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.
Bibliographical noteFunding 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.