Calcium-inducible transmodulation of receptor tyrosine kinase activity

Calcium is a potent mitogen and transmodulator of growth factor receptor activity, but does not activate tyrosine kinases in ligand-deprived cells (Epstein et al. 1992) Cell Growth Different. 3, 157-164). In this study the mitogenic and transcriptional effects of increased extracellular calcium and ionophore are shown to be identical in 3T3 cells, consistent with mediation of these effects via increased intracellular calcium availability. Near-maximal mitogenic and transcriptional effects are seen after brief exposure to increased extracellular calcium or ionophore, while additive effects occur with co-administration of calcium and platelet-derived growth factor (PDGF). Exposure of PDGF-primed cells to calcium or ionophore is associated with a substantial enhancement of receptor tyrosine autophosphorylation which is abrogated by calcium channel blockade or intracellular calcium chelation. In contrast, pretreatment of quiescent cells with calcium or ionophore significantly diminishes subsequent PDGF-inducible receptor autophosphorylation. Intracellular calcium thus appears to potentiate the kinase activity of ligand-stimulated PDGF receptors while inhibiting ligand-inducible activation of unstimulated receptors. These findings suggest a model of receptor tyrosine kinase regulation involving calcium-dependent positive and negative feedback loops which vary with the activation state of the receptor.