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Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs

Jingyin Yue1, Fan Lai1, Felipe Beckedorff1

  • 1Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.

Genes & Development
|October 7, 2017
PubMed

Insights

Integrator, a key complex in cellular signaling, acts downstream of the RAS-MEK-extracellular signal-related kinase (ERK1/2) pathway. Its depletion reduces cancer cell growth, suggesting Integrator as a potential therapeutic target for MAPK-driven cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Gene Regulation

Background:

  • Activating mutations in the mitogen-activated protein kinase (MAPK) cascade drive over 70% of human cancers.
  • While MAPK pathway components are well-studied, downstream transcriptional coactivators remain less understood.

Purpose of the Study:

  • To identify and characterize the key downstream coactivators coordinating the transcriptional response in the MAPK signaling pathway.
  • To investigate the role of the Integrator complex in MAPK-driven transcriptional regulation and cancer growth.

Main Methods:

  • Depletion of Integrator complex subunits using knockdown techniques.
  • Pharmacological inhibition of the MAPK pathway.
  • Analysis of gene expression changes and protein phosphorylation following epidermal growth factor (EGF) stimulation.
  • Comparison with the effects of Mediator complex subunit depletion.

Main Results:

  • Integrator depletion significantly reduces ERK1/2 transcriptional responsiveness and cancer cell growth in MAPK-mutated cancers.
  • Activated ERK1/2 phosphorylates INTS11, the Integrator catalytic subunit, upon EGF stimulation.
  • Integrator recruitment to immediate early genes and enhancers is abrogated by MAPK pathway inhibition.
  • Integrator depletion impacts MAPK-responsive genes more broadly than Mediator subunit depletion.

Conclusions:

  • The Integrator complex is a crucial transcriptional coactivator in the MAPK signaling pathway.
  • Integrator plays a significant role in the growth of human cancers with activating MAPK mutations, including those resistant to targeted therapies.
  • Integrator represents a promising downstream therapeutic target for treating MAPK-driven cancers.
Keywords:
ERK1/2IntegratorMAPK signaling pathwayepidermal growth factorimmediate early genes

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