Inhibition of connexin43 gap junctional intercellular communication by TPA requires ERK activation

Ruch, Randall J.; Trosko, James E.; Madhukar, Burra V.

doi:10.1002/jcb.1227

Cited by 115 publications

(79 citation statements)

References 26 publications

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“…15). In accordance with published data (26)(27)(28)(29), TPA induced Cx43-GFP internalization, as the majority of Cx43-GFP was found in intracellular compartments (Fig. 4A, arrowheads) previously identified as early and late endosomes, as well as lysosomes (30).…”

Section: Resultssupporting

confidence: 92%

The Tumor-Suppressive Function of Connexin43 in Keratinocytes Is Mediated in Part via Interaction with Caveolin-1

et al. 2010

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Connexin43 (Cx43) is known to have tumor-suppressive effects, but the underlying mechanisms are still poorly understood. In keratinocytes, we previously showed that the COOH-terminal domain of Cx43 directly interacts with the tumor suppressor Cav-1. We now show that rat epidermal keratinocytes (REK) that are reduced in Cx43 present features of epithelial-to-mesenchymal transition and are more invasive than their control counterparts, whereas overexpression of Cx43 inhibited the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-and epidermal growth factor (EGF)-induced invasive properties. Carbenoxolone did not alter the inhibitory effect of Cx43 against TPA-and EGF-induced cell invasion, indicating the involvement of a gap junctional intercellular communication-independent mechanism. Interestingly, the association of Cx43 with Cav-1 was found to be reduced after TPA and EGF treatment. Accordingly, the colocalization of Cx43 with Cav-1 was diminished in cells from a human epidermal squamous cell carcinoma, as well as in sections from human keratinocyte tumors, suggesting that Cx43/Cav-1 interaction plays a protective role against keratinocyte transformation. As opposed to cells that overexpress Cx43-GFP, invasion could be induced in rat epidermal keratinocytes that overexpressed a GFP-tagged truncated mutant of Cx43 (Δ244-GFP) that we previously showed not to interact with Cav-1, as well as in cells that overexpressed Cx43-GFP but were reduced in Cav-1. Our data show that Cx43 possesses tumor-suppressive properties in keratinocytes and provide the first evidence that the Cx43/Cav-1 interaction is altered in keratinocyte transformation processes, as well as in human keratinocyte tumors, and that this association might play a role in Cx43-mediated tumor suppression. Cancer Res; (70)10; 4222-32. ©2010 AACR.

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Section: Resultssupporting

confidence: 92%

The Tumor-Suppressive Function of Connexin43 in Keratinocytes Is Mediated in Part via Interaction with Caveolin-1

et al. 2010

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“…16,17 Furthermore, MAPK activation and Cx43 downregulation may be connected, as constitutively activated p-jnk potently reduces Cx43 levels in mouse myocardium, and p-erk has been implicated in Cx43 downregulation in liver epithelial cells. 18,19 Ongoing studies are addressing the physiological importance of the expression changes revealed in the present study, as well as expanding the analysis by means of subproteomic and transcriptome analysis.…”

