, W. Kolch, Eukaryotic translation initiation factor 3, subunit a, regulates the extracellular signal-regulated kinase pathway. Mol. Cell. Biol. 32, 88–95 (2012). [PubMed]