The hormone-induced regulation of contact-dependent cell-cell communication by phosphorylation.
Although there is insufficient evidence to propose an elaborate paradigm for the regulation of connexon gating, a simple model emerges from results of studies done to date. Basically, this centers around the most consistent findings: namely, that activation of pkA has an enhancing effect on cell communication while activation of pkC decreases that process. This fits well the reported phenomena associated with gap junctions, particularly those involving growth control. For example growth factors, including tumor promoters which work via pkC, usually reduce cell-cell communication whereas agents that decrease growth often raise cellular cAMP levels, which can lead to increased communication. It can be argued that this model is too simple because it fails to take into account other intracellular agents that are thought to alter junctional gating: cytoplasmic acidification, cellular free Ca2+, tyrosine protein kinases, and tentatively, pkG. Proton and Ca2+ transporting systems are mainly activated by serine/threonine protein kinases such as pkA and pkC. Some ion channels are not regulated by phosphorylation but instead are modulated by other ions. However, at the moment there is no evidence as to which ion-specific channels mediate the changes in cellular pH or Ca2+ that cause a loss in communication. Neither is it known whether pH or Ca2+ levels are in vivo regulators of the junctions. This is especially so as fairly high levels of injected Ca2+ pass through the gap junctions of viable cells. The role of tyrosine protein kinases in connexon gating may involve interaction with the pkA and pkC regulatory cascades. For example, the pkA inhibitor protein (pkI) is 80-90% inactivated when tyrosine-phosphorylated by the EGF receptor or pp50v-src (D. Walsh, personal communication). In this situation, activity of the C subunit of pkA could be enhanced, or the lifetime of its catalytic activity extended. In some systems, pp60v-src is known to activate the pkC pathway. Thus, tyrosine protein kinases may invoke pkA and pkC pathways; however, the amplitude of enzyme activation and the temporal kinetics of this process are unknown. The fact that gap junctions are regulated at the transcription level and probably at the protein level by protein kinases is of major interest. This is especially so as the only known molecular mechanism that gap junctional communication mediates is the activation of cAMP-dependent protein kinases by hormone-induced signals passed from receptor-bearing cells to receptorless partners.