Section: Discussionmentioning

confidence: 97%

Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart

et al. 2003

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Background-Left ventricular (LV) mechanical dyssynchrony induces regional heterogeneity of mechanical load and is an independent predictor of mortality and sudden death in heart failure (HF) patients. We tested whether dyssynchrony also induces localized disparities in the expression of proteins involved with mechanical stress, function, and arrhythmia susceptibility. Methods and Results-Eleven dogs underwent tachycardia-induced HF pacing, either from the right atrium or high right ventricular free wall. Whereas global LV dysfunction was similar between groups, LV contractile coordination assessed by tagged MRI was markedly dyssynchronous with right ventricular pacing but synchronous with right atrial pacing. In dyssynchronous failing hearts, the lateral LV endocardium displayed a 2-fold increase in phosphorylated erk mitogen-activated protein kinase expression (with no change in phospho-p38 or phospho-jnk), a 30% decline in sarcoplasmic reticulum Ca 2ϩ -ATPase, an 80% reduction in phospholamban, and a 60% reduction in the gap junction protein connexin43, relative to neighboring myocardial segments. In contrast, hearts from both right atrial-paced HF dogs and an additional 4 noninstrumented control animals showed minimal regional variability in protein expression. Conclusions-LV dyssynchrony in failing hearts generates myocardial protein dysregulation concentrated in the late-activated, high-stress lateral endocardium. Such molecular polarization within the LV creates transmural and transchamber expression gradients of calcium handling and gap junction proteins that may worsen chamber function and arrhythmia susceptibility. Key Words: heart failure Ⅲ pacing Ⅲ molecular biology Ⅲ sarcoplasmic reticulum T he pathophysiology of heart failure (HF) involves abnormalities of stress response kinase signaling, neurohumoral stimulation, excitation-contraction coupling, gap junction and ion channel function, and chamber remodeling. 1,2 In addition, recent studies have shown that left ventricular (LV) mechanical coordination is frequently disturbed in HF, particularly in the setting of interventricular conduction delay. HF patients with interventricular conduction delay and concomitant ventricular dyssynchrony have mortality and sudden cardiac death rates above those predicted from the apparent severity of systolic dysfunction, HF etiology, functional class, or concurrent medical therapy. 3,4 Acute mechanical discoordination induced by single-site right ventricular (RV) or LV pacing depresses systolic function, worsens myocardial efficiency, and leads to marked increases in wall stress heterogeneity. 5,6 Stress is highest in late-activated myocardial regions because of both exaggerated stretch in early systole (secondary to septal contraction) and late systolic contraction against increased afterload. Chronic discoordination leads to chamber remodeling of both early-and late-activated segments. 7 However, its effect on myocardial protein expression remains unknown. In the present study, we tested the hypothesis that stress...

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“…Because MAPK activation has been proposed to be involved in relocalization of Cx43 from the plasma membrane to intracellular membranes in response to phorbol esters and growth factors (e.g. Leithe and Rivedal, 2004;Ruch et al, 2001;Sirnes et al, 2008) and phosphorylation at S279 or S282 has been proposed to be involved in association with NEDD4 and turnover of Cx43 (Leykauf et al, 2006), we decided to examine the levels of phosphorylated S279 and/or S282 (pS279/282) during this TPA treatment time course. We found that the level of pS279/282 peaked at 15-30 minutes (Fig.…”

Section: Interaction Between Zo-1 and Cx43 Is Eliminated By S373 Phosmentioning

confidence: 99%

Injury-triggered Akt phosphorylation of Cx43: a ZO-1-driven molecular switch that regulates gap junction size

Dunn

Lampe

2013

Journal of Cell Science

125

177

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The proteins that form vertebrate gap junctions, the connexins, are highly regulated and have short (,2 hour) half-lives. Phosphorylation of connexin43 (Cx43) affects gap junction assembly, channel gating and turnover. After finding dramatic effects on gap junctions with Akt inhibitors, we created an antibody specific for Cx43 phosphorylated on S373, a potential Akt substrate. We found S373 phosphorylation in cells and skin or heart almost exclusively in larger gap-junctional structures that increased dramatically after wounding or hypoxia. We were able to mechanistically show that Akt-dependent phosphorylation of S373 increases gap junction size and communication by completely eliminating the interaction between Cx43 and ZO-1. Thus, phosphorylation on S373 acts as a molecular 'switch' to rapidly increase gap-junctional communication, potentially leading to initiation of activation and migration of keratinocytes or ischemic injury response in the skin and the heart, respectively.

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Inhibition of connexin43 gap junctional intercellular communication by TPA requires ERK activation

Cited by 115 publications

References 26 publications

The Tumor-Suppressive Function of Connexin43 in Keratinocytes Is Mediated in Part via Interaction with Caveolin-1

The Tumor-Suppressive Function of Connexin43 in Keratinocytes Is Mediated in Part via Interaction with Caveolin-1

Regional Alterations in Protein Expression in the Dyssynchronous Failing Heart

Injury-triggered Akt phosphorylation of Cx43: a ZO-1-driven molecular switch that regulates gap junction size

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