Journal Article

RAC-LATS1/2 signaling regulates YAP activity by switching between the YAP-binding partners TEAD4 and RUNX3

Bae, S-C, Chi, X-Z, Kim, D-M, Min, B, Choi, B-Y, Lee, J-Y, Jang, J-W, Lee, J-W, Kim, M-K, Lee, Y-S, Song, S-H

2017

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/95 / 38 / 38/1 / 42 / 631/67/395 / 631/80/86/2368 / 64/24 / 64/60 / 96 / Adaptor Proteins, Signal Transducing - genetics / Adaptor Proteins, Signal Transducing - metabolism / Analysis / Animals / Apoptosis / Biomarkers, Tumor / Carcinogenesis / Cell Biology / Cell cycle / Cell fate / Cell Nucleus - genetics / Cell Nucleus - metabolism / Cell Proliferation / Core Binding Factor Alpha 3 Subunit - genetics / Core Binding Factor Alpha 3 Subunit - metabolism / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Drosophila / Drosophila - genetics / Drosophila - growth & development / Drosophila - metabolism / Drosophila Proteins - genetics / Drosophila Proteins - metabolism / Ectopic expression / Epithelial cells / Gastric cancer / Gene Expression Regulation, Neoplastic / Genetic aspects / Genetic regulation / Genetics / Guanine Nucleotide Exchange Factors - genetics / Guanine Nucleotide Exchange Factors - metabolism / Human Genetics / Humans / Internal Medicine / Kinases / Male / Medicine / Medicine & Public Health / Mice / Mice, Nude / Muscle Proteins - genetics / Muscle Proteins - metabolism / Oncology / original-article / Phenotypes / Phosphoproteins - genetics / Phosphoproteins - metabolism / Phosphorylation / Protein-Serine-Threonine Kinases - genetics / Protein-Serine-Threonine Kinases - metabolism / Proto-Oncogene Proteins c-akt - genetics / Proto-Oncogene Proteins c-akt - metabolism / Runx3 protein / Signal Transduction / Stomach Neoplasms - genetics / Stomach Neoplasms - metabolism / Stomach Neoplasms - pathology / Trans-Activators / Transcription Factors - genetics / Transcription Factors - metabolism / Tumor Cells, Cultured / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism / Tumorigenicity / Tumors / Xenograft Model Antitumor Assays / Yes-associated protein