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Molecular and Cellular Biology, June 2006, p. 4288-4301, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01817-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

A Nuclear Export Signal and Phosphorylation Regulate Dok1 Subcellular Localization and Functions

Yamei Niu,1 François Roy ,1,{dagger},{ddagger} Frédéric Saltel,2,{dagger},§ Charlotte Andrieu-Soler,1,¶ Wen Dong,1 Anne-Lise Chantegrel,1,|| Rosita Accardi,1 Amélie Thépot,1 Nadège Foiselle,1 Massimo Tommasino,1 Pierre Jurdic,2 and Bakary S. Sylla1*

International Agency for Research on Cancer, 69008 Lyon, France,1 LBMC, UMR 5161 CNRS/ENS, IFR 128 Biosciences, 69364 Lyon Cedex 07, France2

Received 15 September 2005/ Returned for modification 12 December 2005/ Accepted 9 March 2006

Dok1 is believed to be a mainly cytoplasmic adaptor protein which down-regulates mitogen-activated protein kinase activation, inhibits cell proliferation and transformation, and promotes cell spreading and cell migration. Here we show that Dok1 shuttles between the nucleus and cytoplasm. Treatment of cells with leptomycin B (LMB), a specific inhibitor of the nuclear export signal (NES)-dependent receptor CRM1, causes nuclear accumulation of Dok1. We have identified a functional NES (348LLKAKLTDPKED359) that plays a major role in the cytoplasmic localization of Dok1. Src-induced tyrosine phosphorylation prevented the LMB-mediated nuclear accumulation of Dok1. Dok1 cytoplasmic localization is also dependent on IKKß. Serum starvation or maintaining cells in suspension favor Dok1 nuclear localization, while serum stimulation, exposure to growth factor, or cell adhesion to a substrate induce cytoplasmic localization. Functionally, nuclear NES-mutant Dok1 had impaired ability to inhibit cell proliferation and to promote cell spreading and cell motility. Taken together, our results provide the first evidence that Dok1 transits through the nucleus and is actively exported into the cytoplasm by the CRM1 nuclear export system. Nuclear export modulated by external stimuli and phosphorylation may be a mechanism by which Dok1 is maintained in the cytoplasm and membrane, thus regulating its signaling functions.

* Corresponding author. Mailing address: Infections and Cancer Biology Group, International Agency for Research on Cancer, 150 cours Albert-Thomas, 69008 Lyon, France. Phone: 33 4 72 73 80 96. Fax: 33 4 72 73 84 42. E-mail: sylla{at}iarc.fr.

{dagger} These authors made equal contributions to the work.

{ddagger} Present address: NUCLEIS, 69008 Lyon, France.

§ Present address: CMU-Centre Médicale Universitaire, 1211 Geneva 4, Switzerland.

Present address: INSERM U450, Institut Biomédical des Cordeliers, 75006 Paris, France.

|| Present address: BioMérieux, 69280 Marcy l'Etoile, France.

Molecular and Cellular Biology, June 2006, p. 4288-4301, Vol. 26, No. 11
0270-7306/06/$08.00+0     doi:10.1128/MCB.01817-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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