title: Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an endogenous secreted peptide and, in preclinical studies, preferentially induces apoptosis in tumor cells rather than in normal cells. The acquisition of resistance in cells exposed to TRAIL or its mimics limits their clinical efficacy. Because kinases are intimately involved in the regulation of apoptosis, we systematically characterized kinases involved in TRAIL signaling. Using RNA interference (RNAi) loss-of-function and cDNA overexpression screens, we identified 169 protein kinases that influenced the dynamics of TRAIL-induced apoptosis in the colon adenocarcinoma cell line DLD-1. We classified the kinases as sensitizers or resistors or modulators, depending on the effect that knockdown and overexpression had on TRAIL-induced apoptosis. Two of these kinases that were classified as resistors were PX domain-containing serine/threonine kinase (PXK) and AP2-associated kinase 1 (AAK1), which promote receptor endocytosis and may enable cells to resist TRAIL-induced apoptosis by enhancing endocytosis of the TRAIL receptors. We assembled protein interaction maps using mass spectrometry-based protein interaction analysis and quantitative phosphoproteomics. With these protein interaction maps, we modeled information flow through the networks and identified apoptosis-modifying kinases that are highly connected to regulated substrates downstream of TRAIL. The results of this analysis provide a resource of potential targets for the development of TRAIL combination therapies to selectively kill cancer cells.
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Jonathan
authors: J
authors: So
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors: Adrian
authors: A
authors: Pasculescu
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors: Anna Y
authors: AY
authors: Dai
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors: Kelly
authors: K
authors: Williton
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors: Andrew
authors: A
authors: James
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors: Vivian
authors: V
authors: Nguyen
authors: Cellular Signal Integration Group (C-SIG), Technical University of Denmark (DTU), DK-2800 Lyngby, Denmark.
authors: Pau
authors: P
authors: Creixell
authors: Cellular Signal Integration Group (C-SIG), Technical University of Denmark (DTU), DK-2800 Lyngby, Denmark.
authors: Erwin M
authors: EM
authors: Schoof
authors: Cell Communication Team, The Institute of Cancer Research, London SW3 6JB, UK.
authors: John
authors: J
authors: Sinclair
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors: Miriam
authors: M
authors: Barrios-Rodiles
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors: Jun
authors: J
authors: Gu
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors: Aldis
authors: A
authors: Krizus
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors: Ryan
authors: R
authors: Williams
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors: Marina
authors: M
authors: Olhovsky
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: James W
authors: JW
authors: Dennis
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Jeffrey L
authors: JL
authors: Wrana
authors: Cellular Signal Integration Group (C-SIG), Technical University of Denmark (DTU), DK-2800 Lyngby, Denmark. Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), DK-2200 Copenhagen, Denmark. linding@lindinglab.org claus.jorgensen@cruk.manchester.ac.uk colwill@lunenfeld.ca.
authors: Rune
authors: R
authors: Linding
authors: Cell Communication Team, The Institute of Cancer Research, London SW3 6JB, UK. linding@lindinglab.org claus.jorgensen@cruk.manchester.ac.uk colwill@lunenfeld.ca.
authors: Claus
authors: C
authors: Jorgensen
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Tony
authors: T
authors: Pawson
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. linding@lindinglab.org claus.jorgensen@cruk.manchester.ac.uk colwill@lunenfeld.ca.
authors: Karen
authors: K
authors: Colwill
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D017209:Apoptosis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C451304:AAK1 protein, human; C508327:PXK protein, human; D017346:Protein Serine-Threonine Kinases