Protein kinase C spatially and temporally regulates gap junctional communication during human wound repair via phosphorylation of connexin43 on serine368

Richards, Theresa S.; Dunn, Clarence A.; Carter, William G.; Usui, Marcia L.; Olerud, John E.; Lampe, Paul D.

doi:10.1083/jcb.200404142

Cited by 106 publications

(141 citation statements)

References 46 publications

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“…As shown in Ref. 3 in human foreskin and using a pSer368 antibody, 24 h after wounding of primary human basal keratinocytes, pSer368Cx43 phosphorylated by PKC was increased in cells adjacent to the scratch and was not evident in suprabasal layers adjacent to the wound. Increases were not seen at 6 or 72 h. Cells at the edge of the scratch transferred dye much less efficiently at 24 h. However, keratinocyte migration, to fill the scratch, required early (within less than 6 h) gap junctional communication.…”

Section: Discussionmentioning

confidence: 99%

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Protein Kinase Cδ-mediated Phosphorylation of Connexin43 Gap Junction Channels Causes Movement within Gap Junctions followed by Vesicle Internalization and Protein Degradation

Cone

Cavin

Ambrosi

et al. 2014

Journal of Biological Chemistry

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Background: Connexin43, a ubiquitous gap junction protein, is phosphorylated by protein kinase C on serine 368. Results: After PKC␦ activation, phospho-Ser-368 Connexin43 channels segregated into the gap junction center and were subsequently internalized and degraded. Conclusion: PKC␦ phosphorylation triggered internalization and degradation of Connexin43 channels without dephosphorylation. Significance: Differential phosphorylation events are used to sort and traffic Connexin43 channels within gap junctions and into the cytoplasm.

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Section: Discussionmentioning

confidence: 99%

“…It has been well established that protein kinase C (PKC) phosphorylates Cx43 at Ser-368 (3)(4)(5)(6)(7)(8)(9). The family of PKC enzymes controls the function of other proteins by phosphorylating specific Ser or Thr residues on these proteins (10).…”

Section: Connexin43 (Cx43)mentioning

confidence: 99%

Protein Kinase Cδ-mediated Phosphorylation of Connexin43 Gap Junction Channels Causes Movement within Gap Junctions followed by Vesicle Internalization and Protein Degradation

Cone

Cavin

Ambrosi

et al. 2014

Journal of Biological Chemistry

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“…For example, phosphorylation of Cx43 on Ser368 by protein kinase C (PKC) decreases gap junctional communication by reducing single channel conductance (Richards et al, 2004). In previous studies, staurosporine was used to block gap junctional communication through inhibition of protein kinase C (PKC) specific phosphorylation of Cx43 (Moreno et al, 1994;Saez et al, 1997).…”

Section: ) Discussionmentioning

confidence: 99%

Herpes simplex virus-type 2 infectivity and agents that block gap junctional intercellular communication

