ABSTRACT
The Hippo pathway plays a major role in organ size control, and its dysregulation contributes to tumorigenesis. The major downstream effectors of the Hippo pathway are the YAP/TAZ transcription co-activators, which are phosphorylated and inhibited by the Hippo pathway kinase LATS1/2. Here, we report a novel mechanism of TAZ regulation by the tight junction protein PARD3. PARD3 promotes the interaction between PP1A and LATS1 to induce LATS1 dephosphorylation and inactivation, therefore leading to dephosphorylation and activation of TAZ. The cytoplasmic, but not the tight junction complex associated, PARD3 is responsible for TAZ regulation. Our study indicates a potential molecular basis for cell growth-promoting function of PARD3 by modulating the Hippo pathway signaling in response to cell contact and cell polarity signals.
Subject(s)
Cell Cycle Proteins/metabolism , Cell Proliferation , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Phosphoprotein Phosphatases/metabolism , Protein Serine-Threonine Kinases/genetics , Adaptor Proteins, Signal Transducing , Cell Cycle Proteins/genetics , Cell Line, Tumor , Cell Polarity , Gene Expression Regulation , HEK293 Cells , Hippo Signaling Pathway , Humans , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Phosphorylation , Signal Transduction , Tight Junction Proteins/genetics , Trans-Activators , Transcription Factors , Transcriptional Coactivator with PDZ-Binding Motif ProteinsABSTRACT
The G protein-coupled estrogen receptor (GPER) mediates both the genomic and nongenomic effects of estrogen and has been implicated in breast cancer development. Here, we compared GPER expression in cancerous tissue and adjacent normal tissue in patients with invasive ductal carcinoma (IDC) of the breast and determined that GPER is highly upregulated in cancerous cells. Additionally, our studies revealed that GPER stimulation activates yes-associated protein 1 (YAP) and transcriptional coactivator with a PDZ-binding domain (TAZ), 2 homologous transcription coactivators and key effectors of the Hippo tumor suppressor pathway, via the Gαq-11, PLCß/PKC, and Rho/ROCK signaling pathways. TAZ was required for GPER-induced gene transcription, breast cancer cell proliferation and migration, and tumor growth. Moreover, TAZ expression positively correlated with GPER expression in human IDC specimens. Together, our results suggest that the Hippo/YAP/TAZ pathway is a key downstream signaling branch of GPER and plays a critical role in breast tumorigenesis.