PARD3 induces TAZ activation and cell growth by promoting LATS1 and PP1 interaction
Xian-Bo Lv1, Chen-Ying Liu2, Zhen Wang1
1Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education and Department of Biochemistry and Molecular Biology Fudan University Shanghai Medical College, Shanghai, China Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai, China School of Life Science, Fudan University, Shanghai, China.
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.
Insights
The tight junction protein PARD3 activates TAZ, a key Hippo pathway effector, by promoting LATS1 kinase inactivation. This novel mechanism reveals PARD3
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- The Hippo pathway regulates organ size and is crucial in preventing tumorigenesis.
- YAP/TAZ transcription co-activators are key downstream effectors inhibited by Hippo kinase LATS1/2.
- Dysregulation of the Hippo pathway is linked to various cancers.
Purpose of the Study:
- To elucidate a novel mechanism of TAZ co-activator regulation.
- To investigate the role of the tight junction protein PARD3 in Hippo pathway signaling.
- To understand how PARD3 influences TAZ activity in response to cellular cues.
Main Methods:
- Investigated protein-protein interactions between PARD3, PP1A, and LATS1.
- Assessed the impact of PARD3 on LATS1 and TAZ phosphorylation states.
- Differentiated the roles of cytoplasmic versus tight junction-associated PARD3.
Main Results:
- PARD3 facilitates the interaction between protein phosphatase 1 (PP1A) and LATS1 kinase.
- This interaction leads to LATS1 dephosphorylation and inactivation.
- Consequently, TAZ is dephosphorylated and activated, promoting cell growth.
- Cytoplasmic PARD3, not junction-associated PARD3, mediates TAZ regulation.
Conclusions:
- PARD3 acts as a novel regulator of the Hippo-YAP/TAZ pathway.
- PARD3 modulates TAZ activity through LATS1 inactivation, influencing cell growth.
- This provides a molecular link between PARD3, cell contact, polarity, and Hippo signaling.
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