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.
Highlights
Signal transduction pathways and networks direct cell responses largely through post-translational modifications, e.g., phosphorylation/dephosphorylation of their protein components
Proteasome inhibitors have shown great promise as cancer therapeutics because they impact a variety of mechanisms affecting tumor cell proliferation and survival; proteasome inhibition interferes with cell cycle progression, upregulates tumor suppressors such as p53, and diminishes activation of pro-proliferation pathways such as those controlled by NFkB and extracellular signal-regulated kinases (ERKs) [3,4]
Furthest upstream is the tyrosine phosphorylation of platelet-derived growth factor (PDGF) receptors; MG132 treatment significantly reduced phosphorylated Tyr751 of PDGF b-receptor, a major phosphorylation site that contributes to the recruitment of phosphoinositide 3-kinase (PI3K), in a PDGF dose-dependent manner (Fig. 1b)
Summary
Signal transduction pathways and networks direct cell responses largely through post-translational modifications, e.g., phosphorylation/dephosphorylation of their protein components. The mitogen-activated protein kinases (MAPKs) ERK2/ MAPK1 and ERK1/MAPK3 (hereafter referred to collectively as ERK1/2) are activated by phosphorylation in a canonical Raf R MEK R ERK kinase cascade in response to most growth factors and cytokines, and ERK1/2 phosphorylate more than 150 cytosolic and nuclear substrates [5,6]. They are master controllers of cell proliferation, differentiation, and migration. Cells treated with MG132 or other proteasome inhibitors exhibit higher expression of MKP3/DUSP6, an ERK1/ 2-specific DUSP, accompanied by lower levels of ERK phosphorylation stimulated by growth factors [12,13,14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
