The Hippo tumor suppressor pathway functions to limit tissue growth and organ size by inhibiting proliferation and inducing apoptosis. Dysregulation of the Hippo pathway contributes to tumorigenesis. The key downstream effectors of the Hippo pathway are the transcription co-activator YAP, which is phosphorylated and inhibited by the Hippo pathway kinase Lats. YAP overexpression and hyperactivation are found in human cancers. Extensive studies have identified many intracellular proteins that modulate the Hippo pathway. However, key questions regarding the extracellular signals and cell surface receptors for the Hippo pathway have not been addressed. We recently discovered that G-protein coupled receptors (GPCR) and their cognate ligands regulate the Hippo pathway. GPCR modulates many intracellular signaling molecules including protein kinase A (PKA) and protein kinase C (PKC). PKA is activated by cAMP, a second messenger that is elevated by stimulation of Gs-coupled receptor. PKC is activated by diacylglycerol that is also a second messenger elevated by Gq/11- coupled receptors. Both PKA and PKC are involved in a wide range of cellular regulation, including gene expression and cell growth. Our preliminary studies reveal that PKA and PKC potently modulate YAP. PKA inhibits YAP by increasing phosphorylation while PKC activates YAP by inducing dephosphorylation. The long- term goal of this project is to elucidate the mechanism of YAP regulation by PKA and PKC, to understand the regulation and function of the Hippo-YAP pathway in cell growth, organ size, tumorigenesis and cancer metastasis, and to provide potential therapeutic targets for cancer treatment.

Public Health Relevance

The Hippo signaling pathway plays a major role in organ size regulation and has also been implicated in human cancer. Our preliminary data indicate that YAP phosphorylation is stimulated by PKA and inhibited by PKC, therefore leading to YAP inhibition and activation, respectively. The goals of this proposal are to understand the mechanism of regulation and function of YAP in PKA and PKC signaling, and to elucidate the pathological functions of YAP in promoting tumorigenesis and cancer metastasis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular and Integrative Signal Transduction Study Section (MIST)
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Watson, Joanna M
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Zhang, Qian; Meng, Fansen; Chen, Shasha et al. (2017) Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade. Nat Cell Biol 19:362-374
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Zha, Zhengyu; Han, Xiao-Ran; Smith, Matthew D et al. (2016) Hypertension-associated C825T polymorphism impairs the function of G?3 to target GRK2 ubiquitination. Cell Discov 2:16005
Hansen, Carsten Gram; Ng, Yuen Lam Dora; Lam, Wai-Ling Macrina et al. (2015) The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1. Cell Res 25:1299-313
Hansen, Carsten Gram; Moroishi, Toshiro; Guan, Kun-Liang (2015) YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol 25:499-513
Meng, Zhipeng; Moroishi, Toshiro; Mottier-Pavie, Violaine et al. (2015) MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat Commun 6:8357
Yu, Fa-Xing; Meng, Zhipeng; Plouffe, Steven W et al. (2015) Hippo pathway regulation of gastrointestinal tissues. Annu Rev Physiol 77:201-27
Yang, Hui; Zhou, Lisha; Shi, Qian et al. (2015) SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth. EMBO J 34:1110-25
Liu, G; Yu, F-X; Kim, Y C et al. (2015) Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the Hippo pathway. Oncogene 34:3536-46

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