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Lkb1 is required for TGFbeta-mediated myofibroblast differentiation

Kari Vaahtomeri1, Eeva Ventelä, Kaisa Laajanen

  • 1Genome-Scale Biology Program, Institute of Biomedicine, Biomedicum Helsinki, P.O. Box 63, 00014 University of Helsinki, Finland.

Journal of Cell Science
|October 9, 2008
PubMed

Insights

Loss of the tumor suppressor LKB1 (liver kinase B1) in mesenchymal cells impairs TGF-beta signaling, leading to defective myofibroblast differentiation and potentially contributing to Peutz-Jeghers syndrome (PJS) tumorigenesis.

Area of Science:

  • Cell Biology
  • Oncology
  • Molecular Biology

Background:

  • Peutz-Jeghers syndrome (PJS) is linked to inactivating mutations in the tumor suppressor gene LKB1.
  • PJS polyps exhibit a distinct smooth-muscle and stromal component.
  • Lkb1 deletion in specific mesenchymal cells induces PJS-type polyps in mice.

Purpose of the Study:

  • To investigate the stromal functions of LKB1 in tumor suppression.
  • To elucidate the role of LKB1 in myofibroblast differentiation and TGF-beta signaling.

Main Methods:

  • Ablation of LKB1 in primary mouse embryo fibroblasts (MEFs).
  • Analysis of Smad activation and TGF-beta-dependent transcription.
  • Assessment of myofibroblast differentiation, alpha-smooth muscle actin (SMA) stress fiber formation, and contractility.
  • Evaluation of serum response factor (SRF) activity.

Main Results:

  • LKB1 ablation in MEFs attenuated Smad activation and TGF-beta-dependent transcription.
  • LKB1-deficient MEFs showed defective myofibroblast differentiation, reduced SMA-positive stress fibers, and decreased contractility.
  • The differentiation defect was independent of SRF activity but rescued by exogenous TGF-beta, indicating impaired TGF-beta signaling.

Conclusions:

  • LKB1 inactivation disrupts TGF-beta signaling, impairing myofibroblast differentiation.
  • Defective myogenic differentiation in LKB1-deficient mesenchymal cells may contribute to PJS tumorigenesis.

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