title: Systemic perturbation of the ERK signaling pathway by the proteasome inhibitor, MG132.
abstract: Inhibition of the ubiquitin-proteasome protein degradation pathway has been identified as a viable strategy for anti-tumor therapy based on its broad effects on cell proliferation. By the same token, the variety of elicited effects confounds the interpretation of cell-based experiments using proteasome inhibitors such as MG132. It has been proposed that MG132 treatment reduces growth factor-stimulated phosphorylation of extracellular signal-regulated kinases (ERKs), at least in part through upregulation of dual specificity phosphatases (DUSPs). Here, we show that the effects of MG132 treatment on ERK signaling are more widespread, leading to a reduction in activation of the upstream kinase MEK. This suggests that MG132 systemically perturbs the intracellular phosphoproteome, impacting ERK signaling by reducing phosphorylation status at multiple levels of the kinase cascade.
authors.affiliation: Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Cirit
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Grant
authors.forename: Jason M
authors.initials: JM
authors.lastname: Haugh
mesh_terms: D000818:Animals; D003198:Computer Simulation; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D004789:Enzyme Activation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007976:Leupeptins; D010982:Platelet-Derived Growth Factor; D061988:Proteasome Inhibitors; D005346:Fibroblast Growth Factors; D020929:Mitogen-Activated Protein Kinase Kinases; D054637:Dual-Specificity Phosphatases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde