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Transforming growth factor-beta modulates the high-affinity receptors for epidermal growth factor and transforming
Abstract:
The epidermal growth factor (EGF) receptor mediates the induction of a transformed phenotype in normal rat kidney (NRK) cells by transforming growth factors (TGFs). The ability of EGF and its analogue TGF-alpha to induce the transformed phenotype in NRK cells is greatly potentiated by TGF-beta, a polypeptide that does not interact directly with binding sites for EGF or TGF-alpha. Our evidence indicates that TGF-beta purified from retrovirally transformed rat embryo cells and human platelets induces a rapid (t 1/2 = 0.3 h) decrease in the binding of EGF and TGF-alpha to high-affinity cell surface receptors in NRK cells. No change due to TGF-beta was observed in the binding of EGF or TGF-alpha to lower affinity sites also present in NRK cells. The effect of TGF-beta on EGF/TGF-alpha receptors was observed at concentrations (0.5-20 pM) similar to those at which TGF-beta is active in promoting proliferation of NRK cells in monolayer culture and semisolid medium. Affinity labeling of NRK cells and membranes by cross-linking with receptor-bound 125I-TGF-alpha and 125I-EGF indicated that both factors interact with a common 170-kD receptor structure. Treatment of cells with TGF-beta decreased the intensity of affinity-labeling of this receptor structure. These data suggest that the 170 kD high-affinity receptors for EGF and TGF-alpha in NRK cells are a target for rapid modulation by TGF-beta.
Insights
Transforming growth factor-beta (TGF-beta) rapidly decreases the binding of epidermal growth factor (EGF) and TGF-alpha to their high-affinity receptors in normal rat kidney cells. This modulation of EGF/TGF-alpha receptors by TGF-beta influences cell transformation.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Epidermal growth factor (EGF) receptor signaling is crucial for cell phenotype.
- Transforming growth factors (TGFs) induce cellular transformation.
- TGF-beta potentiates EGF and TGF-alpha effects without direct receptor binding.
Purpose of the Study:
- To investigate the mechanism by which TGF-beta potentiates EGF/TGF-alpha induced cell transformation.
- To determine if TGF-beta affects the binding of EGF and TGF-alpha to their receptors.
- To identify the specific receptor interactions modulated by TGF-beta.
Main Methods:
- Utilized normal rat kidney (NRK) cells.
- Measured binding of EGF and TGF-alpha to cell surface receptors.
- Employed affinity labeling with 125I-TGF-alpha and 125I-EGF.
- Assessed the effect of TGF-beta on receptor binding and labeling.
Main Results:
- TGF-beta rapidly decreased EGF and TGF-alpha binding to high-affinity receptors in NRK cells (t 1/2 = 0.3 h).
- TGF-beta did not affect binding to lower affinity sites.
- Both EGF and TGF-alpha bind to a common 170-kD receptor structure.
- TGF-beta treatment reduced the intensity of affinity labeling of this 170-kD receptor.
Conclusions:
- TGF-beta rapidly modulates high-affinity EGF/TGF-alpha receptors in NRK cells.
- The 170-kD receptor for EGF and TGF-alpha is a direct target of TGF-beta action.
- This receptor modulation by TGF-beta likely contributes to the potentiation of cell transformation.