Mechanistic insights on spatiotemporal control of Ras-signaling

Proteins of the Ras-family are guanine nucleotide binding proteins (GNBPs) involved in a variety of fundamental cellular processes, including cell proliferation, cell differentiation, cytoskeleton dynamics, vesicular processes and intracellular transport. A dysregulation of Ras-signaling has been found to be causative for the development of diseases, such as diverse cancer types, RASopathies, neurodegenerative diseases and ciliopathies. Ras-proteins cycle between a GTP-bound on-state and a GDP-bound off-state. Ras-proteins show low intrinsic rates for nucleotide exchange and nucleotide hydrolysis. They need guanine-nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) to accelerate both functions in order to act as true molecular switches in the physiological context. Ras-proteins and their regulators/effectors are targets of post-translational modifications (PTMs) such as phosphorylation, ac(et)ylation, lipidation and ubiquitination. These PTMs regulate their activity, subcellular localization and turnover. In a biological perspective, PTMs are essential components for cellular signaling cascades and for molecular pattern formation. Bacterial pathogens use PTMs of Ras-proteins to allow efficient infection processes. Besides, modifications of Ras-proteins were shown to be of therapeutic potential in oncogenic variants such as Ras G12C. In this review, we summarize current knowledge on Ras-signaling, while emphasizing PTMs as dynamic signaling hubs for its precise spatiotemporal control.