Trends in Biochemical Sciences最新文献

Recently developed KRAS inhibitors have delivered clinical benefits but their antitumor efficacy remains limited. A recent study by Klomp et al. reports an unprecedentedly comprehensive profiling of protein phosphorylation dependent on the KRAS pathway and generates new insights and directions to improve the efficacy of KRAS-targeted therapies.

DNA is constantly subject to damage from endogenous and exogenous factors, leading to mutations and disease. While DNA is traditionally repaired in the nucleus, Lascaux et al. reveal a novel role for the lysosome in DNA repair, demonstrating that topoisomerase 1 (TOP1) cleavage complex (TOP1cc) DNA lesions are degraded via TEX264-mediated selective autophagy.

Eph receptor tyrosine kinases, together with their cell surface-anchored ephrin ligands, constitute an important cell-cell communication system that regulates physiological and pathological processes in most cell types. This review focuses on the multiple mechanisms by which Eph receptors initiate signaling via the formation of protein complexes in the plasma membrane. Upon ephrin binding, Eph receptors assemble into oligomers that can further aggregate into large complexes. Eph receptors also mediate ephrin-independent signaling through interplay with intracellular kinases or other cell-surface receptors. The distinct characteristics of Eph receptor family members, as well as their conserved domain structure, provide a framework for understanding their functional differences and redundancies. Possible areas of interest for future investigations of Eph receptor signaling complexes are also highlighted.

G-protein-coupled receptors (GPCRs) are the largest family of cell receptors. They mediate the effects of a multitude of endogenous and exogenous cues, are deeply involved in human physiology and disease, and are major pharmacological targets. Whereas GPCRs were long thought to signal exclusively at the plasma membrane, research over the past 15 years has revealed that they also signal via classical G-protein-mediated pathways on membranes of intracellular organelles such as endosomes and the Golgi complex. This review provides an overview of recent advances and emerging concepts related to endomembrane GPCR signaling, as well as ongoing research aimed at a better understanding of its mechanisms, physiological relevance, and potential therapeutic applications.

A link between epigenetics and metabolism was initially recognized because the cellular metabolic state is communicated to the genome through the concentration of intermediary metabolites that are cofactors of chromatin-modifying enzymes. Recently, an additional interaction was postulated due to the capacity of the epigenome to store substantial amounts of metabolites that could become available again to cellular metabolite pools. Here, we focus on histone acetylation and review recent evidence illustrating this reciprocal relationship: in one direction, signaling-induced acetyl-coenzyme A (acetyl-CoA) changes influence histone acetylation levels to regulate genomic functions, and in the opposite direction histone acetylation acts as an acetate reservoir to directly affect downstream acetyl-CoA-mediated metabolism. This review highlights the current understanding, experimental challenges, and future perspectives of this bidirectional interplay.