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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*, and Rosanna Paciucci^*

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.

T.M.T. and R.P. contributed equally to this work.

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