Connexins, cell motility, and the cytoskeleton

Olk, Stephan; Zoidl, Georg; Dermietzel, Rolf

doi:10.1002/cm.20404

Cited by 78 publications

(80 citation statements)

References 103 publications

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“…It is possible that subtle changes in cytoskeletal function that facilitate cellular susceptibility to mechanical distortions [29,37] and/or directed cell motility through narrow obstacles may accompany elevated Cx43 expression. This explanation is consistent with the reports on the interactions of connexins with cytoskeleton proteins [4,10], resulting in a protective effect against mechanical injury of cancer cells [8]. Importantly, it would explain the formation of cancer cell subpopulations characterised by heterogeneous motile activity on planar substrata and displaying high competence for GJIC -a parameter crucial for penetration of tissue barriers such as endothelium [15-17, 35, 38].…”

Section: Discussionsupporting

confidence: 87%

“…This observation indicates that if Cx43 is directly involved in the determination of DU-145 cell transmigration potential, it exerts this effect in a manner independent of cell motility. In parallel, it remains in opposition to previous reports describing effects of Cx43 on cell adhesion and directed motility [3,4,6,10,14,18]. However, the processes of cell migration on planar surfaces and cell transmigration through narrow obstacles may be governed by discrete regulatory systems [30,36].…”

Section: Discussionmentioning

confidence: 80%

“…However, connexins and connexons affect a range of cellular processes in a manner independent of GJIC. For instance, Cx43 and unpaired Cx43 connexons were demonstrated to inhibit cell proliferation [2][3][4][5] and to enhance directed cell motility [6,7] in a manner potentially dependent on their ability to interact with cytoskeletal components [8][9][10]. GJIC plays a crucial role in tissue homeostasis and its impairment in connexindeficient cell populations is involved in the formation of neoplastic loci and primary tumours [11,12].…”

Section: Introductionmentioning

confidence: 99%

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DU-145 prostate carcinoma cells that selectively transmigrate narrow obstacles express elevated levels of Cx43

Szpak

Wybieralska

Niedzialkowska

et al. 2011

Cellular and Molecular Biology Letters

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The formation of aqueous intercellular channels mediating gap junctional intercellular coupling (GJIC) is a canonical function of connexins (Cx). In contrast, mechanisms of GJIC-independent involvement of connexins in cancer formation and metastasis remain a matter of debate. Because of the role of Cx43 in the determination of carcinoma cell invasive potential, we addressed the problem of the possible Cx43 involvement in early prostate cancer invasion. For this purpose, we analysed Cx43-positive DU-145 cell subsets established from the progenies of the cells most readily transmigrating microporous membranes. These progenies displayed motile activity similar to the control DU-145 cells but were characterized by elevated Cx43 expression levels and GJIC intensity. Thus, apparent links exist between Cx43 expression and transmigration potential of DU-145 cells. Moreover, Cx43 expression profiles in the analysed DU-145 subsets were not affected by intercellular contacts and chemical inhibition of GJIC during the transmigration. Our observations indicate that neither cell motility nor GJIC determines the transmigration efficiency of DU-145 cells. However, we postulate that selective transmigration of prostate cancer cells expressing elevated levels of Cx43 expression may be crucial for the “leading front” formation during cancer invasion.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

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DU-145 prostate carcinoma cells that selectively transmigrate narrow obstacles express elevated levels of Cx43

Szpak

Wybieralska

Niedzialkowska

et al. 2011

Cellular and Molecular Biology Letters

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“…The major determinants of subcellular localization for many large multi-transmembrane domain proteins with intracellular C-termini, for example, neurotransmitter receptors (Hayashi et al, 2009), voltage-gated channels (Swayne & Bourinet, 2008), and the functional homologs of the innexin/pannexin family, the connexins (Olk et al, 2009), are contained within the C-terminus. Given recent elegant studies demonstrating the importance of the C-terminus in channel traffi cking (Gehi et al, 2011) and function (Chekeni et al, 2010;Sandilos et al, 2012), Panx2…”

Section: Discussionmentioning

confidence: 99%

Analysis of a pannexin 2-pannexin 1 chimeric protein supports divergent roles for pannexin C-termini in cellular localization

