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Molecular and Cellular Biology, March 2005, p. 1900-1911, Vol. 25, No. 5
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.5.1900-1911.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

PTOV1 Enables the Nuclear Translocation and Mitogenic Activity of Flotillin-1, a Major Protein of Lipid Rafts

Anna Santamaría,1 Elisabeth Castellanos,1 Valentí Gómez,1 Patricia Benedit,1 Jaime Renau-Piqueras,2 Juan Morote,3 Jaume Reventós,1 Timothy M. Thomson,4*,{dagger} and Rosanna Paciucci*{dagger}

Unitat de Recerca Biomèdica,1 Departamento de Urología, Hospital Vall d'Hebrón,3 Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona,4 Centro de Investigación, Hospital Universitario La Fe, Valencia, Spain2

Received 6 May 2004/ Returned for modification 12 June 2004/ Accepted 2 December 2004

PTOV1 is a mitogenic protein that shuttles between the nucleus and the cytoplasm in a cell cycle-dependent manner. It consists of two homologous domains arranged in tandem that constitute a new class of protein modules. We show here that PTOV1 interacts with the lipid raft protein flotillin-1, with which it copurifies in detergent-insoluble floating fractions. Flotillin-1 colocalized with PTOV1 not only at the plasma membrane but, unexpectedly, also in the nucleus, as demonstrated by immunocytochemistry and subcellular fractionation of endogenous and exogenous flotillin-1. Flotillin-1 entered the nucleus concomitant with PTOV1, shortly before the initiation of the S phase. Protein levels of PTOV1 and flotillin-1 oscillated during the cell cycle, with a peak in S. Depletion of PTOV1 significantly inhibited nuclear localization of flotillin-1, whereas depletion of flotillin-1 did not affect nuclear localization of PTOV1. Depletion of either protein markedly inhibited cell proliferation under basal conditions. Overexpression of PTOV1 or flotillin-1 strongly induced proliferation, which required their localization to the nucleus, and was dependent on the reciprocal protein. These observations suggest that PTOV1 assists flotillin-1 in its translocation to the nucleus and that both proteins are required for cell proliferation.

* Corresponding author. Mailing address for Rosanna Paciucci: Unitat de Recerca Biomèdica, Hospital Vall d'Hebrón, Passeig Vall d'Hebrón 119-129, 00835 Barcelona, Spain. Phone: 34 93 489 4063. Fax: 34 93 489 4064. E-mail: rpaciucci{at}vhebron.net. Mailing address for Timothy M. Thomson: Department of Molecular and Cellular Biology, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Jordi Girona 18-26, 08034 Barcelona, Spain. Phone: 34 93 400 6100. Fax: 34 93 204 5904. E-mail: titbmc{at}cid.csic.es.

{dagger} T.M.T. and R.P. contributed equally to this work.

Molecular and Cellular Biology, March 2005, p. 1900-1911, Vol. 25, No. 5
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.5.1900-1911.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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