Concerted localization-resets precede YAP-dependent transcription

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Yes-associated protein 1 (YAP) is a key transcriptional regulator.
• YAP plays critical roles in mechanotransduction, organ size control, and regeneration.

Purpose of the Study:

• To investigate the dynamics of YAP localization and its impact on target gene transcription.
• To understand the mechanisms controlling YAP activity and its dysregulation in cancer.

Main Methods:

• Real-time visualization of native YAP and target gene transcription dynamics.
• Utilized nascent-transcription reporter knock-ins.
• Analyzed YAP shuttling in normal and oncogenically-transformed cell lines.

Main Results:

• A cycle of rapid nuclear YAP export and reentry ('localization-resets') activates YAP target genes.
• These resets are triggered by calcium signaling, actomyosin contractility modulation, and mitosis.
• Oncogenically-transformed cells lack localization-resets and exhibit increased YAP nucleocytoplasmic shuttling.
• YAP activity is linked to nucleocytoplasmic exchange properties, not just nuclear enrichment.

Conclusions:

• Localization-resets are crucial for YAP-mediated transcriptional activation.
• Dysregulation of YAP compartmentalization control contributes to oncogenic transformation.
• YAP activity is regulated by dynamic nucleocytoplasmic exchange, offering new therapeutic targets.