Open AccessA Nuclear Export Signal and Phosphorylation Regulate Dok1 Subcellular Localization and Functions
Author(s) -
Yamei Niu,
François Roy,
Frédéric Saltel,
Charlotte Andrieu-Soler,
Wen Dong,
Anne-Lise Chantegrel,
Rosita Accardi,
Amélie Thépot,
Nadège Foiselle,
Massimo Tommasino,
Pierre Jurdic,
Bakary S. Sylla
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01817-05
Subject(s) - nuclear export signal , microbiology and biotechnology , nuclear localization sequence , biology , cytoplasm , signal transducing adaptor protein , nuclear transport , phosphorylation , subcellular localization , cell nucleus , cell growth , importin , nuclear protein , signal transduction , biochemistry , transcription factor , gene
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 IKKbeta. 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.