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Sci Signal. 2015 Apr 7;8(371):rs3. doi: 10.1126/scisignal.2005700.

Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy.

Author information

1
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
2
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
3
Cellular Signal Integration Group (C-SIG), Technical University of Denmark (DTU), DK-2800 Lyngby, Denmark.
4
Cell Communication Team, The Institute of Cancer Research, London SW3 6JB, UK.
5
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
6
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.
7
Cell Communication Team, The Institute of Cancer Research, London SW3 6JB, UK. linding@lindinglab.org claus.jorgensen@cruk.manchester.ac.uk colwill@lunenfeld.ca.
8
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.
9
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. linding@lindinglab.org claus.jorgensen@cruk.manchester.ac.uk colwill@lunenfeld.ca.

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.

PMID:
25852190
DOI:
10.1126/scisignal.2005700
[Indexed for MEDLINE]

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