Activation of Akt, Not Connexin 43 Protein Ubiquitination, Regulates Gap Junction Stability

Dunn, Clarence A.; Su, Vivian; Lau, Alan F.; Lampe, Paul D.

doi:10.1074/jbc.m111.276261

Cited by 95 publications

(96 citation statements)

References 56 publications

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“…Akt signalling is necessary for the stability of Cx43 gap junctions, as Akt inhibition and dominant negative Akt expression prevents cell surface localisation of Cx43 (15). Our work suggests that Ppp2r2a up-regulation is one mechanism by which Cx43 can become stabilised at the gap junction.…”

Section: Resultsmentioning

confidence: 68%

The protein phosphatase 2A regulatory subunit Ppp2r2a is required for Connexin‐43 dephosphorlyation during epidermal barrier acquisition

Gerner

Youssef²,

O'Shaughnessy³

2013

Experimental Dermatology

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Epidermal barrier acquisition during late mammalian development is a prerequisite for terrestrial existence. Over a 24-h period, the epidermis goes from being a barrier-deficient, dye permeable epithelium to a barrier-competent epithelium. We have previously shown that Akt signalling is necessary for barrier acquisition in the mouse and that the protein phosphatase 2A regulatory subunit Ppp2r2a causes barrier acquisition by dephosphorylation of cJun. Here, we demonstrate that there is transient interaction between the gap junction protein Connexin 43 (Cx43) and Zonula occludins-1 (Zo-1) during epidermal barrier acquisition. Ppp2r2a knockdown prevented plasma membrane co-localisation and interaction between the two proteins. Ppp2r2a knockdown also increased phosphorylation at Serine 368 of Connexin 43. Cx43 phosphorlyation at Serine368 occurred just prior to the interaction between Connexin 43 and Zo-1. We therefore propose a model in which Ppp2r2a is required both for the initial interaction between Zo-1 and Cx43 and the consequent dephosphorylation of Connexin 43, preventing interaction of Zo-1 and allowing Zo-1 to initiate tight junction formation and barrier acquisition.

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Section: Resultsmentioning

confidence: 68%

The protein phosphatase 2A regulatory subunit Ppp2r2a is required for Connexin‐43 dephosphorlyation during epidermal barrier acquisition

Gerner

Youssef²,

O'Shaughnessy³

2013

Experimental Dermatology

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“…We have previously shown that ubiquitin-mediated activation of Akt is responsible for increased gap-junctional communication and stability following proteasomal inhibition (Dunn et al, 2012). Here, we show that Akt activity is necessary for phosphorylation of Cx43 at S373 and this phosphorylation event causes an increase in gap junction size and communication levels by limiting the interaction of ZO-1 with Cx43.…”

Section: Introductionmentioning

confidence: 54%

“…More recently, we showed that proteasomal inhibition increased gap junction stability through activation of Akt (Dunn et al, 2012). Because S373 has been described as a possible Akt kinase substrate (Park et al, 2007), we decided to create a phosphospecific antibody that reacts with Cx43 when it is phosphorylated at S373 (pS373).…”

Section: Cx43 Phosphorylation On S373mentioning

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

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124

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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“…In addition, Akt (protein kinase B) activity controlled gap junction stability and was necessary to form larger stable gap junctions. Akt activation was increased upon proteasomal inhibition and resulted in phosphorylation of Cx43 at Akt phosphorylation consensus sites (Dunn et al, 2012). The carboxy terminus of Cx43 are adjusted by a Ca(2+)/ calmodulin-dependent mechanism (Xu et al, 2012;Guerineau et al, 2012).…”

Section: Connexins and Phosphorylationmentioning

confidence: 99%

Study progress of homocellular and heterocellular gap junctions in vessel wall

Hedagger;¹

2012

Afr. J. Pharm. Pharmacol.

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There were four different degrees which were related to organs, tissues, cells and molecules in the study of physiopathologic process and treatment of vessel remodeling diseases. More people concentrated on the research of one kind of cell, for example, the vascular smooth muscle cell (VSMC) or adventitial fibroblast (AF) and their effect on the vessel rebuilding. However, the human body is an organic whole, so the structural and functional contacts among vascular endothelial cell, smooth muscle cell (SMC) and AF should be paid more attention to. Books and articles on the gap junction (GJ) were collected and studied. Gap junction between and among cells of the vessel wall played a critical role in many aspects of vascular function and pathology. There was homocellular communication in intima, tunicae media and adventitia singly, and also, heterocellular communication among different cells of the vessel wall. As a result, a link network was formed among cells of the vessel wall and the vessel had integrated function in the physiological and pathological process. Hence, a summary was made about the homocellular and heterocellular gap junctions, hoping that there would be more people concentrating on the whole function of vessels.

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Activation of Akt, Not Connexin 43 Protein Ubiquitination, Regulates Gap Junction Stability

Cited by 95 publications

References 56 publications

The protein phosphatase 2A regulatory subunit Ppp2r2a is required for Connexin‐43 dephosphorlyation during epidermal barrier acquisition

The protein phosphatase 2A regulatory subunit Ppp2r2a is required for Connexin‐43 dephosphorlyation during epidermal barrier acquisition

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

Study progress of homocellular and heterocellular gap junctions in vessel wall

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