title: T-cadherin promotes autophagy and survival in vascular smooth muscle cells through MEK1/2/Erk1/2 axis activation.
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 glycosylphosphatidylinositol-anchored member of the cadherin superfamily of adhesion molecules, is upregulated on smooth muscle cells (SMCs)1in 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.
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Kyriakakis
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Agne
authors.initials: A
authors.lastname: Frismantiene
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Boris
authors.initials: B
authors.lastname: Dasen
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Dennis
authors.initials: D
authors.lastname: Pfaff
authors.affiliation: Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Rivero
authors.affiliation: Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Erne
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland. Electronic address: Therese-J.Resink@unibas.ch.
authors.forename: Therese J
authors.initials: TJ
authors.lastname: Resink
authors.affiliation: Department of Biomedicine, Laboratory for Signal Transduction, Basel University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Philippova
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005419:Flavonoids / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D048370:MAP Kinase Kinase 2 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D015820:Cadherins; D005419:Flavonoids; C099972:H-cadherin; D017382:Reactive Oxygen Species; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Autophagy; Signal transduction; T-cadherin; Unfolded protein response; Vascular smooth muscle cells