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J. Cell Biol. 191 (5): 967-979

Copyright © 2010 by the Rockefeller University Press.

Article

ERK1/2 MAP kinases promote cell cycle entry by rapid, kinase-independent disruption of retinoblastoma–lamin A complexes

Javier Rodríguez1, Fernando Calvo1, José M. González2, Berta Casar1, Vicente Andrés2, , and Piero Crespo1

1 Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas, Investigación Desarrollo e Innovación Cantabria, Departamento de Biología Molecular, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain
2 Laboratoria de Patofisiología Cardiovascular Molecular y Genética, Centro Nacional de Investigaciones Cardiovasculares, 28029 Madrid, Spain

Correspondence to Piero Crespo: crespop{at}unican.es

Abstract: As orchestrators of essential cellular processes like proliferation, ERK1/2 mitogen-activated protein kinase signals impact on cell cycle regulation. A-type lamins are major constituents of the nuclear matrix that also control the cell cycle machinery by largely unknown mechanisms. In this paper, we disclose a functional liaison between ERK1/2 and lamin A whereby cell cycle progression is regulated. We demonstrate that lamin A serves as a mutually exclusive dock for ERK1/2 and the retinoblastoma (Rb) protein. Our results reveal that, immediately after their postactivation entrance in the nucleus, ERK1/2 dislodge Rb from its interaction with lamin A, thereby facilitating its rapid phosphorylation and consequently promoting E2F activation and cell cycle entry. Interestingly, these effects are independent of ERK1/2 kinase activity. We also show that cellular transformation and tumor cell proliferation are dependent on the balance between lamin A and nuclear ERK1/2 levels, which determines Rb accessibility for phosphorylation/inactivation.

Abbreviations: DK, kinase-deficient mutant • DMEM, Dulbecco’s minimum essential medium • ERK, ERK1/2 MAPK • ERNF, extraction-resistant nuclear fraction • FRET, fluorescence resonance energy transfer • GDI, guanine dissociation inhibitor • MEF, mouse embryo fibroblast • Rb, retinoblastoma • SNF, soluble nuclear fraction • wt, wild type

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