Expanding applications of chemical genetics in signal transduction

Abstract

Chemical genetics represents an expanding collection of techniques applied to a variety of signaling processes. These techniques use a combination of chemical reporters and protein engineering to identify targets of a signaling enzyme in a global and non-directed manner without resorting to hypothesisdriven candidate approaches. In the last year, chemical genetics has been applied to a variety of kinases, revealing a much broader spectrum of substrates than had been appreciated. Here, we discuss recent developments in chemical genetics, including insights from our own proteomic screen for substrates of the kinase ERK2. These studies have revealed that many kinases have overlapping substrate specificity, and they often target several proteins in any particular downstream pathway. It remains to be determined whether this configuration exists to provide redundant control, or whether each target contributes a fraction of the total regulatory effect. From a general perspective, chemical genetics is applicable in principle to a broad range of posttranslational modifications (PTMs), most notably, methylation and acetylation, although many challenges remain in implementing this approach. Recent developments in chemical reporters and protein engineering suggest that chemical genetics will soon be a powerful tool for mapping signal transduction through these and other PTMs.

Interrogating Kinase–Substrate Relationships with Proximity Labeling and Phosphorylation Enrichment

“…We identified these sites as potential substrates of PKA in pAPEX. Among all the potential substrates identified for MAPK1, TPX2 has also been identified as a substrate using the analogue sensitive (AS) MAPK1 . pT369 on TPX2 was elevated under kinase “ON” condition in pAPEX of MAPK1 in both cell lines.…”

Adaptive Laboratory Evolution of Microalgae: A Review of the Regulation of Growth, Stress Resistance, Metabolic Processes, and Biodegradation of Pollutants

“…Chemical modulators can perturb the biological system and induce cells to metabolize desired chemicals by specifically targeting enzyme proteins or as signaling molecules (Carlson and White, 2012). This strategy can be used to improve microalgal lipid production, but the direct addition of chemical modulators to the medium has obvious negative effects on biomass accumulation or lipid synthesis (Wase et al, 2017).…”

Applications of targeted proteomics in systems biology and translational medicine

“…Rather, they operate in a large number of biological contexts, spatial, and temporal scales and functional states exemplified by protein‐specific properties such as reaction mechanisms, substrate/ motif binding and complex formation. In addition, properties of protein networks such as information processing, noise, adaptability, robustness, and even seemingly paradoxical arrangement of components and functions, such as enzyme promiscuity 19, 20, 21, 22, 23, 24, 25, 26. Moreover, a protein can exist with different variant sequences due to splicing or mutations, and be subject to different PTMs at different sites, resulting in a vast number of theoretical combination of PTMs, known as “mod‐forms”, see for example the histone‐code 18.…”