title: The immune receptor Tim-3 mediates activation of PI3 kinase/mTOR and HIF-1 pathways in human myeloid leukaemia cells.
abstract: The T-cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane-associated protein that is highly expressed in human acute myeloid leukaemia cells. As an acute myeloid leukaemia antigen, it could therefore be considered as a potential target for immune therapy and highly-specific drug delivery. However, a conceptual understanding of its biological role is required before consideration of this protein for therapeutic settings. Here, we reveal the detailed mechanism of action underlying the biological responses mediated by the Tim-3 receptor in myeloid cells. Our studies demonstrate that Tim-3 triggers growth factor type responses in acute myeloid leukaemia cells by activating a phosphatidylinositol-3 kinase (PI-3K)/mammalian target of rapamycin (mTOR) pathway. In addition, the receptor activates hypoxic signalling pathways upregulating glycolysis and pro-angiogenic responses. These findings suggest that Tim-3 could be used as a potential therapeutic target for immune therapy and drug delivery in human acute myeloid leukaemia cells.
authors.affiliation: School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Prokhorov
authors.affiliation: School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK.
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Gibbs
authors.affiliation: Institute for Research in Biomedicine, Via Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Bardelli
authors.affiliation: School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK; High School of Life Sciences, University of Applied Sciences North-Western Switzerland, Muttenz, Switzerland.
authors.forename: Laura
authors.initials: L
authors.lastname: Rüegg
authors.affiliation: High School of Life Sciences, University of Applied Sciences North-Western Switzerland, Muttenz, Switzerland; Department of Biomedicine, University of Basel and University Hospital Basel, CH-4031 Basel, Switzerland. Electronic address: e.fasler@unibas.ch.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Fasler-Kan
authors.affiliation: Institute for Research in Biomedicine, Via Vela 6, 6500 Bellinzona, Switzerland. Electronic address: luca.varani@irb.usi.ch.
authors.forename: Luca
authors.initials: L
authors.lastname: Varani
authors.affiliation: School of Pharmacy, University of Kent, Anson Building, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK. Electronic address: V.Sumbayev@kent.ac.uk.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Sumbayev
mesh_terms: D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D037161:Galectins / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D051793:Hypoxia-Inducible Factor 1; C105032:LGALS9 protein, human; D008024:Ligands; D008565:Membrane Proteins; D019089:Stem Cell Factor; D042461:Vascular Endothelial Growth Factor A; D010768:Phosphoserine; D019000:Phosphotyrosine; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D010738:Type C Phospholipases; D002118:Calcium
keywords: HIF-1; Mammalian target of rapamycin (mTOR) pathway; Myeloid leukaemia cells; Tim-3