Regulation of Mitogen-Activated Protein Kinase Signaling Pathways by the Ubiquitin-Proteasome System and Its Pharmacological Potential

protein kinase (MAPK) cascades are evolutionarily conserved signal -ing pathways that play essential roles in transducing extracellular environmental signals into diverse cellu-lar responses to maintain homeostasis. These path-ways are classically organized into an architecture of three sequentially acting protein kinases: a MAPK kinase kinase that phosphorylates and activates a MAPK kinase, which in turn phosphorylates and acti-vates the effector MAPK. The activity of MAPKs is tightly regulated by phosphorylation of their activa-tion loop, which can be modulated by positive and neg-ative feedback mechanisms to control the amplitude and duration of the signal. The signaling outcomes of MAPK pathways are further regulated by interactions of MAPKs with scaffolding and regulatory proteins. Accumulating evidence indicates that, in addition to these mechanisms, MAPK signaling is commonly regu-lated by ubiquitin-proteasome system (UPS)-mediated control of the stability and abundance of MAPK path-way components. Notably, the biologic activity of some MAPKs appears to be regulated mainly at the level of protein turnover. Recent studies have started to explore the potential of targeted protein degradation as a powerful strategy to investigate the biologic func-tions of individual MAPK pathway components and as a new therapeutic approach to overcome resistance to current small-molecule kinase inhibitors. Here, we comprehensively review the mechanisms, physiologic importance, and pharmacological potential of UPS-mediated protein degradation in the control of MAPK signaling. Significance Statement--Accumulating evidence highlights the importance of targeted protein degra-dati on by the ubiquitin-proteasome system in regu-lating and fine-tuning the signaling output of mitogen-activated protein kinase (MAPK) pathways. Manipulating protein levels of MAPK cascade com-ponents may provide a novel approach for the devel-opment of selective pharmacological tools and therapeutics.

Automated summary

MAPK cascades are evolutionarily conserved signaling pathways that play essential roles in transducing extracellular signals. These pathways are tightly regulated by phosphorylation and also modulated by the ubiquitin-proteasome system. Manipulating protein turnover may provide new therapeutic approaches.