title: T-cadherin attenuates insulin-dependent signalling, eNOS activation, and angiogenesis in vascular endothelial cells.
abstract: OBJECTIVE
  T-cadherin (T-cad) is a glycosylphosphatidylinositol-anchored cadherin family member. Experimental, clinical, and genomic studies suggest a role for T-cad in vascular disorders such as atherosclerosis and hypertension, which are associated with endothelial dysfunction and insulin resistance (InsRes). In endothelial cells (EC), T-cad and insulin activate similar signalling pathways [e.g. PI3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR)] and processes (e.g. angiogenesis). We hypothesize that T-cad is a regulatory component of insulin signalling in EC and therefore a determinant of the development of endothelial InsRes.
  
  
  RESULTS
  We investigated T-cad-dependent effects on insulin sensitivity using human EC stably transduced with respect to T-cad overexpression or T-cad silencing. Responsiveness to insulin was examined at the level of effectors of the insulin signalling cascade, EC nitric oxide synthase (eNOS) activation, and angiogenic behaviour. Overexpression and ligation of T-cad on EC attenuates insulin-dependent activation of the PI3K/Akt/mTOR signalling axis, eNOS, EC migration, and angiogenesis. Conversely, T-cad silencing enhances these actions of insulin. Attenuation of EC responsiveness to insulin results from T-cad-mediated chronic activation of the Akt/mTOR-dependent negative feedback loop of the insulin cascade and enhanced degradation of the insulin receptor (IR) substrate. Co-immunoprecipitation experiments revealed an association between T-cad and IR. Filipin abrogated inhibitory effects of T-cad on insulin signalling, demonstrating localization of T-cad-insulin cross-talk to lipid raft plasma membrane domains. Hyperinsulinaemia up-regulates T-cad mRNA and protein levels in EC.
  
  
  CONCLUSIONS
  T-cad expression modulates signalling and functional responses of EC to insulin. We have identified a novel signalling mechanism regulating insulin function in the endothelium and attribute a role for T-cad up-regulation in the pathogenesis of endothelial InsRes.
authors.affiliation: Laboratory for Signal Transduction, Department of Biomedicine,  Basel University Hospital, Hebelstrasse 20, CH 4031 Basel,  Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Philippova
authors.forename: Manjunath B
authors.initials: MB
authors.lastname: Joshi
authors.forename: Dennis
authors.initials: D
authors.lastname: Pfaff
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Kyriakakis
authors.forename: Kseniya
authors.initials: K
authors.lastname: Maslova
authors.forename: Paul
authors.initials: P
authors.lastname: Erne
authors.forename: Thérèse J
authors.initials: TJ
authors.lastname: Resink
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D020868:Gene Silencing; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D021962:Membrane Microdomains / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D015820:Cadherins; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D011972:Receptor, Insulin; D058570:TOR Serine-Threonine Kinases; C099972:H-cadherin; C526292:IRS1 protein, human; C496314:NOS3 protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human