Hormone-induced modification of EGF receptor proteolysis in the induction of EGF action.
A proposal that EGF action is mediated through enhanced internalization of EGF receptors is modified to account for more recent evidence. EGF receptors turn over at a rapid rate, and the maintenance of a steady state of EGF receptors on the cell surface is provided through a rapid synthesis of EGF receptors, balancing their removal. This rapid turnover of unoccupied receptors may arise through their internalization and proteolysis in the lysosomes, in much the same way as receptors are internalized and degraded when exposed to EGF, which enhances internalization. This provides a dilemmma for the endocytic activation concept, since slight enhancement of receptor internalization gives rise to a strong hormone response. This problem may be solved by the observation that EGF induces a change in its receptor, exposing an otherwise unavailable site for proteolytic cleavage. This hormone-dependent modification of receptors may be the critical step in the induction of responses to EGF and other hormones that are internalized with their receptors. Both platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) are shown to down-regulate EGF receptors, though transiently, placing still more stringent requirements on the specificity by which hormones might act through endocytic activation of their receptors.
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D005312:Fetal Blood; D005346:Fibroblast Growth Factors; D006133:Growth Substances; D006801:Humans; D007700:Kinetics; D051379:Mice; D008934:Mitogens; D008968:Molecular Conformation; D010447:Peptide Hydrolases; D010455:Peptides / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor; D011863:Radioimmunoassay; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism
D006133:Growth Substances; D008934:Mitogens; D010455:Peptides; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D003513:Cycloheximide; D010447:Peptide Hydrolases