The role of the Cx43 C-terminus in GJ plaque formation and internalization

Wayakanon, Praween; Bhattacharjee, Rajib; Nakahama, Ken-ichi; Morita, Ikuo

doi:10.1016/j.bbrc.2012.03.018

Cited by 23 publications

(19 citation statements)

References 26 publications

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“…By mutating the potential AP-2 binding site motifs (YXX⌽; see below) in Cx43 and transiently expressing these constructs in HeLa cells, we found that these Cx43 mutants exhibit longer protein halflives and insufficiently internalize GJ plaques (Fong J, Falk M, unpublished data). Recently, a report describing a Cx43 COOH-terminal domain comprised of residues cysteine 271 to asparagine 302 playing a significant role in GJ internalization has been published (209). This report is consistent with our own findings described above.…”

Section: Clathrin-mediated Gj Internalizationsupporting

confidence: 92%

“…Cx43, rendered "ZO-1 binding-incompetent" with either its extreme most isoleucine or most of its COOH terminus deleted, has been shown to still be capable of forming plaques in HeLa cells, albeit slightly less efficiently (24). At least in the case of Cx43, as long as the microtubule-interaction region in the COOH terminus remains intact for trafficking to the PM, Cx43 plaques can still assemble without ZO-1 (56, 163,209). However, the same form of deletions in Cx50 results in the inability of the cells to form Cx50-based plaques.…”

Section: And Its Interaction With Cx43mentioning

confidence: 94%

“…In general for Cx43, CK1, PKA, and Akt phosphorylation increase and PKC, MAPKs, Src, and CDC2 reduce GJIC (79,141,144,(177)(178)(179) (FIGURE 3; Table 1). Although, surprisingly, none of these COOH-terminal phosphorylation sites are required for Cx43 assembly, trafficking, and the formation of dye-transferring GJ plaques [deletions at amino acid 239 and higher traffic to the cell membrane and form GJs (209)], precise regulation of GJ function in situ is likely dependent on phosphorylation/dephosphorylation at these sites, with multiple events probably occurring simultaneously. For example, homozygous Cx43K258Stop mice die shortly after birth due Kinases discussed in this review are labeled red.…”

Section: Cx43 Phosphorylationmentioning

confidence: 99%

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Proteins and Mechanisms Regulating Gap-Junction Assembly, Internalization, and Degradation

et al. 2013

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Gap junctions (GJs) are the only known cellular structures that allow a direct cell-to-cell transfer of signaling molecules by forming densely packed arrays or "plaques" of hydrophilic channels that bridge the apposing membranes of neighboring cells. The crucial role of GJ-mediated intercellular communication (GJIC) for all aspects of multicellular life, including coordination of development, tissue function, and cell homeostasis, has been well documented. Assembly and degradation of these membrane channels is a complex process that includes biosynthesis of the connexin (Cx) subunit proteins (innexins in invertebrates) on endoplasmic reticulum (ER) membranes, oligomerization of compatible subunits into hexameric hemichannels (connexons), delivery of the connexons to the plasma membrane (PM), head-on docking of compatible connexons in the extracellular space at distinct locations, arrangement of channels into dynamic spatially and temporally organized GJ channel plaques, as well as internalization of GJs into the cytoplasm followed by their degradation. Clearly, precise modulation of GJIC, biosynthesis, and degradation are crucial for accurate function, and much research currently addresses how these fundamental processes are regulated. Here, we review posttranslational protein modifications (e.g., phosphorylation and ubiquitination) and the binding of protein partners (e.g., the scaffolding protein ZO-1) known to regulate GJ biosynthesis, internalization, and degradation. We also look closely at the atomic resolution structure of a GJ channel, since the structure harbors vital cues relevant to GJ biosynthesis and turnover.

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Section: Clathrin-mediated Gj Internalizationsupporting

confidence: 92%

Section: And Its Interaction With Cx43mentioning

confidence: 94%

Section: Cx43 Phosphorylationmentioning

confidence: 99%

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Proteins and Mechanisms Regulating Gap-Junction Assembly, Internalization, and Degradation

et al. 2013

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“…Many deletion and mutagenesis studies have shown that the C terminus is at least in part dispensable for membrane trafficking of Cx43. However, a recent study demonstrated that deletion mutations within the tubulin binding domain i.e., aa 235-242 (unlike previous mutations that retain this domain) inhibit gap junctions and gap junction intercellular communication (Wayakanon et al, 2012). These studies clearly define that interactions between connexins and the microtubule network result in efficient signaling microdomain formation but demonstrate that the C-terminal binding site is not essential.…”

Section: A Gap Junction Channelsmentioning

confidence: 89%

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

et al. 2014

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“…The Cx43-mediated gap junction intercellular communication (GJIC) facilitates and maintains the transmission of information and energy between cells, regulation of cell growth, proliferation and differentiation, and homeostasis. Therefore, blockade of the Cx43 expression in tumor cells could inhibit tumor cell proliferation (Wayakanon et al 2012). Very few studies (at home and abroad) have reported any correlation between Cx43 and the proliferation, invasion, and migration of lung squamous cells.…”

Section: Introductionmentioning

confidence: 99%

Effects of Cx43 gene modification on the proliferation and migration of the human lung squamous carcinoma cell line NCI-H226

Jp¹,

Wei²

2015

Genet. Mol. Res.

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ABSTRACT. In this study, the human lung squamous carcinoma cell line NCI-H226 was transfected with the recombinant plasmid pBudCE4.1_Cx43 to explore the role of the Cx43 gene in cell growth, cell cycle, and tumor migration. pBudCE4.1-Cx43 was transfected into human lung squamous carcinoma NCI-H226 cells using Lipofectamine TM2000. The mRNA and protein expressions of Cx43 in the transfected cells were detected by reverse transcriptase polymerase chain reaction and western blot analysis. The cell-cell communication was detected using the scratch dye tracer method and the cell cycle was detected by flow cytometry. The CCK-8 proliferation, scratch healing, and cell invasion assays were performed to evaluate the effect of the Cx43 gene transfection on the proliferation, migration, and invasive abilities of NCI-H226 cells. Cx43 mRNA and protein expressions and the fluorescence intensity in the scratch healing test were significantly higher in the experimental group than those in the control and blank groups (P < 0.05 and < 0.01, respectively). The CCK-8 proliferation assay and the scratch healing experiment revealed significantly inhibited NCI-H226 cell proliferation (especially 72 h after incubation) and cell migration, respectively, in the experimental group, compared to the control and 13110-13119 (2015) blank groups (P < 0.001 and <0.05, respectively). The transwell chamber test showed a statistically significant decrease in the invasive ability of NCI-H226 cells in the experimental group (P < 0.05). Therefore, Cx43 gene transfection could inhibit the migration of human lung squamous carcinoma cell line NCI-H226, thereby inhibiting tumor cell proliferation.

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The role of the Cx43 C-terminus in GJ plaque formation and internalization

Cited by 23 publications

References 26 publications

Proteins and Mechanisms Regulating Gap-Junction Assembly, Internalization, and Degradation

Proteins and Mechanisms Regulating Gap-Junction Assembly, Internalization, and Degradation

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

Effects of Cx43 gene modification on the proliferation and migration of the human lung squamous carcinoma cell line NCI-H226

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