A-type lamins are essential for TGF-β1 induced PP2A to dephosphorylate transcription factors

J. H. Van Berlo, J. W. Voncken, N. Kubben, J. L.V. Broers, R. Duisters, R. E.W. van Leeuwen, H. J.G.M. Crijns, F. C.S. Ramaekers, C. J. Hutchison, Y. M. Pinto

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105 Scopus citations

Abstract

Diseases caused by mutations in lamins A and C (laminopathies) suggest a crucial role for A-type lamins in different cellular processes. Laminopathies mostly affect tissues of mesenchymal origin. As transforming growth factor-β1 (TGF-β1) signalling impinges on the retinoblastoma protein (pRB) and SMADs, we tested the hypothesis that lamins modulate cellular responses to TGF-β1 signalling, via the regulation of these transcription factors in mesenchymal cells. Here, we report that A-type lamins are essential for the inhibition of fibroblast proliferation by TGF-β1. TGF-β1 dephosphorylated pRB through PP2A, both of which, we show, are associated with lamin A/C. In addition, lamin A/C modulates the effect of TGF-β1 on collagen production, a marker of mesenchymal differentiation. Our findings implicate lamin A/C in control of gene activity downstream of TGF-β1, via nuclear phosphatases such as PP2A. This biological function provides a novel explanation for the observed mesenchymal dysfunction in laminopathies.

Original languageEnglish (US)
Pages (from-to)2839-2849
Number of pages11
JournalHuman molecular genetics
Volume14
Issue number19
DOIs
StatePublished - Oct 2005

Bibliographical note

Funding Information:
We would like to thank B. Burke and C.L. Stewart for providing cells and reagents. J.H.vB. was supported by NHF grant 2002T016, J.W.V. was supported by VIDI grant NWO/ ZonMW 016.046.362 and Y.M.P. was supported by VIDI grant NWO/ZonMW 016.036.346.

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