Regulation of Connexin-43 Gap Junctional Intercellular Communication by Mitogen-activated Protein Kinase

Warn-Cramer, Bonnie J.; Cottrell, G. Trevor; Burt, Janis M.; Lau, Alan F.

doi:10.1074/jbc.273.15.9188

Cited by 325 publications

(268 citation statements)

References 42 publications

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“…Similar to lung, the number of MAPK-activated liver tumors diminished in the absence of p27 indicating some interaction between Cx32 and p27 in the origination/ progression of MAPK-active liver tumors. Interestingly, MAPK has previously been shown to directly modulate connexin/GJIC life cycle and activity both in vitro and in vivo (Warn-Cramer et al, 1996;Warn-Cramer et al, 1998;Defamie et al, 2003), particularly with an association between decreased GJIC and increased MAPK activation (Upham et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

et al. 2005

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Connexin32 knockout mice (Cx32-KO) exhibit increased chemical-and radiation-induced liver and lung tumor formation with many lung tumors demonstrating decreased levels of the tumor suppressor p27 KIP1 . To determine if p27 deficiency alters Cx32-influenced tumorigenesis, we have generated a Cx32/p27 double-deficient mouse strain (DKO) and show here that exposure of these mice to X-ray radiation resulted in an increase or decrease in tumorigenesis depending on the tissue. Several tissues were highly sensitive to loss of p27 tumor suppressor function (intestine, adrenal, pituitary) resulting in an increased overall tumor burden in DKO mice compared to both wild-type (Po0.005) and Cx32-KO mice (P ¼ 0.066). However, additional deletion of p27 in a Cx32-KO background resulted in a statistically significant decrease in the liver tumor incidence suggesting that Cx32 and p27 pathways mechanistically interact. Immunohistochemical analysis revealed an increased percentage of Cx32-KO liver and lung tumors harboring active mitogen-activated protein kinase (Erk1, Erk2) pathways in contrast to lower percentages of activated wild-type (Po0.005) and DKO tumors (P ¼ 0.027). Increased MAPK activation in liver tumors did not correlate with Ha-ras codon-61 mutation status. This study demonstrates that tissues dependent on Cx32 tumor suppression, such as the liver and lung, exhibit altered tumorigenesis and tumor biology (MAPK pathway activation) related to p27 status.

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Section: Discussionmentioning

confidence: 99%

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

et al. 2005

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“…However, which sites might be responsible was not determined. The sites where ERK1/2 phosphorylates Cx43 have been determined to be S255, S279 and S282 and when wild type Cx43 or S279/S282/S255A mutant Cx43 were expressed in HeLa cells, EGF treatment led to a migration shift in both wild type and mutant expressing cells, although inhibition of communication was only observed in wild type Cx43 expressing cells (Warn-Cramer et al, 1998;Warn-Cramer et al, 1996). Inhibition of ERK1/2 reversed both of these effects.…”

Section: Induced Phosphorylation Can Lead To a Distinct P2mentioning

confidence: 99%

Key Connexin 43 Phosphorylation Events Regulate the Gap Junction Life Cycle

2007

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Connexin43 (Cx43), the most widely expressed and abundant vertebrate gap junction protein, is phosphorylated at multiple different serine residues during its life cycle. Cx43 is phosphorylated soon after synthesis and phosphorylation changes as it traffics through the endoplasmic reticulum and Golgi to the plasma membrane ultimately forming into a gap junction structure. The electrophoretic mobility of Cx43 changes as the protein proceeds through its life cycle with prominent bands often labeled P0, P1 and P2. Many reports have indicated changes in "phosphorylation" based on these mobility shifts and others that occur in response to growth factors or other biological effectors. Here we indicate how phosphospecific and epitope specific antibodies can be utilized to show when and where certain phosphorylation events occur during the Cx43 life cycle. These reagents show that phosphorylation at S364 and or S365 is involved in forming the P1 isoform, an event that apparently regulates trafficking to or within the plasma membrane. Phosphorylation at S325, 328, and/or 330 is necessary to form a P2 isoform and this phosphorylation event is present only in gap junctions. Treatment with protein kinase C activators led to phosphorylation at S368, S279/S282 and S262 with a shift in mobility in CHO cells but not MDCK cells. The shift was dependent on MAPK activity but not phosphorylation at S279/282. However, phosphorylation at S262 could explain the shift. By defining these phosphorylation events, we have begun to be able to sort out the critical signaling pathways that regulate gap junction function.

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“…Phosphorylation of Cx43 by pp60-src has been found to decrease gap junctional communication and correlates with a lack in growth control (163,176,313). MAP kinase signaling pathways have also been implicated in Cx43 phosphorylation to inhibit channel permeability (126,285,288,289) and may be the pathway activated by the gap junction inhibitor methanandamide (65).…”

Section: Open and Shut: Gating Connexin Channels And Regulation Of Cementioning

confidence: 99%

Sharing signals: connecting lung epithelial cells with gap junction channels

Koval

2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Gap junction channels enable the direct flow of signaling molecules and metabolites between cells. Alveolar epithelial cells show great variability in the expression of gap junction proteins (connexins) as a function of cell phenotype and cell state. Differential connexin expression and control by alveolar epithelial cells have the potential to enable these cells to regulate the extent of intercellular coupling in response to cell stress and to regulate surfactant secretion. However, defining the precise signals transmitted through gap junction channels and the cross talk between gap junctions and other signaling pathways has proven difficult. Insights from what is known about roles for gap junctions in other systems in the context of the connexin expression pattern by lung cells can be used to predict potential roles for gap junctional communication between alveolar epithelial cells.

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Regulation of Connexin-43 Gap Junctional Intercellular Communication by Mitogen-activated Protein Kinase

Abstract: Activation of the Ras

Cited by 325 publications

References 42 publications

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

Key Connexin 43 Phosphorylation Events Regulate the Gap Junction Life Cycle

Sharing signals: connecting lung epithelial cells with gap junction channels

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