Erk/p90RSK/14-3-3 signalling impacts on expression of PEA3 Ets transcription factors via the transcriptional repressor capicúa

Abstract : Compounds that inhibit signalling upstream of Erk are promising anti-cancer therapies, motivating research to define how this pathway promotes cancers. Here, we show that human capicúa represses mRNA expression for PEA3 Ets transcription factors ETV1, ETV4 and ETV5, and this repression is relieved by multisite controls of capicúa by Erk, p90RSK and 14-3-3 proteins. Specifically, 14-3-3 binds to p90RSK-phosphorylated Ser173 of capicúa thereby inhibiting DNA binding to its HMG box, while Erk phosphorylations prevent binding of a C-terminal NLS to importin alpha 4 (KPNA3). ETV1, 4 and 5 mRNA levels in melanoma cells are elevated by siRNA knockdown of capicúa, and decreased by inhibiting Erk and/or expressing a form of capicúa that cannot bind to 14-3-3s. Capicúa knockdown also enhances cell migration. Our findings give further mechanistic insights into why ETV1 is highly expressed in certain cancers, indicate that loss of capicúa can desensitise cells to the effects of Erk pathway inhibitors, and highlight interconnections among growth factor signalling, spinocerebellar ataxias and cancers.
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Submitted on : Friday, January 21, 2011 - 2:54:52 AM
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Kumara Dissanayake, Rachel Toth, Jamie Blakey, Olof Olsson, David G Campbell, et al.. Erk/p90RSK/14-3-3 signalling impacts on expression of PEA3 Ets transcription factors via the transcriptional repressor capicúa. Biochemical Journal, Portland Press, 2011, 433 (3), pp.515-525. ⟨10.1042/BJ20101562⟩. ⟨hal-00558100⟩

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