Connexin Functions

Abstract

AbstractAlthough connexins connect two cells by gap junctions, their expression in cells is known to regulate cell growth and differentiations. In fact, connexin expression shows an inverse relationship with the cell growth, and thus they have been aptly named as tumour suppressors. The role of connexins in regulating cell growth has been established from the observation that different types of tumour cells and tumorigenic cell lines, as well as solid tumours, show decreased or altered connexin expression and/or localization. Moreover, expression of connexins in the cancer cells is known to revert the oncogenicity of these cells, albeit to varying degrees. The role of connexins as tumour suppressors has been highlighted by the knockout animal models and knockdown strategies. It has been shown that Cx43-heterozygous and Cx32 knockout mice have increased susceptibility to tumorigenesis, whereas knockdown of the endogenous Cx43 expression, by small interfering RNA, resulted in a more aggressive tumour growth. In additions to the tumour growth, connexins also play an important role in the metastatic potential of the tumour cells. The extravasation of metastatic cells is dependent on the connexin expression. Thus there remains little doubt that connexins, in particular Cx43, Cx32, and Cx26, are crucial growth regulators in many types of cancer as well as in the normal cells. However, the mechanisms by which connexins and gap junction communication regulate growth are far from clear. This is likely due to many facets of connexin function and regulation. Connexins are known to regulate cell growth in a gap junction-dependent manner as well as gap junction-independent way. It is known that the carboxy-terminal domain of connexin is critical for the cell growth regulation. Connexin 43 is the most important player in regulating cell growth. Its C-terminal module hosts a number of phosphorylation sites and has the ability to interact with multiple proteins. As far as the channel-dependent role of connexins in regulating cell growth is concerned, it is believed that many specific and permeable metabolites or ions are responsible for growth control. Although many of these metabolites are not known, however, many potential candidates, like Ca2+, cAMP, and inositol triphosphate, have been identified. Besides the role of gap junctional communication in growth control, evidences are accumulating that connexins can inhibit growth in the absence of functional gap junction communication. For example, isolated cells, or use of gap junction uncoupling agents and prevention of membrane localization of the connexins, the regulatory effects of connexins on cell growth persist. Moreover, the C-terminal domain of Cx43, which lacks the capability of forming gap junction channels, is still able to inhibit cell growth as much as the full-length connexin. The molecular mechanism employed by the C-terminal domain of Cx43, in controlling cell growth, is still emerging. Association of C-terminal domain of Cx43 with many other proteins is regarded as one of the mechanisms responsible for the growth-regulating properties of Cx43. For example, protein tyrosine phosphatase is reported to bind to the carboxy-terminal of Cx43. Its association with Cx43 is expected to bring it to junctional complexes and enable it to dephosphorylate nearby proteins such as tyrosine kinase receptors or tyrosine-phosphorylated effectors of growth factor signalling. The second mechanism reflects the ability of cytosolic domains present in adhesion/junction proteins to interact with kinases, phosphatases, transcription factors, and structural proteins that are implicated in growth regulation. This interaction sequesters proteins from and prevents their signalling action on other possible targets at the cytosol and/or nucleus or at the cell surface. The C-terminal of Cx43 serves as an interactive platform for a variety of cellular proteins, like CCN3 with transcription factor properties. Several of these interacting partners are participants in the field of growth control; their interaction (and regulation of the interaction) with Cx43 or other connexins anchored to the plasma membrane may affect their subcellular localization and thus their site(s) of action. In one such study, it was demonstrated that the protein CCN3 interacts with the carboxy-terminal of Cx43. In the absence of Cx43, CCN3 is localized to the nucleus/cytosol; upregulation of CCN3 by Cx43 resulted in sub-membrane localization as well as secretion to the medium. Thus, Cx43 may inhibit growth by stimulating CCN3 expression as well as determining its subcellular localization.KeywordsRegulate Cell GrowthIschaemic PreconditionProtein CCN3Connexin ExpressionConnexin HemichannelsThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.