Integrator orchestrates RAS/ERK1/2 signaling transcriptional programs

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.