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 #
5R01CA132809-07
Application #
8627562
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
2014-03-01
Budget End
2015-02-28
Support Year
7
Fiscal Year
2014
Total Cost
$280,779
Indirect Cost
$99,631
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
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
Hong, Audrey W; Meng, Zhipeng; Guan, Kun-Liang (2016) The Hippo pathway in intestinal regeneration and disease. Nat Rev Gastroenterol Hepatol 13:324-37
Han, X-R; Zha, Z; Yuan, H-X et al. (2016) KDM2B/FBXL10 targets c-Fos for ubiquitylation and degradation in response to mitogenic stimulation. Oncogene 35:4179-90
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
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
Mo, Jung-Soon; Meng, Zhipeng; Kim, Young Chul et al. (2015) Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway. Nat Cell Biol 17:500-10
Moroishi, Toshiro; Hansen, Carsten Gram; Guan, Kun-Liang (2015) The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 15:73-79
Yu, Fa-Xing; Zhao, Bin; Guan, Kun-Liang (2015) Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. Cell 163:811-28
Ma, Shenghong; Jiang, Bowen; Deng, Wanglong et al. (2015) D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth. Oncotarget 6:8606-20
Plouffe, Steven W; Hong, Audrey W; Guan, Kun-Liang (2015) Disease implications of the Hippo/YAP pathway. Trends Mol Med 21:212-22

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