MEK, p38, and PI-3K mediate cross talk between EGFR and TNFR in enhancing hepatocyte growth factor production from human mesenchymal stem cells

Yue Wang, Brent R. Weil, Jeremy L. Herrmann, Aaron M. Abarbanell, Jiangning Tan, Troy A. Markel, Megan L. Kelly, Daniel R. Meldrum

Research output: Contribution to journalArticle

30 Scopus citations


Human bone marrow mesenchymal stem cells (MSCs) are a potent source of growth factors, which are partly responsible for their beneficial paracrine effects. We reported previously that transforming growth factor-α (TGF-α), a putative mediator of wound healing and the injury response, increases the release of vascular endothelial growth factor (VEGF), augments tumor necrosis factor-α (TNF-α)-stimulated VEGF production, and activates mitogen-activated protein kinases and phosphatidylinositol 3-kinase (PI-3K) pathway in human MSCs. The experiments described in this report indicate that TGF-α increases MSC-derived hepatocyte growth factor (HGF) production. TGF-α-stimulated HGF production was abolished by inhibition of MEK, p38, PI-3K, or by small interfering RNA (siRNA) targeting TNF receptor 2 (TNFR2), but was not attenuated by siRNA targeting TNF receptor 1 (TNFR1). Ablation of TNFR1 significantly increased basal and stimulated HGF. A potent synergy between TGF-α and TNF-α was noted in MSC HGF production. This synergistic effect was abolished by MEK, P38, PI-3K inhibition, or by ablation of both TNF receptors using siRNA. We conclude that 1) novel cross talk occurs between tumor necrosis factor receptor and TGF-α/epidermal growth factor receptor in stimulating MSC HGF production; 2) this cross talk is mediated, at least partially, via activation of MEK, p38, and PI-3K; 3) TGF-α stimulates MSCs to produce HGF by MEK, p38, PI-3K, and TNFR2-dependent mechanisms; and 4) TNFR1 acts to decrease basal TGF-α and TNF-α-stimulated HGF.

Original languageEnglish (US)
Pages (from-to)C1284-C1293
JournalAmerican Journal of Physiology - Cell Physiology
Issue number5
StatePublished - Nov 1 2009



  • Epidermal growth factor receptor
  • Phosphatidylinositol 3-kinase
  • Transforming growth factor-α
  • Tumor necrosis factor receptor
  • Tumor necrosis factor-α
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Cell Biology
  • Physiology

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