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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA132809-06
Application #
8501889
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Watson, Joanna M
Project Start
2008-04-08
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
6
Fiscal Year
2013
Total Cost
$311,976
Indirect Cost
$110,701
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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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
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Wang, Pu; Wu, Jing; Ma, Shenghong et al. (2015) Oncometabolite D-2-Hydroxyglutarate Inhibits ALKBH DNA Repair Enzymes and Sensitizes IDH Mutant Cells to Alkylating Agents. Cell Rep 13:2353-2361
Park, Hyun Woo; Kim, Young Chul; Yu, Bo et al. (2015) Alternative Wnt Signaling Activates YAP/TAZ. Cell 162:780-94
Zha, Zhengyu; Han, Xiaoran; Smith, Matthew D et al. (2015) A Non-Canonical Function of G? as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation. Mol Cell 58:794-803
Taniguchi, Koji; Wu, Li-Wha; Grivennikov, Sergei I et al. (2015) A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519:57-62
Moroishi, Toshiro; Park, Hyun Woo; Qin, Baodong et al. (2015) A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev 29:1271-84

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