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RAS ubiquitylation modulates effector interactions.

Ryan Thurman1, Edhriz Siraliev-Perez1, Sharon L Campbell1,2

  • 1Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.

Small Gtpases
|November 30, 2017
PubMed
Summary
This summary is machine-generated.

Monoubiquitylation of KRAS (mUbRAS) enhances RAS activation by impairing GTPase activating protein (GAP) function. This modification alters RAS effector interactions, potentially promoting RAF-MAPK signaling independently of nucleotide binding.

Keywords:
RAS GTPaseallosteryeffectorsignal transductionubiquitylation

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Area of Science:

  • Cellular biology
  • Molecular oncology
  • Signal transduction

Background:

  • RAS proteins are key regulators of cell growth, cycling between GTP-bound active and GDP-bound inactive states.
  • Post-translational modifications, including ubiquitylation, modulate RAS protein function.
  • Monoubiquitylation of KRAS at lysine 147 (mUbRAS) has been linked to enhanced RAS activation and signaling through RAF and PI3K pathways.

Purpose of the Study:

  • To investigate how mUbRAS affects RAS binding to downstream effectors.
  • To determine the impact of mUbRAS on RAS-mediated transformation and signaling pathways.

Main Methods:

  • Chemical ubiquitylation of KRAS at residue 147.
  • Characterization of mUbRAS binding to RAS Binding Domains (RBDs) of CRAF, PI3Kcγ, and RALGDS.
  • Assessment of binding affinities in the presence of GTP or GDP.

Main Results:

  • mUbRAS showed decreased binding (7-10-fold) to CRAF RBD, PI3Kcγ, and RALGDS RBD compared to non-ubiquitylated KRAS.
  • Intriguingly, mUbRAS exhibited significantly enhanced binding (>40-fold) to the CRAF RBD when KRAS was bound to GDP.
  • mUbRAS impairs RAS binding to the p120 GAP catalytic domain, mimicking oncogenic mutations.

Conclusions:

  • mUbRAS promotes RAS activation through a defect in GAP-mediated downregulation.
  • mUbRAS facilitates RAF association and MAPK signaling in a nucleotide-independent manner.
  • Monoubiquitylation at KRAS lysine 147 may contribute to tumorigenesis by enhancing downstream signaling and transformation.