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First published online 7 October 2008
doi: 10.1242/jcs.032706

Journal of Cell Science 121, 3531-3540 (2008)
Published by The Company of Biologists 2008
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Research Article

Lkb1 is required for TGFβ-mediated myofibroblast differentiation

Kari Vaahtomeri1, Eeva Ventelä1,*, Kaisa Laajanen1,*, Pekka Katajisto1,*, Pierre-Jean Wipff2, Boris Hinz2, Tea Vallenius1, Marianne Tiainen1,{ddagger} and Tomi P. Mäkelä1,§

1 Genome-Scale Biology Program, Institute of Biomedicine, Biomedicum Helsinki, P.O. Box 63, 00014 University of Helsinki, Finland
2 Laboratory of Cell Biophysics, Bâtiment SG-AA-B143, Station 15, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland

§ Author for correspondence (e-mail: tomi.makela{at}helsinki.fi)

Accepted 21 July 2008

Inactivating mutations of the tumor-suppressor kinase gene LKB1 underlie Peutz-Jeghers syndrome (PJS), which is characterized by gastrointestinal hamartomatous polyps with a prominent smooth-muscle and stromal component. Recently, it was noted that PJS-type polyps develop in mice in which Lkb1 deletion is restricted to SM22-expressing mesenchymal cells. Here, we investigated the stromal functions of Lkb1, which possibly underlie tumor suppression. Ablation of Lkb1 in primary mouse embryo fibroblasts (MEFs) leads to attenuated Smad activation and TGFβ-dependent transcription. Also, myofibroblast differentiation of Lkb1–/– MEFs is defective, resulting in a markedly decreased formation of {alpha}-smooth muscle actin (SMA)-positive stress fibers and reduced contractility. The myofibroblast differentiation defect was not associated with altered serum response factor (SRF) activity and was rescued by exogenous TGFβ, indicating that inactivation of Lkb1 leads to defects in myofibroblast differentiation through attenuated TGFβ signaling. These results suggest that tumorigenesis by Lkb1-deficient SM22-positive cells involves defective myogenic differentiation.

Key words: Lkb1, Myofibroblast differentiation, TGFβ


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