Transforming growth factor β signaling via ras in mesenchymal cells requires p21-activated kinase 2 for extracellular signal-regulated kinase-dependent transcriptional responses

Kaori Suzuki, Mark C. Wilkes, Nandor Garamszegi, Maryanne Edens, Edward B Leof

Research output: Contribution to journalArticle

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Abstract

Transforming growth factor β (TGF-β) signaling via Smad proteins occurs in various cell types. However, whereas the biological response to TGF-β can be as distinct as growth promoting (i.e., mesenchymal cells) versus growth inhibiting (i.e., epithelial cells), few discernible differences in TGF-β signaling have been reported. In the current study, we examined the role of Ras in the proliferative response to TGF-β and how it might interface with Smad-dependent and Smad-independent TGF-β signaling targets. TGF-β stimulated Ras activity in a subset of mesenchymal, but not epithelial, cultures and was required for extracellular signal-regulated kinase (ERK)-dependent transcriptional responses. Although dominant negative Ras had no effect on TGF-β internalization or Smad-dependent signaling (i.e., phosphorylation, nuclear translocation, or SBE-luciferase activity), it did prevent the hyperphosphorylation of the Smad transcriptional corepressor TG-interacting factor (TGIF). This was not sufficient, however, to overcome the mitogenic response stimulated by TGF-β, which was dependent on signals downstream of p21-activated kinase 2 (PAK2). Moreover, although the initial activation of Ras and PAK2 are distinctly regulated, TGF-β-stimulated PAK2 activity is required for Ras-dependent ERK phosphorylation and Elk-1 transcription. These findings show the requirement for crosstalk between two Smad-independent pathways in regulating TGF-β proliferation and indicate that the mechanism(s) by which TGF-β stimulates growth is not simply the opposite of its growth inhibitory actions.

Original languageEnglish (US)
Pages (from-to)3673-3682
Number of pages10
JournalCancer Research
Volume67
Issue number8
DOIs
StatePublished - Apr 15 2007

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p21-Activated Kinases
Extracellular Signal-Regulated MAP Kinases
Transforming Growth Factors
Growth
Phosphorylation
Smad Proteins
Co-Repressor Proteins
Luciferases

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Transforming growth factor β signaling via ras in mesenchymal cells requires p21-activated kinase 2 for extracellular signal-regulated kinase-dependent transcriptional responses. / Suzuki, Kaori; Wilkes, Mark C.; Garamszegi, Nandor; Edens, Maryanne; Leof, Edward B.

In: Cancer Research, Vol. 67, No. 8, 15.04.2007, p. 3673-3682.

Research output: Contribution to journalArticle

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