Negative feedback regulation of the ERK1/2 MAPK pathway

The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signalling pathway regulates many cellular functions, including proliferation, differentiation, and transformation. To reliably convert external stimuli into specific cellular responses and to adapt to environmental circumstances, the pathway must be integrated into the overall signalling activity of the cell. Multiple mechanisms have evolved to perform this role. In this review, we will focus on negative feedback mechanisms and examine how they shape ERK1/2 MAPK signalling. We will first discuss the extensive number of negative feedback loops targeting the different components of the ERK1/2 MAPK cascade, specifically the direct posttranslational modification of pathway components by downstream protein kinases and the induction of de novo gene synthesis of specific pathway inhibitors. We will then evaluate how negative feedback modulates the spatiotemporal signalling dynamics of the ERK1/2 pathway regarding signalling amplitude and duration as well as subcellular localisation. Aberrant ERK1/2 activation results in deregulated proliferation and malignant transformation in model systems and is commonly observed in human tumours. Inhibition of the ERK1/2 pathway thus represents an attractive target for the treatment of malignant tumours with increased ERK1/2 activity. We will, therefore, discuss the effect of ERK1/2 MAPK feedback regulation on cancer treatment and how it contributes to reduced clinical efficacy of therapeutic agents and the development of drug resistance

PRMT Inhibitors

The methylation of arginine residues in numerous protein targets is a post-translational modification that has gained increased interest in the scientific community over the past two decades. Arginine methylation is performed by the dedicated family of protein arginine methyltransferases and is known to be involved in a plethora of cellular pathways and biochemical mechanisms in both healthy and disease states. The development of inhibitors for these enzymes for use as biological tools can lead to a more detailed understanding of the functions of the different members of the PRMT family. In addition, a number of recent studies point towards PRMTs as therapeutic targets for a number of diseases and the first clinical trials with compounds inhibiting PRMTs are now underway. We here provide a broad overview of the current status of the inhibitors that have been developed against PRMTs using both high-throughput screening and rational design approaches.Microbial Biotechnolog