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. 2023 Jan 13;480(1):1-23.
doi: 10.1042/BCJ20220234.

Dynamic regulation of RAS and RAS signaling

Walter Kolch  1   2 , Dénes Berta  3 , Edina Rosta  3
Affiliations

Dynamic regulation of RAS and RAS signaling

Walter Kolch et al. Biochem J. .

Abstract

RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact with a wide range of effectors that control fundamental biochemical and biological processes. Emerging evidence suggests that RAS proteins are not simple on/off switches but sophisticated information processing devices that compute cell fate decisions by integrating external and internal cues. A critical component of this compute function is the dynamic regulation of RAS activation and downstream signaling that allows RAS to produce a rich and nuanced spectrum of biological outputs. We discuss recent findings how the dynamics of RAS and its downstream signaling is regulated. Starting from the structural and biochemical properties of wild-type and mutant RAS proteins and their activation cycle, we examine higher molecular assemblies, effector interactions and downstream signaling outputs, all under the aspect of dynamic regulation. We also consider how computational and mathematical modeling approaches contribute to analyze and understand the pleiotropic functions of RAS in health and disease.

Keywords: RAS proteins; biological networks; cancer; dynamics; signaling.

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Conflict of interest statement

W.K. is consulting for Boehringer Ingelheim. The other authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1.
Figure 1.. RAS activation cycle and RAS effectors.
Fifty-six bona fide RAS effectors can be grouped into 12 classes according to sequence homology and regulation of downstream biochemical and biological processes. Adapted from [5].
Figure 2.
Figure 2.. RAS activation kinetics determine cell fate decisions in PC12 cells.
PC12 cells proliferate in response to EGF, which causes transient RAS and ERK pathway activation, whereas NGF causes sustained RAS and ERK activation and neuronal differentiation (visible as the extension of long neurites). Feedback phosphorylation of the NF1 GAP by ERK occurs selectively in response to NGF stimulation [9]. It interferes with NF1 binding to RAS thereby allowing RAS activation to persist.
Figure 3.
Figure 3.. RAS protein activation cycle.
(A) Complex of p120GAP (red surface, PDB 1WQ1), SOS1 (yellow surface, PDB 6V6M) and the effector PI3K (blue surface, PDB 1HE8) showing a shared binding interface with GTP loaded RAS (gray cartoon, PDB 1QRA). (B) Comparison of GTP-bound RAS (gray cartoon, PDB 1QRA) and GDP-bound RAS (cyan cartoon, PDB 6P0Z), conformational changes of Switches I and II are highlighted by arrows. (C) Kinetic network of the RAS signaling cycle and downstream signaling. Adapted from [19]. (D) Alternative proton transfer mechanisms in the GTP hydrolysis. Adapted from [32]. (E) Oncogenic mutation hot spots (red surfaces) highlighted in the GTP-bound RAS structure (gray cartoon, PDB 1QRA).
Figure 4.
Figure 4.. Dynamic RAS regulation by GEFs and GAPs.
(A) RAS immobilized on microbeads is used to study the effects of GEFs and GAPs on RAS activation as measured by the recruitment of a labeled RAF1-RBD. (B) A positive feedback that recruits more GEF (RBD-RasGRF) to beads as more RAS is activated amplifies weak input signals under high GAP conditions. (C) The allosteric feedback whereby RAS:GTP binds to and activates SOS reduces overshoot in the output dynamics. Panels (A–C) are adapted from [52]. (D) Feedback regulation of SOS and NF1. Green arrow, activation; red blunt-end lines, inhibition.
Figure 5.
Figure 5.. RAS regulation by posttranslational modifications.
(A) PKC phosphorylation of KRAS at S181 sustains activation by preventing GAP binding and induces mitochondrial translocation of KRAS, where it promotes apoptosis by binding to and inhibiting the function of the anti-apoptotic Bcl-XL protein. (B) SRC phosphorylation of tyrosines 32 and 64 inhibits RAS by interfering with RAF binding and promoting association with GAPs. (C) The RIN1 effector can stimulate the ABL kinase to phosphorylate tyrosine 137 in HRAS promoting activation and enhanced RAF binding with subsequent ERK activation. On the other hand, RIN1 can stimulate the ubiquitin ligase Rabex-5, which mono-/di-ubiquinates HRAS leading to endosomal sequestration and HRAS inactivation.
Figure 6.
Figure 6.. RAS nanoclusters and signaling output.
Each RAS nanocluster delivers a defined ‘digital’ signaling output. Increasing concentrations of growth factor induce more nanoclusters thereby transforming an analog input of growth factor stimulation into a digital output of ERK activity.
Figure 7.
Figure 7.. Increasing RAS activity shifts effector binding to low- affinity interactors.
Results shown are based on experimental results and a mathematical model of RAS — effector binding reported in [113].
Figure 8.
Figure 8.. Tissue-specific expression of RAS effectors compiled from the Human Protein Atlas (HPA) [114,115].
Protein expression is given as scored by the HPA. Where protein expression data were not available, mRNA expression data were used. Transcripts per million (TPM) were classified by the following cutoffs: <1 no, 1–10 low, 10–30 medium, and >30 TPM high expression. n.m., not measured.
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