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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability.

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Ras GTPase signaling exhibits switch-like activity. Its bimodal activation, driven by SOS processivity and LAT condensation, creates stochastic bursts, offering potential resistance to drug inhibition.

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Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biophysics

Background:

  • Ras GTPases are crucial regulators of cellular functions.
  • Ras signaling is known to exhibit switch-like, bimodal activity.
  • Understanding the mechanisms of Ras activation is key to deciphering cell fate decisions.

Purpose of the Study:

  • To reconstitute and analyze the receptor-mediated Ras activation-deactivation cycle in vitro.
  • To investigate the underlying mechanisms driving the observed bimodal Ras activation.
  • To explore the role of SOS processivity and LAT condensation in Ras signaling dynamics.

Main Methods:

  • Utilized supported lipid membrane microarrays for in vitro reconstitution of Ras signaling.
  • Employed biochemical assays to monitor Ras activation and deactivation.
  • Investigated the influence of SOS activator processivity and LAT scaffold protein condensation.

Main Results:

  • Successfully reconstituted a complete receptor-mediated Ras activation-deactivation reaction.
  • Demonstrated that Ras activation is bimodal, driven by SOS activator processivity, not deterministic bistability.
  • Showed that LAT scaffold protein condensation state controls the bimodal Ras response.
  • Observed stochastic bursts of Ras activation due to processivity-driven bimodality, even under deactivating conditions.

Conclusions:

  • Ras activation exhibits processivity-driven bimodality, distinct from deterministic bistability.
  • The condensation state of LAT is a critical regulator of Ras signaling dynamics.
  • This unique activation mechanism may confer resistance to pharmacological interventions targeting Ras pathways.