Phosphorylation-dependent intra-domain interaction of the Cx37 carboxyl-terminus controls cell survival

Nicole L. Jacobsen, Tasha K. Pontifex, Paul R. Langlais, Janis M. Burt

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number188
JournalCancers
Volume11
Issue number2
DOIs
StatePublished - Feb 2019

Keywords

  • Cell cycle
  • Cell death
  • Connexin
  • Gap junction
  • Gating
  • Phosphorylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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