The Hormone-Induced Regulation of Contact-Dependent Cell-Cell Communication by Phosphorylation*

Abstract

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.

Connexin 43 expression in the mouse embryo: Localization of transcripts within developmentally significant domains

“…It is likely that other parameters are also of importance in defining the pattern of gap junctional communication in the embryo. Recent studies have indicated that the expression of cell adhesion molecules (Keane et al, 1988;Mege et al, 1988;Musil et al, 1990;Jongen et al, 19911, matrix components (Spray et al, 1987), and the differential phosphorylation of some connexin polypeptides (Saez et al, 1986;Filson et al, 1990;Musil et al, 1990;Stagg and Fletcher, 1990;Swenson et al, 1990;Kadle et al, 1991;Laird et al, 1991) can affect coupling between cells. It has also been shown that heterotypic gap junctions assembled in the Xenopus oocyte assay system exhibit conductance properties unlike that of gap junctions generated by a single connexins species (Swenson et al, 1989;Werner et al, 1990;Barrio et al, 1991).…”

Role of gap junctions during early embryo development

“…Gap junctions may be regulated by hormones and other extracellular signalling molecules such as neurotransmitters, growth factors and cytokines (Stagg & Fletcher 1990, Bruzzone et al 1996b, Sáez et al 1998. The extent to which cells are coupled depends on several mechanisms: gene transcription, stability of the message, translational and post-translational modifications and assembly of the protein into the membrane (Sáez et al 1998).…”

The effects of connexin phosphorylation on gap junctional communication

“…Connexin phosphorylation has been previously reviewed Saez, Martinez, Branes, & Gonzalez, 1998;Stagg & Fletcher, 1990) and, thus, this review concentrates on the most recent developments. The total number of references has been limited by the journal and, thus, we apologize in advance for the curtailed citations and the use of reviews.…”