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Molecular and Cellular Biology, February 2004, p. 1206-1218, Vol. 24, No. 3
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.3.1206-1218.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

ERF Nuclear Shuttling, a Continuous Monitor of Erk Activity That Links It to Cell Cycle Progression

Lionel Le Gallic,1,{dagger} Laura Virgilio,1 Philip Cohen,2 Benoit Biteau,3,{ddagger} and George Mavrothalassitis1,3*

IMBB, FORTH, Heraklion, Crete 711 10,1 Medical School, University of Crete, Heraklion, Crete 710 03, Greece,3 MRC Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom2

Received 24 April 2003/ Returned for modification 13 July 2003/ Accepted 30 October 2003

The ets domain transcriptional repressor ERF is an effector of the receptor tyrosine kinase/Ras/Erk pathway, which, it has been suggested, is regulated by subcellular localization as a result of Erk-dependent phosphorylation and is capable of suppressing cell proliferation and ras-induced tumorigenicity. Here, we analyze the effect of ERF phosphorylation on nuclear import and export, the timing of its phosphorylation and dephosphorylation in relation to its subcellular location, Erk activity, and the requirements for ERF-induced cell cycle arrest. Our findings indicate that ERF continuously shuttles between the nucleus and the cytoplasm and that both phosphorylation and dephosphorylation of ERF occur within the nucleus. While nuclear import is not affected by phosphorylation, ERF nuclear export and cytoplasmic release require multisite phosphorylation and dephosphorylation. ERF export is CRM1 dependent, although ERF does not have a detectable nuclear export signal. ERF phosphorylation and export correlate with the levels of nuclear Erk activity. The cell cycle arrest induced by nonphosphorylated ERF requires the wild-type retinoblastoma protein and can be suppressed by overexpression of cyclin. These data suggest that ERF may be a very sensitive and constant sensor of Erk activity that can affect cell cycle progression through G1, providing another link between the Ras/Erk pathway and cellular proliferation.

* Corresponding author. Mailing address: Medical School, University of Crete, Heraklion, Crete 710 03, Greece. Phone and fax: 30 2810 394537. E-mail: mavro{at}imbb.forth.gr.

{dagger} Present address: Genepep, Faculté de Pharmacie, 34093 Montpellier Cedex 5, France.

{ddagger} CEA Saclay, DSV/DBJC/SBGM/LSOC, 91191 Gif sur Yvette Cedex, France.

Molecular and Cellular Biology, February 2004, p. 1206-1218, Vol. 24, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.3.1206-1218.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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