MRTF potentiates TEAD‐YAP transcriptional activity causing metastasis. (27th December 2016)

• Record Type: Journal Article
• Authors: Kim, Tackhoon; Hwang, Daehee; Lee, Dahye; Kim, Jeong‐Hwan; Kim, Seon‐Young; Lim, Dae‐Sik
• Is Part Of: EMBO journal. Volume 36:Number 4(2017)
• Page Start: 520
• Page End: 535
• Publication Date: 2016-12-27
• Subjects: cytoskeletal damage -- metastasis -- MRTF -- TEAD‐YAP; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201695137
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Yes‐associated protein (YAP) and myocardin‐related transcription factor (MRTF) play similar roles and exhibit significant crosstalk in directing transcriptional responses to chemical and physical extracellular cues. The mechanism underlying this crosstalk, however, remains unclear. Here, we show MRTF family proteins bind YAP via a conserved PPXY motif that interacts with the YAP WW domain. This interaction allows MRTF to recruit NcoA3 to the TEAD‐YAP transcriptional complex and potentiate its transcriptional activity. We show this interaction of MRTF and YAP is critical for LPA‐induced cancer cell invasion in vitro and breast cancer metastasis to the lung in vivo . We also demonstrate the significance of MRTF‐YAP binding in regulation of YAP activity upon acute actin cytoskeletal damage. Acute actin disruption induces nucleo‐cytoplasmic shuttling of MRTF, and this process underlies the LATS‐independent regulation of YAP activity. Our results provide clear evidence of crosstalk between MRTF and YAP independent of the LATS kinases that normally act upstream of YAP signaling. Our results also suggest a mechanism by which extracellular stimuli can coordinate physiological events downstream of YAP. Synopsis: Oncogenic activity of TEAD‐YAP transcription complex is enhanced by MRTF proteins, which recruit NcoA3. MRTF–YAP interaction highlights a novel mode of signal transduction that regulates YAP activity independently of subcellular localization. MRTF family proteins activate TEAD‐YAP by direct binding through PPXY–WW domain interaction. MRTF–YAP interaction is required for TEAD‐YAP target gene expression and promotion of cancer cell invasion and metastasis. MRTF binding to TEAD‐YAP recruits NcoA3 for full potentiation of TEAD‐YAP activity. MRTF–YAP interaction constitutes a LATS‐independent regulatory mechanism on TEAD‐YAP activity. Abstract : Crosstalk with transcription factor MRTF enhances TEAD‐YAP oncogenic activity, coordinating signal transduction of extracellular GPCR ligands involved in cancer cell invasion or actin cytoskeletal disruption.