Ionic signalling by growth factor receptors.
The proliferation of cells in vivo and in culture is regulated by polypeptide growth factors, such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Growth factors initiate their action by binding to specific cell surface receptors. Receptor occupancy triggers a cascade of physiological changes in the target cell which ultimately lead to DNA synthesis and cell division. Immediate consequences of receptor activation include tyrosine-specific protein phosphorylations, a sustained increase in cytoplasmic pH (pHi) and a transient rise in free Ca2+. The rise in pHi has a permissive effect on DNA synthesis and is mediated by an otherwise quiescent Na+/H+ exchange mechanism in the plasma membrane, which is turned on by protein kinase C, the cellular receptor for phorbol esters. The rapid Ca2+ signal is due to either release from internal stores (PDGF) or net entry via a voltage-independent channel in the plasma membrane (EGF). Phorbol esters, acting via kinase C, inhibit the growth factor-induced Ca2+ signals without affecting resting Ca2+ levels. Monoclonal antibodies against the human EGF receptor can act as partial agonists in that they activate the tyrosine-specific protein kinase without inducing any of the ionic signals. These antibodies fail to induce DNA synthesis when added to quiescent fibroblasts, indicating that the Ca2+ and pHi signals can be dissociated from tyrosine kinase activity and suggesting that these signals are indispensable for the stimulation of cell proliferation.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division; D003600:Cytosol / Q000378:metabolism; D004261:DNA Replication; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000502:physiology*; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor; D017923:Sodium-Hydrogen Exchangers; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002352:Carrier Proteins; D007473:Ion Channels; D010982:Platelet-Derived Growth Factor; D011956:Receptors, Cell Surface; D017923:Sodium-Hydrogen Exchangers; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium