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, 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., 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, 8(371), [rs3]. https://doi.org/10.1126/scisignal.2005700