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Updated: Nov 10, 2025
Mimicking the Function of Signaling Proteins: Toward Artificial Signal Transduction Therapy
Published on: September 29, 2016
RAS Nanoclusters: Dynamic Signaling Platforms Amenable to Therapeutic Intervention
Que N Van1, Priyanka Prakash1, Rebika Shrestha1
1Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, National Cancer Institute RAS Initiative, Inc., Frederick, MD 21702, USA.
Abstract:
RAS proteins are mutated in approximately 20% of all cancers and are generally associated with poor clinical outcomes. RAS proteins are localized to the plasma membrane and function as molecular switches, turned on by partners that receive extracellular mitogenic signals. In the on-state, they activate intracellular signal transduction cascades. Membrane-bound RAS molecules segregate into multimers, known as nanoclusters. These nanoclusters, held together through weak protein-protein and protein-lipid associations, are highly dynamic and respond to cellular input signals and fluctuations in the local lipid environment. Disruption of RAS nanoclusters results in downregulation of RAS-mediated mitogenic signaling. In this review, we discuss the propensity of RAS proteins to display clustering behavior and the interfaces that are associated with these assemblies. Strategies to therapeutically disrupt nanocluster formation or the stabilization of signaling incompetent RAS complexes are discussed.
Insights
RAS proteins, mutated in 20% of cancers, form dynamic nanoclusters at the plasma membrane. Disrupting these RAS nanoclusters may offer new cancer therapy strategies.
Area of Science:
- Molecular biology
- Cell signaling
- Cancer research
Background:
- RAS proteins are critical regulators of cell signaling, acting as molecular switches.
- Mutations in RAS proteins are common in cancer (approx. 20%) and linked to poor prognosis.
- RAS proteins localize to the plasma membrane and form dynamic assemblies called nanoclusters.
Purpose of the Study:
- To review the clustering behavior of RAS proteins and the interfaces involved.
- To discuss the role of RAS nanoclusters in signal transduction.
- To explore therapeutic strategies targeting RAS nanocluster formation or stabilization.
Main Methods:
- Literature review of studies on RAS protein behavior, nanocluster formation, and signaling.
- Analysis of protein-protein and protein-lipid interactions stabilizing RAS nanoclusters.
- Discussion of potential therapeutic interventions based on nanocluster modulation.
Main Results:
- RAS proteins exhibit a propensity for forming dynamic nanoclusters at the plasma membrane.
- These nanoclusters are stabilized by weak protein-protein and protein-lipid interactions.
- Disruption of RAS nanoclusters leads to reduced RAS-mediated mitogenic signaling.
Conclusions:
- RAS nanoclusters are key functional units regulating RAS signaling.
- Targeting the disruption of nanocluster formation or stabilizing inactive RAS complexes presents a promising therapeutic avenue for cancers driven by RAS mutations.
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