et al. 2007

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SUMMARYIn rat liver epithelial (WB) cells, the protein kinase C inhibitor H7 blocked gap junctional intercellular communication (GJIC) and reduced virus infectivity. Octanol, 18-beta-glycyrrhetinic acid, and staurosporine, agents that reduce GJIC, had no effect upon virus infectivity. Previous studies demonstrated that herpes simplex virus-type 2 (HSV-2) infection was accompanied by attenuated GJIC. Of agents tested, only H7 reduced plaque forming unit (pfu) ability in a dose-dependent manner with 100% plaque reduction at 40 μM without evidence of cytotoxicity. Dye transfer indicated that H7 decreased GJIC, although Western blotting revealed that it did not alter phosphorylation of the gap junction protein, connexin 43 (Cx43). Using indirect immunofluorescence, Cx43 was found to localize in membrane plaques in uninfected cells and H-7 did not alter this distribution. However, Cx43 was lost from the membrane at 24 hrs in both H-7 treated and untreated cells infected with HSV-2. Viral infection increased serine phosphorylation, particularly in the nuclear region, and this effect was reduced following H-7 treatment. Thus, H-7 attenuated both GJIC and infectivity of HSV-2 in WB cells but the anti-viral effects were due to reduced nuclear protein phosphorylation rather than alterations in phosphorylation or localization of Cx43. KeywordsGap junctions; Connexin 43; protein kinase C; H7; HSV-2 1) INTRODUCTIONIt has long been known that certain RNA and tumor viruses decrease gap junctional communication among infected cells (Atkinson et al., 1981;Crow et al., 1990;Danave et al., 1994;Ennaji et al., 1995;Faccini et al., 1996, Jou et al., 1995. Recent studies have shown electrophysiologically that down-regulation of gap junctions by herpes simplex virus-type 2 (HSV-2) begins before viral DNA replication, and long before morphological signs of infection (Fischer et al., 2001). In addition, Musee et al. (2002) demonstrated that antiviral agents affect electrical coupling in HSV-2 infected cells in different ways, depending on the mechanism of action of the agent. However, it was not clear if GJIC down-regulation was initiated by the infected cells or by their surrounding uninfected neighbors. If the latter, drugs that reduce GJIC might protect neighboring cells from infection.* To whom all correspondence should be addressed: Phone -(610)-436-2985, Fax -(610)-436-2183, e-mail-mknabb@wcupa.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. How HSV-2 induces gap junctional down-regulation is unknown although both viral-or cellmediated mechanisms are possible. Gap junction channels are...

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“…Cx43 is the major connexin and represents a key target in GJIC regulation (4). It is differentially phosphorylated at a dozen or more residues throughout its life cycle (5)(6)(7)(8)(9). Alteration of GJIC caused by changes in Cx43 has been proposed to be involved in the pathophysiology of diverse IEC barrier diseases, including inflammatory bowel diseases, necrotizing enterocolitis, cancer, and enteric infection (10 -12).…”

mentioning

confidence: 99%

TLR2 Mediates Gap Junctional Intercellular Communication through Connexin-43 in Intestinal Epithelial Barrier Injury

Eyking

Gerken

et al. 2009

Journal of Biological Chemistry

104

105

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Gap junctional intercellular communication (GJIC) coordinates cellular functions essential for sustaining tissue homeostasis; yet its regulation in the intestine is not well understood. Here, we identify a novel physiological link between Toll-like receptor (TLR) 2 and GJIC through modulation of Connexin-43 (Cx43) during acute and chronic inflammatory injury of the intestinal epithelial cell (IEC) barrier. Data from in vitro studies reveal that TLR2 activation modulates Cx43 synthesis and increases GJIC via Cx43 during IEC injury. The ulcerative colitis-associated TLR2-R753Q mutant targets Cx43 for increased proteasomal degradation, impairing TLR2-mediated GJIC during intestinal epithelial wounding. In vivo studies using mucosal RNA interference show that TLR2-mediated mucosal healing depends functionally on intestinal epithelial Cx43 during acute inflammatory stress-induced damage. Mice deficient in TLR2 exhibit IEC-specific alterations in Cx43, whereas administration of a TLR2 agonist protects GJIC by blocking accumulation of Cx43 and its hyperphosphorylation at Ser 368 to prevent spontaneous chronic colitis in MDR1␣-deficient mice. Finally, adding the TLR2 agonist to three-dimensional intestinal mucosalike cultures of human biopsies preserves intestinal epithelial Cx43 integrity and polarization ex vivo. In conclusion, Cx43 plays an important role in innate immune control of commensal-mediated intestinal epithelial wound repair.

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Protein kinase C spatially and temporally regulates gap junctional communication during human wound repair via phosphorylation of connexin43 on serine368

Cited by 106 publications

References 46 publications

Protein Kinase Cδ-mediated Phosphorylation of Connexin43 Gap Junction Channels Causes Movement within Gap Junctions followed by Vesicle Internalization and Protein Degradation

Protein Kinase Cδ-mediated Phosphorylation of Connexin43 Gap Junction Channels Causes Movement within Gap Junctions followed by Vesicle Internalization and Protein Degradation

Herpes simplex virus-type 2 infectivity and agents that block gap junctional intercellular communication

TLR2 Mediates Gap Junctional Intercellular Communication through Connexin-43 in Intestinal Epithelial Barrier Injury

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