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Epidermal growth factor and transforming growth factor-alpha: differential intracellular routing and processing of
1Department of Developmental Biology, Genentech, Inc., South San Francisco, California 94080.
Abstract:
Two structurally related but different polypeptide growth factors, epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha), exert their activities after interaction with a common cell-surface EGF/TGF-alpha-receptor. Comparative studies of the effects of both ligands have established that TGF-alpha is more potent than EGF in a variety of biological systems. This observation is not explained by differences in affinities of the ligands for the receptor, because the affinity-constants of both factors are very similar. We have compared the intracellular processing of ligand-receptor complexes using either EGF or TGF-alpha in two different cell systems. We found that TGF-alpha dissociates from the EGF/TGF-alpha-receptor at much higher pH than EGF, which may reflect the substantial difference in the calculated isoelectric points. After internalization, the intracellular TGF-alpha is more rapidly cleared than EGF, and a substantial portion of the released TGF-alpha represents undegraded TGF-alpha in contrast to the mostly degraded EGF. In addition, TGF-alpha did not induce a complete down-regulation of cell surface receptors, as observed with EGF, which is at least in part responsible for a much sooner recovery of the ligand-binding ability after down-regulation, in the case of TGF-alpha. These differences in processing of the ligand-receptor complexes may explain why TGF-alpha exerts quantitatively higher activities than EGF.
Insights
Transforming growth factor-alpha (TGF-alpha) is more potent than epidermal growth factor (EGF) due to differences in how their cell surface receptor complexes are processed intracellularly. These processing variations explain TGF-alpha's higher biological activity compared to EGF.
Area of Science:
- Cell biology
- Molecular signaling
- Biochemistry
Background:
- Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) are related growth factors.
- Both bind to the common cell-surface EGF/TGF-alpha-receptor.
- TGF-alpha exhibits greater potency than EGF across various biological systems, a difference not explained by receptor binding affinity.
Purpose of the Study:
- To investigate the intracellular processing of EGF and TGF-alpha receptor complexes.
- To elucidate the mechanisms behind TGF-alpha's higher biological potency compared to EGF.
Main Methods:
- Comparative analysis of ligand-receptor complex processing in two cell systems.
- Measurement of ligand dissociation pH, intracellular clearance rates, and receptor down-regulation.
Main Results:
- TGF-alpha dissociates from its receptor at a higher pH than EGF.
- Intracellular TGF-alpha is cleared more rapidly and less degraded than EGF.
- TGF-alpha induces less complete receptor down-regulation, leading to faster recovery of ligand-binding ability.
Conclusions:
- Differences in intracellular processing, including dissociation pH, degradation, and receptor down-regulation, explain TGF-alpha's superior potency over EGF.
- These processing variations are key to understanding the differential biological activities of EGF and TGF-alpha.