The Hippo tumor suppressor pathway plays a crucial role in regulating organ size by inhibiting cell proliferation and promoting apoptosis, and limitin stem/progenitor cell self- renewal and expansion. The YAP/TAZ transcription co-activators are the major downstream effectors of the Hippo pathway. Despite extensive studies, upstream signals regulating the Hippo pathway are unknown. Currently, no extracellular ligand or cell surface receptor has been identified to regulate the mammalian Hippo-YAP. Our preliminary studies have discovered that lysophosphatidic acid (LPA) and sphingosine 1- phosphophate (S1P) are important signaling molecules that regulating the Hippo pathway. LPA and S1P act through their respective G-protein coupled receptors (GPCRs) to activate YAP. Both LPA and S1P have been implicated in cancer development and metastasis. Notably, activating mutations of Gq/11 are frequently found (83%) in uveal melanoma, which is the most common intraocular tumor in the eye with strong propensity of metastasis into the liver. Our preliminary study showed that active Gq/11 potently stimulates YAP activity. The major goals of this proposal are to investigate the mechanism of Hippo-YAP regulation by GPCR and to determine the functional significance of YAP/TAZ activation in the biology of LPA, S1P and other extracellular signals. Moreover, we will investigate the pathophysiological function of YAP/TAZ activation in the development of uveal melanoma and aim to provide scientific basis for treatment of this disease.

Public Health Relevance

The Hippo signaling pathway plays a major role in organ size regulation by controlling cell number and has also been implicated in human cancer. Preliminary studies from the PI's laboratory have identified the first extracellular signals and cell surface receptors that regulate the Hippo pathway, and suggested a critical role of the Hippo pathway in uveal melanoma, which is the most common intraocular tumor in the eye. The goal of this proposal is to gain knowledge of Hippo-YAP pathway regulation and its role in uveal melanoma development.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022611-02
Application #
8529541
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Neuhold, Lisa
Project Start
2012-09-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$368,125
Indirect Cost
$130,625
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
Mo, Jung-Soon; Park, Hyun Woo; Guan, Kun-Liang (2014) The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep 15:642-56
Luk, John M; Guan, Kun-Liang (2014) An alternative DNA damage pathway to apoptosis in hematological cancers. Nat Med 20:587-8
Yu, Fa-Xing; Guan, Kun-Liang (2014) Transcription and processing: multilayer controls of RNA biogenesis by the Hippo pathway. EMBO J 33:942-4
Yu, Fa-Xing; Luo, Jing; Mo, Jung-Soon et al. (2014) Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25:822-30
Zhao, Bin; Guan, Kun-Liang (2014) Hippo pathway key to ploidy checkpoint. Cell 158:695-6