Wicki-Stordeur

Boyce

Swayne

2013

Cell Communication & Adhesion

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Pannexins (Panxs) are a three-member family of large pore ion channels permeable to ions and small molecules. Recent elegant work has demonstrated that the Panx1 C-terminus plays an important role in channel traffi cking. Panx2, another family member, has a longer and highly dissimilar C-terminus. Interestingly, Panx1 is readily found at the plasma membrane, while Panx2 is mainly present on intracellular membranes. Here we used overlap-extension cloning to create the fi rst chimeric Panx, consisting of Panx2 with the Panx1 C-terminus (Panx2 Panx1CT ), to determine whether the Panx1 C-terminus infl uences the traffi cking of Panx2. We are the fi rst to observe a high level of co-localization between Panx2 and the endolysosomal enriched mannose-6-phosphate receptor. Interestingly this distinct localization of Panx2 is altered by the presence of the Panx1 C-terminus. These novel observations support previous data indicating the importance of the C-terminus in the control of Panx traffi cking, and highlight the complexity of molecular signals involved.

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“…Moreover, cytoskeletal disrupting agents have been shown to interfere with normal connexin delivery to the plasma membrane (5,6,29). Such targeted delivery through cytoskeletal networks is likely to be especially important in polarized cells such as hepatocytes, where apical and basolateral membrane domains are segregated by tight junctions (30).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Motility of Liver Connexin Vesicles along Microtubules Utilizes Kinesin Motors

Fort

Murray

Dandachi

et al. 2011

Journal of Biological Chemistry

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Trafficking of the proteins that form gap junctions (connexins) from the site of synthesis to the junctional domain appears to require cytoskeletal delivery mechanisms. Although many cell types exhibit specific delivery of connexins to polarized cell sites, such as connexin32 (Cx32) gap junctions specifically localized to basolateral membrane domains of hepatocytes, the precise roles of actin-and tubulin-based systems remain unclear. We have observed fluorescently tagged Cx32 trafficking linearly at speeds averaging 0.25 m/s in a polarized hepatocyte cell line (WIF-B9), which is abolished by 50 M of the microtubule-disrupting agent nocodazole. To explore the involvement of cytoskeletal components in the delivery of connexins, we have used a preparation of isolated Cx32-containing vesicles from rat hepatocytes and assayed their ATP-driven motility along stabilized rhodamine-labeled microtubules in vitro. These assays revealed the presence of Cx32 and kinesin motor proteins in the same vesicles. The addition of 50 M ATP stimulated vesicle motility along linear microtubule tracks with velocities of 0.4 -0.5 m/s, which was inhibited with 1 mM of the kinesin inhibitor AMP-PNP (adenylyl-imidodiphosphate) and by anti-kinesin antibody but only minimally affected by 5 M vanadate, a dynein inhibitor, or by anti-dynein antibody. These studies provide evidence that Cx32 can be transported intracellularly along microtubules and presumably to junctional domains in cells and highlight an important role of kinesin motor proteins in microtubule-dependent motility of Cx32.Gap junction channels form direct intercellular passageways that allow the exchange of ions and second messenger molecules between cells, thereby spreading signals and unifying cellular responses within a tissue. Gap junctions are formed by the connexin family of proteins that are co-translationally inserted into endoplasmic reticulum membranes (1) and assembled into hexameric connexons or hemichannels within the endoplasmic reticulum or Golgi compartments depending on connexin, cell type, or both (2-6). Connexins are tetra-spanning transmembrane proteins with both termini (N termini and C termini) facing the cytoplasm. This conformation results in two extracellular loops required for connexon docking and one cytoplasmic loop.Knowing the mechanisms of delivery is crucial to understanding connexin regulation because insertion into the plasma membrane is a prerequisite to connexin function. The route of delivery of connexons from the trans-Golgi to the surface membrane has been the subject of many studies, most recently focusing on exogenously expressed connexins with carboxylterminally tagged fluorescent proteins. These studies have indicated that the vesicular structures in which connexins are delivered to the surface occur in a variety of sizes and are motile. Moreover, although delivery appears to be facilitated by microtubules, intact cytoskeleton is not absolutely required for trafficking, as evidenced by the variable effects reported for microtubule-disrupt...

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Connexins, cell motility, and the cytoskeleton

Cited by 78 publications

References 103 publications

DU-145 prostate carcinoma cells that selectively transmigrate narrow obstacles express elevated levels of Cx43

DU-145 prostate carcinoma cells that selectively transmigrate narrow obstacles express elevated levels of Cx43

Analysis of a pannexin 2-pannexin 1 chimeric protein supports divergent roles for pannexin C-termini in cellular localization

In Vitro Motility of Liver Connexin Vesicles along Microtubules Utilizes Kinesin Motors

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