Occludin S471 phosphorylation contributes to epithelial monolayer maturation

Mark T. Bolinger, Aniket Ramshekar, Helen V. Waldschmidt, Scott D. Larsen, Maria C. Bewley, John M. Flanagan, David A. Antonetti

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Multiple organ systems require epithelial barriers for normal function, and barrier loss is a hallmark of diseases ranging from inflammation to epithelial cancers. However, the molecular processes regulating epithelial barrier maturation are not fully elucidated. After contact, epithelial cells undergo size-reductive proliferation and differentiate, creating a dense, highly ordered monolayer with high resistance barriers. We provide evidence that the tight junction protein occludin contributes to the regulation of epithelial cell maturation upon phosphorylation of S471 in its coiled-coil domain. Overexpression of a phosphoinhibitory occludin S471A mutant prevents size-reductive proliferation and subsequent tight junction maturation in a dominant manner. Inhibition of cell proliferation in cell-contacted but immature monolayers recapitulated this phenotype. A kinase screen identified G-protein-coupled receptor kinases (GRKs) targeting S471, and GRK inhibitors delayed epithelial packing and junction maturation. We conclude that occludin contributes to the regulation of size-reductive proliferation and epithelial cell maturation in a phosphorylation-dependent manner.

Original languageEnglish (US)
Pages (from-to)2051-2066
Number of pages16
JournalMolecular and cellular biology
Volume36
Issue number15
DOIs
StatePublished - 2016

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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