T-cadherin promotes autophagy and survival in vascular smooth muscle cells through MEK1/2/Erk1/2 axis activation

Emmanouil Kyriakakis, Agne Frismantiene, Boris Dasen, Dennis Pfaff, Olga Rivero, Klaus-Peter Lesch, Paul Erne, Therese J. Resink*, Maria Philippova

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Web of Science)

Abstract

Autophagy is an evolutionary conserved intracellular catabolic process of vital importance to cell and tissue homeostasis. Autophagy is implicated in the pathogenesis of atherosclerosis but participating cells, molecular mechanisms and functional outcomes have not been fully elucidated. T-cadherin, an atypical glycosylpho-sphatidylinositol-anchored member of the cadherin superfamily of adhesion molecules, is upregulated on smooth muscle cells (SMCs)(1) in atherosclerotic lesions. Here, using rat and murine aortic SMCs as experimental models, we surveyed the ability of T-cadherin to regulate autophagy in SMCs during serum-starvation stress. Ectopic upregulation of T-cadherin in SMCs resulted in augmented autophagy characterized by increased autophagic flux, LC3-II abundance and autophagosome formation. Analysis of signal transduction pathway effectors and use of specific pharmacological inhibitors demonstrated that T-cadherin-associated enhancement of the autophagic response to serum-deprivation was dependent on MEK1/2/Erk1/2 activation and independent of PI3K/Akt/mTORC1, reactive oxygen species or endoplasmic reticulum stress. T-cadherin upregulation on SMCs conferred a survival advantage during prolonged serum-starvation which was sensitive to inhibition of MEK1/2/Erkl/2 by PD98059 or U0126 and to blockade of autophagy by chloroquine. Loss of T-cadherin expression in SMCs diminished autophagy responsiveness and compromised survival under conditions of serum starvation. Overall our findings have identified T-cadherin as a novel positive regulator of autophagy and survival in SMCs.

Original languageEnglish
Pages (from-to)163-175
Number of pages13
JournalCellular Signalling
Volume35
DOIs
Publication statusPublished - Jul 2017

Keywords

  • T-cadherin
  • Vascular smooth muscle cells
  • Autophagy
  • Signal transduction
  • Unfolded protein response
  • STRESS-INDUCED APOPTOSIS
  • ENDOTHELIAL-CELLS
  • SIGNALING PATHWAYS
  • STIMULATES AUTOPHAGY
  • OXIDATIVE STRESS
  • EPITHELIAL-CELLS
  • GLIOMA-CELLS
  • CROSS-TALK
  • ADHESION
  • DEATH

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