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

D M Simeone1, L Zhang, K Graziano

  • 1Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. simeone@umich.edu

American Journal of Physiology. Cell Physiology
|June 13, 2001
PubMed

Insights

Transforming growth factor-beta (TGF-beta) activates MAP kinases, including ERKs and p38, in pancreatic acinar cells. This activation is Smad-dependent and biologically relevant, impacting gene transcription.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Gastroenterology

Background:

  • Transforming growth factor-beta (TGF-beta) is a key regulator of cell growth, often inhibiting it.
  • Smad proteins are central mediators of TGF-beta signaling in many cell types.
  • Potential interactions between Smad and mitogen-activated protein (MAP) kinase pathways are increasingly recognized.

Purpose of the Study:

  • To investigate the interplay between TGF-beta and MAP kinase signaling in rat pancreatic acinar cells.
  • To elucidate the specific MAP kinases activated by TGF-beta in this cell type.
  • To determine the role of Smad proteins in mediating TGF-beta-induced MAP kinase activation.

Main Methods:

  • Treatment of isolated rat pancreatic acinar cells with TGF-beta.
  • Analysis of MAP kinase activities (ERK, p38, JNK) via Western blotting or kinase assays.
  • Use of specific inhibitors (PD-98059) and adenoviral vectors for dominant-negative constructs (RasN17, Smad4).
  • Assessment of transcription factor activation (AP-1).

Main Results:

  • TGF-beta activated extracellular signal-related kinases (ERKs) and p38, but not c-jun NH2-terminal kinase.
  • MAP kinase activation by TGF-beta was time-dependent (maximal at 4 hours), concentration-dependent, and required protein synthesis.
  • Inhibition of MAP kinase kinase 1 (MEK1) or expression of dominant-negative RasN17 blocked ERK activation.
  • Adenoviral expression of dominant-negative Smad4 abrogated TGF-beta-induced MAP kinase activation, indicating it is downstream of Smads.
  • Inhibition of ERK signaling by PD-98059 blocked TGF-beta-induced activation of activator protein-1 (AP-1).

Conclusions:

  • TGF-beta activates ERKs and p38 in pancreatic acinar cells through a Smad-dependent pathway.
  • This activation is a crucial step in mediating TGF-beta's biological effects, including the regulation of transcription factors like AP-1.
  • These findings provide novel insights into the molecular mechanisms of TGF-beta signaling in pancreatic acinar cells.

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