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

• Published in: Cellular signalling 2017-07, Vol.35, p.163-175
• Main Authors: Kyriakakis, Emmanouil, Frismantiene, Agne, Dasen, Boris, Pfaff, Dennis, Rivero, Olga, Lesch, Klaus-Peter, Erne, Paul, Resink, Therese J., Philippova, Maria
• Format: Article
• Language: English
• Subjects: Animals; Aorta - cytology; Aorta - metabolism; Apoptosis - genetics; Autophagy; Autophagy - genetics; Cadherins - genetics; Endoplasmic Reticulum Stress - genetics; Flavonoids - administration & dosage; Gene Expression Regulation - drug effects; Humans; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 2 - genetics; MAP Kinase Signaling System - drug effects; Mice; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Rats; Reactive Oxygen Species - metabolism; Signal transduction; T-cadherin; Transcriptional Activation - genetics; Unfolded protein response; Vascular smooth muscle cells
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2017.04.004

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 glycosylphosphatidylinositol-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/Erk1/2 by PD98059 or UO126 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. T-cadherin increases autophagy-dependent survival in smooth muscle cells via MEK1/2/Ek1/2 axis activation [Display omitted] •Existence of cadherin-based autophagy regulation in vascular SMCs•T-cadherin upregulation in SMCs augments pro-survival autophagic flux•MEK1/2/Erk1/2 axis activation underlies T-cadherin-augmentation of autophagy.•T-cadherin may be a target for promoting SMC survival during bioenergetic stress.