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

A qualitative study of secondary distribution of HIV self-test kits by female sex workers in Kenya

Promoting awareness of serostatus and frequent HIV testing is especially important among high risk populations such as female sex workers (FSW) and their sexual partners. HIV self-testing is an approach that is gaining ground in sub-Saharan Africa as a strategy to increase knowledge of HIV status and promote safer sexual decisions. However, little is known about self-test distribution strategies that are optimal for increasing testing access among hard-to-reach and high risk individuals. We conducted a qualitative study with 18 FSW who participated in a larger study that provided them with five oral fluid-based self-tests, training on how to use the tests, and encouragement to offer the self-tests to their sexual partners using their discretion. Women demonstrated agency in the strategies they used to introduce self-tests to their partners and to avoid conflict with partners. They carefully considered with whom to share self-tests, often assessing the possibility for negative reactions from partners as part of their decision making process. When women faced negative reactions from partners, they drew on strategies they had used before to avoid conflict and physical harm from partners, such as not responding to angry partners and forgoing payment to leave angry partners quickly. Some women also used self-tests to make more informed sexual decisions with their partners