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

TY - JOUR

T1 - Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy

AU - So, Jonathan

AU - Pasculescu, Adrian

AU - Dai, Anna Y

AU - Williton, Kelly

AU - James, Andrew

AU - Nguyen, Vivian

AU - Creixell, Pau

AU - Schoof, Erwin M

AU - Sinclair, John

AU - Barrios-Rodiles, Miriam

AU - Gu, Jun

AU - Krizus, Aldis

AU - Williams, Ryan

AU - Olhovsky, Marina

AU - Dennis, James W

AU - Wrana, Jeffrey L

AU - Linding, Rune

AU - Jorgensen, Claus

AU - Pawson, Tony

AU - Colwill, Karen

N1 - Copyright © 2015, American Association for the Advancement of Science.

PY - 2015/4/7

Y1 - 2015/4/7

N2 - 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.

AB - 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.

U2 - 10.1126/scisignal.2005700

DO - 10.1126/scisignal.2005700

M3 - Journal article

C2 - 25852190

SN - 1945-0877

VL - 8

SP - rs3

JO - Science Signaling

JF - Science Signaling

IS - 371

ER -