Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival
Differential phosphorylation of the carboxyl-terminus of connexin 37 (Cx37-CT) regulates phenotypic switching between cell growth phenotypes (cell death, cell cycle arrest, proliferation). The specific phosphorylation events in the Cx37-CT that are necessary for these growth regulatory effects are c...
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doaj-a23419b3146249b98939a0904325ed5c2020-11-25T01:33:49ZengMDPI AGCancers2072-66942019-02-0111218810.3390/cancers11020188cancers11020188Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell SurvivalNicole L. Jacobsen0Tasha K. Pontifex1Paul R. Langlais2Janis M. Burt3Department of Physiology, University of Arizona, Tucson, AZ 85724, USADepartment of Physiology, University of Arizona, Tucson, AZ 85724, USADepartment of Medicine, University of Arizona, Tucson, AZ 85724, USADepartment of Physiology, University of Arizona, Tucson, AZ 85724, USADifferential phosphorylation of the carboxyl-terminus of connexin 37 (Cx37-CT) regulates phenotypic switching between cell growth phenotypes (cell death, cell cycle arrest, proliferation). The specific phosphorylation events in the Cx37-CT that are necessary for these growth regulatory effects are currently unknown. Through the combined use of deletion and site specific (de)phospho-mimetic Cx37-CT mutants, our data suggest a phosphorylation-dependent interaction between the mid-tail (aa 273⁻317) and end-tail (aa 318⁻333) portions of the Cx37-CT that regulates cell survival. As detected by mass spectrometry, Cx37 was phosphorylated at serines 275, 321, and 328; phosphomimetic mutations of these sites resulted in cell death when expressed in rat insulinoma cells. Alanine substitution at S328, but not at S275 or S321, also triggered cell death. Cx37-S275D uniquely induced the death of only low density, non-contact forming cells, but neither hemichannel open probability nor channel conductance distinguished death-inducing mutants. As channel function is necessary for cell death, together the data suggest that the phosphorylation state of the Cx37-CT controls an intra-domain interaction within the CT that modifies channel function and induces cell death.https://www.mdpi.com/2072-6694/11/2/188gap junctionconnexincell cyclecell deathgatingphosphorylation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nicole L. Jacobsen Tasha K. Pontifex Paul R. Langlais Janis M. Burt |
spellingShingle |
Nicole L. Jacobsen Tasha K. Pontifex Paul R. Langlais Janis M. Burt Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival Cancers gap junction connexin cell cycle cell death gating phosphorylation |
author_facet |
Nicole L. Jacobsen Tasha K. Pontifex Paul R. Langlais Janis M. Burt |
author_sort |
Nicole L. Jacobsen |
title |
Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival |
title_short |
Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival |
title_full |
Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival |
title_fullStr |
Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival |
title_full_unstemmed |
Phosphorylation-Dependent Intra-Domain Interaction of the Cx37 Carboxyl-Terminus Controls Cell Survival |
title_sort |
phosphorylation-dependent intra-domain interaction of the cx37 carboxyl-terminus controls cell survival |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2019-02-01 |
description |
Differential phosphorylation of the carboxyl-terminus of connexin 37 (Cx37-CT) regulates phenotypic switching between cell growth phenotypes (cell death, cell cycle arrest, proliferation). The specific phosphorylation events in the Cx37-CT that are necessary for these growth regulatory effects are currently unknown. Through the combined use of deletion and site specific (de)phospho-mimetic Cx37-CT mutants, our data suggest a phosphorylation-dependent interaction between the mid-tail (aa 273⁻317) and end-tail (aa 318⁻333) portions of the Cx37-CT that regulates cell survival. As detected by mass spectrometry, Cx37 was phosphorylated at serines 275, 321, and 328; phosphomimetic mutations of these sites resulted in cell death when expressed in rat insulinoma cells. Alanine substitution at S328, but not at S275 or S321, also triggered cell death. Cx37-S275D uniquely induced the death of only low density, non-contact forming cells, but neither hemichannel open probability nor channel conductance distinguished death-inducing mutants. As channel function is necessary for cell death, together the data suggest that the phosphorylation state of the Cx37-CT controls an intra-domain interaction within the CT that modifies channel function and induces cell death. |
topic |
gap junction connexin cell cycle cell death gating phosphorylation |
url |
https://www.mdpi.com/2072-6694/11/2/188 |
work_keys_str_mv |
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