title: RAC-LATS1/2 signaling regulates YAP activity by switching between the YAP-binding partners TEAD4 and RUNX3.
abstract: The tumor-suppressor RUNX3 has a critical role in a lineage determination, cell cycle arrest and apoptosis. Lozenge (Lz), a Drosophila homolog of mammalian RUNX family members, has integral roles in these processes and specifically in eye cell fate determination. To elucidate the genetic modifiers of Lz/RUNX3, we performed a large-scale functional screen in a fly mutant library. The screen revealed genetic interactions between the Lz, Rac and Hippo pathways. Analysis of interactions among these genes revealed that the defective phenotype resulting from activation of Yki, an end point effector of the Hippo pathway, was suppressed by Lz and enhanced by Rac-Trio. Molecular biological analysis using mammalian homologs reveled that LATS1/2-mediated YAP phosphorylation-facilitated dissociation of the YAP-TEAD4 complex and association of the YAP-RUNX3 complex. When cells were stimulated to proliferate, activated RAC-TRIO signaling inhibited LATS1/2-mediated YAP phosphorylation; consequently, YAP dissociated from RUNX3 and associated with TEAD, thereby replacing the YAP-RUNX3 complex with YAP-TEAD. RUNX3 contributed to both association and dissociation of YAP-TEAD complex, most likely through the formation of the YAP-TEAD-RUNX3 ternary complex. Ectopic expression of RUNX3 in MKN28 gastric cancer cells reduced tumorigenicity, and the tumor-suppressive activity of RUNX3 was associated with its ability to interact with YAP. These results identify a novel regulatory mechanism, mediated by the Hippo and RAC-TRIO pathways, that changes the binding partner of YAP.
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: J-W
authors.initials: JW
authors.lastname: Jang
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: M-K
authors.initials: MK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: J-W
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: D-M
authors.initials: DM
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Song
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: B-Y
authors.initials: BY
authors.lastname: Choi
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: B
authors.initials: B
authors.lastname: Min
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: X-Z
authors.initials: XZ
authors.lastname: Chi
authors.affiliation: Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, South Korea.
authors.forename: S-C
authors.initials: SC
authors.lastname: Bae
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000091262:TEA Domain Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D020662:Guanine Nucleotide Exchange Factors; D009124:Muscle Proteins; D010750:Phosphoproteins; C493729:Runx3 protein, human; D000091262:TEA Domain Transcription Factors; C486309:TEAD4 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C092745:LATS1 protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C099628:TRIO protein, human