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Activation of p21ras by transforming growth factor beta in epithelial cells
1Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey 17033.
Abstract:
The transforming growth factor beta (TGF beta) family members are ubiquitously expressed and control a variety of cellular processes by interacting with at least two types of high affinity cell surface receptors. However, the primary signal transduction mechanism of the receptors is unknown. The ras-encoded 21-kDa GTP binding proteins have recently been shown to mediate the effects of other polypeptide growth factors. Here we show that both TGF beta 1 and TGF beta 2 (5 ng/ml) result in a rapid (within 6 or 12 min, respectively) stimulation of GTP bound to p21ras in TGF beta-sensitive intestinal epithelial cells. Further, the CCL64 epithelial cell line, extremely sensitive to growth inhibition by TGF beta, displayed a concentration-dependent increase in GTP bound to p21ras by TGF beta 1 and a rapid activation of p21ras by TGF beta 2. The results provide the first direct evidence for rapid activation of a receptor coupling component for TGF beta in epithelial cells.
Insights
Transforming growth factor beta (TGF beta) rapidly activates p21ras GTP-binding proteins in intestinal epithelial cells. This study provides the first direct evidence of TGF beta receptor coupling component activation in epithelial cells.
Area of Science:
- Cellular biology
- Molecular signaling
Background:
- Transforming growth factor beta (TGF beta) family members regulate cellular processes via cell surface receptors.
- The primary signal transduction pathway for TGF beta receptors remains largely unknown.
- Ras-encoded 21-kDa GTP-binding proteins (p21ras) are implicated in mediating other growth factor effects.
Purpose of the Study:
- To investigate the role of p21ras in TGF beta signaling.
- To determine if TGF beta activates p21ras in epithelial cells.
- To elucidate the primary signal transduction mechanism of TGF beta receptors.
Main Methods:
- Treatment of TGF beta-sensitive intestinal epithelial cells and CCL64 epithelial cells with TGF beta 1 and TGF beta 2.
- Measurement of GTP-bound p21ras levels to assess p21ras activation.
- Analysis of concentration-dependent and time-dependent responses.
Main Results:
- Both TGF beta 1 and TGF beta 2 rapidly stimulated GTP-bound p21ras in intestinal epithelial cells within minutes.
- The CCL64 cell line showed a concentration-dependent increase in GTP-bound p21ras with TGF beta 1 and rapid activation with TGF beta 2.
- These findings indicate a direct link between TGF beta and p21ras activation.
Conclusions:
- TGF beta signaling involves the rapid activation of p21ras in epithelial cells.
- This study provides the first direct evidence for the activation of a receptor coupling component for TGF beta in epithelial cells.
- p21ras is a key component in the early signal transduction pathway of TGF beta.