Gap junction proteins on the move: Connexins, the cytoskeleton and migration

Abstract

Connexin43 (Cx43) has roles in cell-cell communication as well as channel independent roles in regulating motility and migration. Loss of function approaches to decrease Cx43 protein levels in neural cells result in reduced migration of neurons during cortical development in mice and impaired glioma tumor cell migration. In other cell types, correlations between Cx43 expression and cell morphology, adhesion, motility and migration have been noted. In this review we will discuss the common themes that have been revealed by a detailed comparison of the published results of neuronal cells with that of other cell types. In brief, these comparisons clearly show differences in the stability and directionality of protrusions, polarity of movement, and migration, depending on whether a) residual Cx43 levels remain after siRNA or shRNA knockdown, b) Cx43 protein levels are not detectable as in cells from Cx43(-/-) knockout mice or in cells that normally have no endogenous Cx43 expression, c) gain-of-function approaches are used to express Cx43 in cells that have no endogenous Cx43 and, d) Cx43 is over-expressed in cells that already have low endogenous Cx43 protein levels. What is clear from our comparisons is that Cx43 expression influences the adhesiveness of cells and the directionality of cellular processes. These observations are discussed in light of the ability of cells to rearrange their cytoskeleton and move in an organized manner. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.

Connexin 43 (Cx43) Expression in Laryngeal Squamous Cell Carcinomas: Preliminary Data on Its Possible Prognostic Role

“…Among 21 connexins, Cx43 is the best known and studied; it is widely expressed in epithelial cells, hematopoietic cells, neurons and astrocytes, cardiac neuronal crest cells, and fibroblasts [4,5]. Its channel function depends on phosphorylation and dephosphorylation of the C-terminal domain, but recent evidence suggests its potential role as scaffold protein promoting the different assembly of the actin cytoskeleton and microtubules [4,6].…”

“…Its channel function depends on phosphorylation and dephosphorylation of the C-terminal domain, but recent evidence suggests its potential role as scaffold protein promoting the different assembly of the actin cytoskeleton and microtubules [4,6]. It seems that the C-terminal domain of Cx43 is responsible either for the tumor suppressor effect or the invasiveness, regulating also the epithelial-mesenchymal transition [7]; therefore the presence of two different activities of Cx43 protein has been proposed, one involving intercellular communication across communicating hemichannels and one acting as scaffold for cytoskeleton associated proteins [4]. Experimental data have shown the role of Cx43 in the control of cell proliferation and apoptosis for its ability to form hemichannels exchanging apoptotic and cell growth factors between extracellular and intracellular matrix, but also its role in promoting tumor progression and metastasis [7].…”

“…Experimental data have shown the role of Cx43 in the control of cell proliferation and apoptosis for its ability to form hemichannels exchanging apoptotic and cell growth factors between extracellular and intracellular matrix, but also its role in promoting tumor progression and metastasis [7]. Recent reports suggest a more complex role of Cx43 in the different stages of tumor progression [4,7,8]; Cx43 downregulation has been associated with development of cancer phenotype [2,9], while aberrant Cx43 upregulation in advanced stages of carcinomas suggests the possibility that cancer cells may communicate with normal host cells across hemichannels, playing a role in migration and growth of metastatic cells. Aberrant Cx43 expression has been detected in advanced stages of prostatic and colonic adenocarcinomas [8,10], and metastatic cutaneous melanoma [11].…”

Identification and Dynamic Regulation of Tight Junction Protein Expression in Human Neural Stem Cells

“…Spontaneous Ca 2 + signaling through gap junctions is a highly ordered transduction event in the SGZ and SVZ that is essential for NSC proliferation [23]. Functional gap junctions expressed by NSCs consist of two hemichannels, formed by either homo or heterohexamers of Cx43, have been implicated in regulating NSC adhesion to radial glial cells that aid in progenitor cell migration from the stem cell niche and into mature neural networks [19]. Cx43 is highly expressed by NSCs; however, as these cells depart upon differentiation, Cx43 expression and, subsequently, the intracellular communication through Cx43 in the stem cell niches begin to subside [20,24,25].…”

“…Interestingly, the TJP accessory proteins, ZO-1 and ZO-2, interact with the C terminus domain of connexin 43 (Cx43). As a principle component of CNS gap junctions, Cx43 contains numerous proteinbinding sites for cytoskeletal attachment and participates in modulating the function of neurovascular/astrocytic gap junctions (reviewed by Matsuuchi and Naus) [19,20].…”