Gap junctions comprise arrays of intercellular channels formed by connexin proteins and provide for the direct communication between adjacent cells. This type of intercellular communication permits the coordination of cellular activities and plays key roles in the control of cell growth and differentiation and in the maintenance of tissue homoeostasis. After more than 50 years, deciphering the links among connexins, gap junctions and cancer, researchers are now beginning to translate this knowledge to the clinic. The emergence of new strategies for connexin targeting, combined with an improved understanding of the molecular bases underlying the dysregulation of connexins during cancer development, offers novel opportunities for clinical applications. However, different connexin isoforms have diverse channel-dependent and-independent functions that are tissue and stage specific. This can elicit both pro-and anti-tumorigenic effects that engender significant challenges in the path towards personalised medicine. Here, we review the current understanding of the role of connexins and gap junctions in cancer, with particular focus on the recent progress made in determining their prognostic and therapeutic potential.

Post-translational modifications of connexins play an important role in the regulation of gap junction and hemichannel permeability. The prerequisite for the formation of functional gap junction channels is the assembly of connexin proteins into hemichannels and their insertion into the membrane. Hemichannels can affect cellular processes by enabling the passage of signaling molecules between the intracellular and extracellular space. For the intercellular communication hemichannels from one cell have to dock to its counterparts on the opposing membrane of an adjacent cell to allow the transmission of signals via gap junctions from one cell to the other. The controlled opening of hemichannels and gating properties of complete gap junctions can be regulated via post-translational modifications of connexins. Not only channel gating, but also connexin trafficking and assembly into hemichannels can be affected by post-translational changes. Recent investigations have shown that connexins can be modified by phosphorylation/dephosphorylation, redox-related changes including effects of nitric oxide (NO), hydrogen sulfide (H2S) or carbon monoxide (CO), acetylation, methylation or ubiquitination. Most of the connexin isoforms are known to be phosphorylated, e.g. Cx43, one of the most studied connexin at all, has 21 reported phosphorylation sites. In this review, we provide an overview about the current knowledge and relevant research of responsible kinases, connexin phosphorylation sites and reported effects on gap junction and hemichannel regulation. Regarding the effects of oxidants we discuss the role of NO in different cell types and tissues and recent studies about modifications of connexins by CO and H2S.

The expression of connexin 43 (Cx43) has been shown to correlate with an enhanced migration of several cell types such as glioma or neural crest cells, but the mechanism remains unclear. We studied whether Cx43 also affects migration in non-neural cells and whether or not this is related to gap junction formation. Therefore, we analysed the migratory activity of HeLa cells under conditions of controlled connexin (Cx) expression. The expression of Cx43 enhanced their migration significantly as compared to Cx deficient wild-type cells. Expression of only the carboxyl tail of Cx43 (Cx43CT, AA 257-382) without channel forming capacity enhanced migration similarly as the full length protein. In contrast, the expression of the N-terminal part of Cx43 (Cx43NT, AA 1-257), which partially retained the gap junction channel function of Cx43, did not increase migration. The enhanced cell migration of HeLa cells expressing either full length Cx43 or the Cx43CT was associated with an increased activation of the p38 MAP kinase. The additional incubation with a specific inhibitor of p38 activation diminished the migration of HeLa-Cx43 cells to levels of control transfected cells. As a proof of concept, we studied whether Cx43 also modulates the migration of endothelial progenitor cells (EPC) which play an important role in angiogenesis. In these cells, which expressed Cx43 as the only connexin, the downregulation of Cx43 by siRNA resulted in a significantly decreased migration. These results demonstrate that expression of Cx43 augments migration via modulation of p38 MAP kinase activity. The carboxyl tail of Cx43 plays an essential role in this signalling pathway which is independent of gap junction function.

In this review we focus on the role of connexins, especially of Cx43, as modulators of migration - a fundamental process in embryogenesis and in physiologic functions of the adult organism. This impact of connexins is partly mediated by their function as intercellular channels but an increasing number of studies support the view that at least part of the effects are truly independent of the channel function. The channel-independent function comprises extrinsic guidance of migrating cells due to connexin mediated cell adhesion as well as intracellular processes. Cx43 has been shown to exert effects on migration by interfering with receptor signalling, cytoskeletal remodelling and tubulin dynamics. These effects are mainly dependent on the presence of the carboxyl tail of Cx43. The molecular basis of this channel-independent connexin function is still not yet fully understood but early results open an exciting view towards new functions of connexins in the cell. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.