Phosphoinositide Hydrolysis and Ensuing Calcium and Potassium Fluxes: Role in the Action of EGF and Other Growth Factors

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Abstract
Phosphoinositide hydrolysis and stimulated ion fluxes are part of the host of rapid intracellular events triggered by the activation of growth factor receptors. In the case of EGF and other factors (PDGF, FGF) addressed to receptors endowed with endogenous tyrosine kinase activity, the phospholipase C responsible for the signalling reaction is the γ1 isoform. The enzyme can bind directly to a recently identified domain of the EGF receptor when the latter undergoes autophosphorylation as a consequence of ligand binding. The bound enzyme is then phosphorylated at multiple sites, an event that markedly increases its activity. Of the second messengers generated by the hydrolysis, one, diacylglycerol, activates protein kinase C, an enzyme that mediates (among other effects) the feedback desensitization of the EGF receptor; the other messenger, inositol-1,4,5-trisphosphate, activates the release of Ca2+ from intracellular stores. Concomitantly, Ca2+ influx across the plasma membrane is stimulated via cationic, nonselective channels, and the membrane potential is increased by the activation of Ca2+-dependent K+ channels. Recent results with selective blockers of those two responses (imidazole drugs and charibdotoxin, respectively) have revealed that hyperpolarization has only a marginal role in the EGF-induced cell proliferation whereas Ca2+ influx is important since its block results in a substantial decrease of cell growth. The final part of the review concerns the role of phosphoinositide hydrolysis in the process of T lymphocyte activation. In these cells, the T cell receptor has been shown to interact with tyrosine kinases that are not directly inserted across the plasma membrane, and to activate them. The mechanism of transmembrane signalling resembles therefore (from this point of view) that of the EGF receptor. The mechanism by which changes in [Ca2+]i and of other cytoplasmatic parameters are transferred to the nucleus and stimulate proliferation are still poorly understood. The possible involvement of G proteins, such as ras, and of protein phosphatases is discussed.

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