Sci. Signal., 7 December 2010
Cell Biology ERKed About Lamin A
Elizabeth M. Adler
Science Signaling, AAAS, Washington, DC 20005, USA
The extracellular signal–regulated mitogen-activated protein kinases (ERK MAPKs) transduce extracellular stimuli to regulate such processes as cell proliferation, differentiation, and survival. ERKs can promote cell proliferation through various mechanisms, some of which are mediated though the phosphorylation and inactivation of the retinoblastoma (Rb) protein and the consequent release of E2F transcription factors. For instance, ERK activation leads to its translocation to the nucleus, where its phosphorylation of transcription factors leads to the production of cyclin D, which forms complexes with cyclin-dependent kinases to phosphorylate Rb. A fraction of nuclear ERK binds to lamin A, a nuclear protein to which Rb binds, at the same region through which lamin A binds Rb, leading Rodríguez et al. to investigate the effects of mitogenic stimulation on Rb association with lamin A. Stimulation of quiescent NIH3T3 cells with platelet-derived growth factor (PDGF) elicited redistribution of Rb from an extraction-resistant nuclear fraction (ERNF, associated mainly with the nucleoskeleton and nuclear envelope) to a soluble fraction, which occurred concomitantly with ERK2 association with the ERNF and was prevented by blocking ERK activation. PDGF decreased coimmunoprecipitation of Rb with lamin A, increased coimmunoprecipitation of lamin A with ERK2, and elicited the appearance of phosphorylated Rb. Analyses of nuclear-localized ERK2 mutants indicated that Rb displacement from lamin A did not depend on ERK phosphorylation or its kinase activity but required the region responsible for binding to lamin A. Moreover, in vitro analyses confirmed that ERK2 directly displaced Rb from lamin A. Nuclear-localized ERK constructs induced the cyclin A-, D-, and E-independent appearance of phosphorylated Rb in the soluble nuclear fraction, and experiments in mouse embryo fibroblasts (MEFs) indicated that these constructs stimulated E2F-dependent transcription through a mechanism that depended on Rb inactivation. Indeed, nuclear-localized ERK promoted MEF entry into the cell cycle, an effect that depended on both Rb and lamin A. Intriguingly, cotransfection of lamin A antagonized the ability of nuclear ERK2 to enhance v-Src–mediated NIH3T3 cell transformation, and stable overexpression of lamin A in a line of breast cancer cells led to increased association of Rb with lamin A, decreased Rb phosphorylation, and decreased rates of proliferation. Thus, ERK can promote cell proliferation through a mechanism independent of its catalytic activity.
J. Rodríguez, F. Calvo, J. M. González, B. Casar, V. Andrés, P. Crespo, ERK1/2 MAP kinases promote cell cycle entry by rapid, kinase-independent disruption of retinoblastoma–lamin A complexes. J. Cell Biol. 191, 967–979 (2010). [Abstract] [Full Text]
Citation: E. M. Adler, ERKed About Lamin A. Sci. Signal. 3, ec371 (2010).
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