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Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species

Ana Martín-Vega1,2, Laura Ruiz-Peinado1,2, Rocío García-Gómez1,2

  • 1Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC) - Universidad de Cantabria, Santander 39011, Spain.

Science Advances
|February 15, 2023
PubMed

Insights

Scaffold proteins KSR1 and IQGAP1 interact, enabling "trans-phosphorylation" in the RAS-ERK pathway. This cross-talk influences adipogenesis and drug responses, revealing new signaling regulation.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biochemistry

Background:

  • The RAS-ERK pathway is crucial for cellular processes and is regulated by scaffold proteins.
  • Existing models depict scaffold proteins as isolated units in linear signaling cascades.
  • Scaffold proteins like KSR1 and IQGAP1 are known to be involved in ERK pathway regulation.

Purpose of the Study:

  • To investigate the interaction between different scaffold proteins in the RAS-ERK pathway.
  • To explore the phenomenon of 'trans-phosphorylation' between scaffold-bound kinases.
  • To determine the functional significance of scaffold-scaffold interactions in biological processes and drug efficacy.

Main Methods:

  • Co-immunoprecipitation to detect protein-protein interactions.
  • In vitro kinase assays to measure phosphorylation events.
  • Cell-based assays to assess adipogenesis and drug-induced cytotoxicity.

Main Results:

  • KSR1 and IQGAP1 form a complex, facilitating cross-talk between scaffold-bound kinases.
  • MEK bound to IQGAP1 phosphorylates ERK docked on KSR1, termed 'trans-phosphorylation'.
  • ERK trans-phosphorylation is implicated in KSR1-mediated adipogenesis and the cytotoxicity of KSR inhibitors.

Conclusions:

  • Scaffold protein interactions and trans-phosphorylation represent a novel regulatory mechanism in the ERK cascade.
  • This finding broadens our understanding of signal transduction.
  • The identified interactions offer new avenues for designing scaffold protein-targeted therapeutics.

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