MRTF potentiates TEAD-YAP transcriptional activity causing metastasis

Area of Science:

• Cellular Biology
• Molecular Biology
• Cancer Research

Background:

• Yes-associated protein (YAP) and myocardin-related transcription factor (MRTF) are key regulators of cellular responses to extracellular cues.
• The precise mechanism of crosstalk between YAP and MRTF remains largely undefined.

Purpose of the Study:

• To elucidate the molecular mechanism underlying the crosstalk between YAP and MRTF.
• To investigate the functional significance of YAP-MRTF interaction in cancer progression and YAP regulation.

Main Methods:

• Co-immunoprecipitation assays to detect protein-protein interactions.
• Reporter assays to measure transcriptional activity.
• In vitro cell invasion assays and in vivo metastasis models in mice.
• Analysis of YAP and MRTF localization upon actin cytoskeletal disruption.

Main Results:

• MRTF directly binds YAP through a conserved PPXY motif interacting with the YAP WW domain.
• This interaction facilitates NcoA3 recruitment to the TEAD-YAP complex, enhancing transcriptional activity.
• The MRTF-YAP interaction is crucial for lysophosphatidic acid (LPA)-induced cancer cell invasion and breast cancer lung metastasis.
• Actin cytoskeletal disruption triggers MRTF nucleo-cytoplasmic shuttling, leading to LATS-independent YAP regulation.

Conclusions:

• A novel mechanism of YAP-MRTF crosstalk is identified, involving direct binding and potentiation of YAP transcriptional activity.
• This interaction plays a critical role in YAP-mediated cancer cell invasion and metastasis.
• MRTF-YAP binding offers a pathway for LATS-independent regulation of YAP activity in response to cytoskeletal changes.
• The findings reveal how extracellular stimuli can coordinate YAP-driven physiological events.