Smad4 mediates activation of mitogen-activated protein kinases by TGF-β in pancreatic acinar cells

Diane M. Simeone, Lizhi Zhang, Kathleen Graziano, Barbara Nicke, Trinh Pham, Claus Schaefer, Craig D. Logsdon

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Transforming growth factor-β (TGF-β) inhibits pancreatic acinar cell growth. In many cell types, TGF-β mediates its growth inhibitory effects by activation of Smad proteins. Recently, it has been reported that Smad proteins may interact with the mitogen-activated protein (MAP) kinase signaling pathways. In this study, we report on the interactions between the TGF-β and MAP kinase signaling pathways in isolated rat pancreatic acinar cells. TGF-β activated the MAP kinases extracellular signal-related kinases (ERKs) and p38 in pancreatic acinar cells, but had no effect on c-jun NH2-terminal kinase activity. Activation of MAP kinase by TGF-β was maximal 4 h after treatment. The ability of TGF-β to activate ERKs was concentration dependent and dependent on protein synthesis. TGF-β's stimulation of ERK activation was blocked by PD-98059, an inhibitor of MAP kinase kinase 1, and by adenoviral transfer of dominant negative RasN17. Furthermore, adenoviral-mediated expression of dominant negative Smad4 blocked the ability of TGF-β to activate acinar cell MAP kinase, demonstrating that this activation is downstream of Smads. The biological relevance of ERK activation by TGF-β was indicated by demonstrating that inhibition of ERK signaling by PD-98059 blocked the ability of TGF-β to activate the transcription factor activator protein-1. These studies provide new insight into the signaling mechanisms by which TGF-β mediates biological actions in pancreatic acinar cells.

Original languageEnglish (US)
Pages (from-to)C311-C319
JournalAmerican Journal of Physiology - Cell Physiology
Issue number1 50-1
StatePublished - 2001


  • Transforming growth factor-β

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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