Genome-wide RNA interference screening reveals a COPI-MAP2K3 pathway required for YAP regulation

Area of Science:

• Cell Biology
• Molecular Oncology
• Signal Transduction

Background:

• The transcriptional regulator YAP is crucial in development, regeneration, and tumorigenesis, typically regulated by the Hippo kinase cascade.
• Mechanisms controlling YAP activity in low-Hippo contexts remain largely unknown, representing a significant gap in understanding cancer biology.

Purpose of the Study:

• To identify novel regulators of YAP activity in a Hippo-null background using a genome-wide screen.
• To investigate the role of the coatomer protein complex I (COPI) in YAP regulation and its therapeutic implications in cancer.

Main Methods:

• Genome-wide RNA interference (RNAi) screen in a Hippo-null cell model.
• Analysis of YAP nuclear localization and activity.
• Investigating the link between COPI, MAP2K3, endoplasmic reticulum stress, and YAP phosphorylation.

Main Results:

• COPI is essential for YAP nuclear enrichment, revealing a dependency that sensitizes YAP-driven cancer cells to COPI disruption.
• MAP2K3 was identified as a key mediator of YAP inhibitory phosphorylation upon COPI subunit depletion.
• COPI malfunction triggers endoplasmic reticulum stress, linking COPI and MAP2K3 pathways.

Conclusions:

• COPI acts as a critical regulator of YAP activity independently of the Hippo pathway.
• Disruption of COPI presents a potential therapeutic vulnerability in YAP-driven cancers.
• YAP regulation by COPI may influence inflammatory responses, suggesting links to COPI-associated inflammatory diseases.