A-type lamins are essential for TGF-beta1 induced PP2A to dephosphorylate transcription factors.
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-beta1 (TGF-beta1) signalling impinges on the retinoblastoma protein (pRB) and SMADs, we tested the hypothesis that lamins modulate cellular responses to TGF-beta1 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-beta1. TGF-beta1 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-beta1 on collagen production, a marker of mesenchymal differentiation. Our findings implicate lamin A/C in control of gene activity downstream of TGF-beta1, via nuclear phosphatases such as PP2A. This biological function provides a novel explanation for the observed mesenchymal dysfunction in laminopathies.
Van Berlo
J H
JH
Experimental and Molecular Cardiology, Cardiovascular Research Institute Maastricht, The Netherlands.
Voncken
J W
JW
Kubben
N
N
Broers
J L V
JL
Duisters
R
R
van Leeuwen
R E W
RE
Crijns
H J G M
HJ
Ramaekers
F C S
FC
Hutchison
C J
CJ
Pinto
Y M
YM
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D034904:Lamin Type A; D016160:Retinoblastoma Protein; C508961:Tgfb1 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D010749:Phosphoprotein Phosphatases