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 Jørgensen, Tony Pawson, Karen Colwill

    Research output: Contribution to journalJournal articleResearchpeer-review

    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.
    Original languageEnglish
    Article numberrs3
    JournalScience Signaling
    Volume8
    Issue number371
    ISSN1945-0877
    DOIs
    Publication statusPublished - 2015

    Keywords

    • apoptosis
    • cancer Neoplasms (MeSH) neoplastic disease
    • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] DLD-1 cell line cell_line human colon adenocarcinoma cells
    • AAK1
    • cDNA complementary DNA expression
    • protein kinase 372092-80-3 EC 2.7.13.3
    • PXK
    • TRAIL receptor
    • TRAIL signaling
    • 02508, Cytology - Human
    • 10060, Biochemistry studies - General
    • 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines
    • 10802, Enzymes - General and comparative studies: coenzymes
    • 12512, Pathology - Therapy
    • 22002, Pharmacology - General
    • 22005, Pharmacology - Clinical pharmacology
    • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
    • combination therapy therapeutic and prophylactic techniques, clinical techniques
    • mass spectrometry-based protein interaction analysis laboratory techniques, spectrum analysis techniques
    • RNA interference RNAi laboratory techniques, genetic techniques
    • Biochemistry and Molecular Biophysics
    • Pharmacology
    • Tumor Biology
    • BIOCHEMISTRY
    • CELL
    • NF-KAPPA-B
    • DEPENDENT PROTEIN-KINASE
    • INTEGRIN-LINKED KINASE
    • CASPASE RECRUITMENT DOMAIN
    • HIGHLY OPTIMIZED TOLERANCE
    • LIGAND-INDUCED APOPTOSIS
    • LIGHT-INDUCED APOPTOSIS
    • ALPHA-INDUCED APOPTOSIS
    • CELL-CYCLE ARREST
    • CANCER-CELLS
    • Research Resources
    • Systems Biology

    Cite this

    So, Jonathan ; Pasculescu, Adrian ; Dai, Anna Y. ; Williton, Kelly ; James, Andrew ; Nguyen, Vivian ; Creixell, Pau ; Schoof, Erwin M. ; Sinclair, John ; Barrios-Rodiles, Miriam ; Gu, Jun ; Krizus, Aldis ; Williams, Ryan ; Olhovsky, Marina ; Dennis, James W. ; Wrana, Jeffrey L. ; Linding, Rune ; Jørgensen, Claus ; Pawson, Tony ; Colwill, Karen. / Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy. In: Science Signaling. 2015 ; Vol. 8, No. 371.
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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.",
    keywords = "apoptosis, cancer Neoplasms (MeSH) neoplastic disease, Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] DLD-1 cell line cell_line human colon adenocarcinoma cells, AAK1, cDNA complementary DNA expression, protein kinase 372092-80-3 EC 2.7.13.3, PXK, TRAIL receptor, TRAIL signaling, 02508, Cytology - Human, 10060, Biochemistry studies - General, 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines, 10802, Enzymes - General and comparative studies: coenzymes, 12512, Pathology - Therapy, 22002, Pharmacology - General, 22005, Pharmacology - Clinical pharmacology, 24004, Neoplasms - Pathology, clinical aspects and systemic effects, combination therapy therapeutic and prophylactic techniques, clinical techniques, mass spectrometry-based protein interaction analysis laboratory techniques, spectrum analysis techniques, RNA interference RNAi laboratory techniques, genetic techniques, Biochemistry and Molecular Biophysics, Pharmacology, Tumor Biology, BIOCHEMISTRY, CELL, NF-KAPPA-B, DEPENDENT PROTEIN-KINASE, INTEGRIN-LINKED KINASE, CASPASE RECRUITMENT DOMAIN, HIGHLY OPTIMIZED TOLERANCE, LIGAND-INDUCED APOPTOSIS, LIGHT-INDUCED APOPTOSIS, ALPHA-INDUCED APOPTOSIS, CELL-CYCLE ARREST, CANCER-CELLS, Research Resources, Systems Biology",
    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 J{\o}rgensen and Tony Pawson and Karen Colwill",
    year = "2015",
    doi = "10.1126/scisignal.2005700",
    language = "English",
    volume = "8",
    journal = "Science Signaling",
    issn = "1945-0877",
    publisher = "American Association for the Advancement of Science",
    number = "371",

    }

    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, Jørgensen, 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, vol. 8, no. 371, rs3. https://doi.org/10.1126/scisignal.2005700

    Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy. / So, Jonathan; Pasculescu, Adrian; Dai, Anna Y.; Williton, Kelly; James, Andrew; Nguyen, Vivian; Creixell, Pau; Schoof, Erwin M.; Sinclair, John; Barrios-Rodiles, Miriam; Gu, Jun; Krizus, Aldis; Williams, Ryan; Olhovsky, Marina; Dennis, James W.; Wrana, Jeffrey L.; Linding, Rune; Jørgensen, Claus; Pawson, Tony; Colwill, Karen.

    In: Science Signaling, Vol. 8, No. 371, rs3, 2015.

    Research output: Contribution to journalJournal articleResearchpeer-review

    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 - Jørgensen, Claus

    AU - Pawson, Tony

    AU - Colwill, Karen

    PY - 2015

    Y1 - 2015

    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.

    KW - apoptosis

    KW - cancer Neoplasms (MeSH) neoplastic disease

    KW - Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] DLD-1 cell line cell_line human colon adenocarcinoma cells

    KW - AAK1

    KW - cDNA complementary DNA expression

    KW - protein kinase 372092-80-3 EC 2.7.13.3

    KW - PXK

    KW - TRAIL receptor

    KW - TRAIL signaling

    KW - 02508, Cytology - Human

    KW - 10060, Biochemistry studies - General

    KW - 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines

    KW - 10802, Enzymes - General and comparative studies: coenzymes

    KW - 12512, Pathology - Therapy

    KW - 22002, Pharmacology - General

    KW - 22005, Pharmacology - Clinical pharmacology

    KW - 24004, Neoplasms - Pathology, clinical aspects and systemic effects

    KW - combination therapy therapeutic and prophylactic techniques, clinical techniques

    KW - mass spectrometry-based protein interaction analysis laboratory techniques, spectrum analysis techniques

    KW - RNA interference RNAi laboratory techniques, genetic techniques

    KW - Biochemistry and Molecular Biophysics

    KW - Pharmacology

    KW - Tumor Biology

    KW - BIOCHEMISTRY

    KW - CELL

    KW - NF-KAPPA-B

    KW - DEPENDENT PROTEIN-KINASE

    KW - INTEGRIN-LINKED KINASE

    KW - CASPASE RECRUITMENT DOMAIN

    KW - HIGHLY OPTIMIZED TOLERANCE

    KW - LIGAND-INDUCED APOPTOSIS

    KW - LIGHT-INDUCED APOPTOSIS

    KW - ALPHA-INDUCED APOPTOSIS

    KW - CELL-CYCLE ARREST

    KW - CANCER-CELLS

    KW - Research Resources

    KW - Systems Biology

    U2 - 10.1126/scisignal.2005700

    DO - 10.1126/scisignal.2005700

    M3 - Journal article

    VL - 8

    JO - Science Signaling

    JF - Science Signaling

    SN - 1945-0877

    IS - 371

    M1 - rs3

    ER -