Lkb1 is required for TGF beta-mediated myofibroblast differentiation

Kari Vaahtomeri, Eeva Ventelae, Kaisa Laajanen, Pekka Katajisto, Pierre-Jean Wipff, Boris Hinz, Tea Vallenius, Marianne Tiainen, Tomi P. Mäkelä

Research output: Contribution to journalArticleScientificpeer-review

Abstract

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 TGF beta-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 TGF beta, indicating that inactivation of Lkb1 leads to defects in myofibroblast differentiation through attenuated TGF beta signaling. These results suggest that tumorigenesis by Lkb1-deficient SM22-positive cells involves defective myogenic differentiation.
Original languageEnglish
JournalJournal of Cell Science
Volume121
Pages (from-to)3531-3540
Number of pages10
ISSN0021-9533
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed

Fields of Science

  • Lkb1
  • Myofibroblast differentiation
  • TGF beta
  • SMOOTH MUSCLE ACTIN
  • SERUM RESPONSE FACTOR
  • FOCAL ADHESION KINASE
  • PEUTZ-JEGHERS-SYNDROME
  • GRANULATION-TISSUE MYOFIBROBLASTS
  • ACTIVATED PROTEIN-KINASE
  • TRANSFORMING GROWTH-FACTOR-BETA-1
  • IN-VIVO
  • GENE-EXPRESSION
  • CAROTID-ARTERY

Cite this