title: Network-level effects of kinase inhibitors modulate TNF-α-induced apoptosis in the intestinal epithelium.
abstract: Individual signaling pathways operate in the context of the broader signaling network. Thus, the response of a cell to signals from the environment is affected by the state of the signaling network, such as the clinically relevant example of whether some components in the network are inhibited. The cytokine tumor necrosis factor-α (TNF-α) promotes opposing cellular behaviors under different conditions; the outcome is influenced by the state of the network. For example, in the mouse intestinal epithelium, inhibition of the mitogen-activated protein kinase (MAPK) kinase MEK alters the timing of TNF-α-induced apoptosis. We investigated whether MAPK signaling directly influences TNF-α-induced apoptosis or whether network-level effects secondary to inhibition of the MAPK pathway alter the cellular response. We found that inhibitors of the MAPK kinase kinase Raf, MEK, or extracellular signal-regulated kinase (ERK) exerted distinct effects on the timing and magnitude of TNF-α-induced apoptosis in the mouse intestine. Furthermore, even different MEK inhibitors exerted distinct effects; one, CH5126766, potentiated TNF-α-induced apoptosis, and the others reduced cell death. Computational modeling and experimental perturbation identified the kinase Akt as the primary signaling node that enhanced apoptosis in the context of TNF-α signaling in the presence of CH5126766. Our work emphasizes the importance of integrated network signaling in specifying cellular behavior in response to experimental or therapeutic manipulation. More broadly, this study highlighted the importance of considering the network-level effects of pathway inhibitors and showed the distinct effects of inhibitors that share the same target.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Gierut
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Levi B
authors.initials: LB
authors.lastname: Wood
authors.affiliation: Department of Chemical and Physical Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.|Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
authors.forename: Ken S
authors.initials: KS
authors.lastname: Lau
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yi-Jang
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Casie
authors.initials: C
authors.lastname: Genetti
authors.affiliation: TheraMet Biosciences, Princeton Junction, NJ 08550.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Samatar
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt