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

Jonathan So; Adrian Pasculescu; Anna Y Dai; Kelly Williton; Andrew James; Vivian Nguyen; Pau Creixell; Erwin M Schoof; John Sinclair; Miriam Barrios-Rodiles; Jun Gu; Aldis Krizus; Ryan Williams; Marina Olhovsky; James W Dennis; Jeffrey L Wrana; Rune Linding; Claus Jorgensen; Tony Pawson; Karen Colwill

doi:10.1126/scisignal.2005700

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

Jonathan So, Adrian Pasculescu, Anna Y Dai, Kelly Williton, Andrew James, Vivian Nguyen, Pau Creixell, Erwin M Schoof, John Sinclair, Miriam Barrios-Rodiles, Jun Gu, Aldis Krizus, Ryan Williams, Marina Olhovsky, James W Dennis, Jeffrey L Wrana, Rune Linding, Claus Jorgensen, Tony Pawson, Karen Colwill

26 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Science Signaling
Vol/bind	8
Udgave nummer	371
Sider (fra-til)	rs3
ISSN	1945-0877
DOI	https://doi.org/10.1126/scisignal.2005700
Status	Udgivet - 7 apr. 2015

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So, J., Pasculescu, A., Dai, A. Y., Williton, K., James, A., Nguyen, V., Creixell, P., Schoof, E. M., Sinclair, J., Barrios-Rodiles, M., Gu, J., Krizus, A., Williams, R., Olhovsky, M., Dennis, J. W., Wrana, J. L., Linding, R., Jorgensen, C., Pawson, T., & Colwill, K. (2015). Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy. Science Signaling, 8(371), rs3. https://doi.org/10.1126/scisignal.2005700

So, J, Pasculescu, A, Dai, AY, Williton, K, James, A, Nguyen, V, Creixell, P, Schoof, EM, Sinclair, J, Barrios-Rodiles, M, Gu, J, Krizus, A, Williams, R, Olhovsky, M, Dennis, JW, Wrana, JL, Linding, R, Jorgensen, C, Pawson, T & Colwill, K 2015, 'Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy', Science Signaling, bind 8, nr. 371, s. rs3. https://doi.org/10.1126/scisignal.2005700

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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.",

author = "Jonathan So and Adrian Pasculescu and Dai, {Anna Y} and Kelly Williton and Andrew James and Vivian Nguyen and Pau Creixell and Schoof, {Erwin M} and John Sinclair and Miriam Barrios-Rodiles and Jun Gu and Aldis Krizus and Ryan Williams and Marina Olhovsky and Dennis, {James W} and Wrana, {Jeffrey L} and Rune Linding and Claus Jorgensen and Tony Pawson and Karen Colwill",

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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

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 -

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

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