Altered translation initiation of Gja1 limits gap junction formation during epithelial-mesenchymal transition

Molecular Biology of the Cell
Carissa C JamesJames W Smyth

Abstract

Epithelial-mesenchymal transition (EMT) is activated during development, wound healing, and pathologies including fibrosis and cancer metastasis. Hallmarks of EMT are remodeling of intercellular junctions and adhesion proteins, including gap junctions. The GJA1 mRNA transcript encoding the gap junction protein connexin43 (Cx43) has been demonstrated to undergo internal translation initiation, yielding truncated isoforms that modulate gap junctions. The PI3K/Akt/mTOR pathway is central to translation regulation and is activated during EMT, leading us to hypothesize that altered translation initiation would contribute to gap junction loss. Using TGF-β-induced EMT as a model, we find reductions in Cx43 gap junctions despite increased transcription and stabilization of Cx43 protein. Biochemical experiments reveal suppression of the internally translated Cx43 isoform, GJA1-20k in a Smad3 and ERK-dependent manner. Ectopic expression of GJA1-20k does not halt EMT, but is sufficient to rescue gap junction formation. GJA1-20k localizes to the Golgi apparatus, and using super resolution localization we find retention of GJA1-43k at the Golgi in mesenchymal cells lacking GJA1-20k. NativePAGE reveals that levels of GJA1-20k regulate GJA1-4...Continue Reading

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Citations

Apr 28, 2018·International Journal of Molecular Sciences·Trond AasenMichael Koval
Jun 4, 2020·Journal of Cellular and Molecular Medicine·Derek J HausenloyFabio Di Lisa
Jun 3, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Patrick J CalhounJames W Smyth
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Datasets Mentioned

BETA
GM130

Methods Mentioned

BETA
confocal microscopy
Phase contrast
solubility assay
electrophoresis
GTPase
electron microscopy
Protein Assay
scraping

Software Mentioned

Vutara SRX
ImageJ

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