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The Grb2 splice variant, Grb3-3, is a negative regulator of RAS activation

Caroline Seiler1, Amy K Stainthorp1, Sophie Ketchen1

  • 1School of Molecular and Cellular Biology, University of Leeds, Leeds, UK.

Communications Biology
|September 28, 2022
PubMed

Insights

A new GRB2 gene splice variant, Grb3-3, prevents RAS-MAPK pathway activation by sequestering Sos in the cytoplasm. This finding reveals a novel mechanism regulating cancer cell signaling and offers potential therapeutic targets.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Cancer research

Background:

  • RAS-MAPK pathway activation is critical for cell functions like proliferation and differentiation.
  • Receptor tyrosine kinases (RTKs) initiate this pathway by recruiting Grb2-Sos complexes to the plasma membrane for RAS interaction.
  • Dysregulation at this RTK convergence point is a major driver of various cancers.

Purpose of the Study:

  • To investigate the functional impact of the Grb3-3 splice variant of GRB2.
  • To elucidate the mechanism by which Grb3-3 affects RAS-MAPK signaling.
  • To explore the role of heterogenous nuclear riboproteins C1/C2 in Grb3-3 splicing and its expression in colon tissues.

Main Methods:

  • Analysis of Grb3-3 variant's interaction with Sos and its cellular localization.
  • Assessment of the Grb3-3-Sos complex's ability to engage with RAS.
  • Investigation of competition between Grb2 and Grb3-3 for Sos binding.
  • Examination of heterogenous nuclear riboproteins C1/C2's role in splicing.
  • Differential expression analysis of Grb3-3 in normal and malignant colon tissues.

Main Results:

  • The Grb3-3 variant, unable to bind RTKs, forms a cytoplasmic Grb3-3-Sos complex that cannot interact with RAS.
  • Competition between Grb2 and Grb3-3 for Sos binding modulates MAPK signaling.
  • Heterogenous nuclear riboproteins C1/C2 regulate Grb3-3 splicing.
  • Differential Grb3-3 expression is observed between normal and malignant colon tissues.

Conclusions:

  • Grb3-3 acts as a negative regulator of RAS-MAPK signaling by sequestering Sos in the cytoplasm.
  • Differential Grb3-3 expression in colon cancer suggests its involvement in tumorigenesis.
  • Understanding Grb3-3 regulation and function may provide new avenues for cancer therapy.

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