Understanding the basic mechanisms of cell growth regulation and how alteration of such regulatory networks leads to cancer is fundamentally important for understanding cancer development and designing new strategies for treating cancer. The mTORC1 and Hippo signaling pathways are two major pathways that control cell growth and tissue/organ homeostasis. mTORC1 is a central cell growth controller which promotes cell growth by stimulating biosynthesis and inhibiting autophagy. The Hippo tumor suppressor pathway limits tissue and organ size by inhibiting proliferation and stimulating apoptosis. Dysregulation of either pathway contributes to human cancer. As such, mTORC1 inhibitors have received FDA approval for cancer treatment and there is an intensive effort in searching for drugs that can target the Hippo pathway for cancer indication. Previous works from the PI have revealed the molecular mechanisms of mTORC1 regulation by growth factors and cellular energy status via AKT and AMPK, respectively. Amino acids are arguably the most important stimuli of mTORC1. The PI has also identified Rag GTPases as critical mediators of mTORC1 activation by amino acids. Despite rapid progress in the field, key issues in amino acid signaling to mTORC1, such as the nature of amino acid sensors, remain to be solved. One major goal of this R35 proposal is to elucidate the molecular mechanism of mTORC1 activation by amino acids. The Hippo pathway is an exciting emerging field. The PI's group has made key contributions in establishing the major framework of the Hippo pathway, including identification of upstream signals, the biochemical mechanism of YAP regulation, and demonstration of the YAP-TEAD transcription module. However, fundamental issues such as regulation of core Hippo pathway components, molecular basis of YAP in promoting oncogenesis, and physiological signals that control organ size are key open questions that have yet to be answered. The overall mission of this R35 proposal is to obtain a comprehensive molecular understanding of the mTORC1 and Hippo pathways under normal physiological conditions and to elucidate how dysregulation of these pathways contributes to tumorigenesis.

Public Health Relevance

The mTORC1 and Hippo signaling pathways are two major pathways that control cell and organ growth. The overall goal of this R35 proposal is to obtain a comprehensive molecular understanding of the mTORC1 and Hippo pathways under normal physiological conditions and how alterations of these pathways contribute to tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
1R35CA196878-01
Application #
8947756
Study Section
Special Emphasis Panel (ZCA1-GRB-I (M1))
Program Officer
Watson, Joanna M
Project Start
2015-08-05
Project End
2022-07-31
Budget Start
2015-08-05
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$414,749
Indirect Cost
$145,312
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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Meng, Zhipeng; Qiu, Yunjiang; Lin, Kimberly C et al. (2018) RAP2 mediates mechanoresponses of the Hippo pathway. Nature 560:655-660
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Li, Fu-Long; Liu, Jin-Ping; Bao, Ruo-Xuan et al. (2018) Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis. Nat Commun 9:508
Wang, Zhen; Liu, Peng; Zhou, Xin et al. (2017) Endothelin Promotes Colorectal Tumorigenesis by Activating YAP/TAZ. Cancer Res 77:2413-2423
Ma, Shenghong; Sun, Renqiang; Jiang, Bowen et al. (2017) L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration. Mol Cell Biol 37:
Ma, Xi; Zhang, Shen; He, Long et al. (2017) MTORC1-mediated NRBF2 phosphorylation functions as a switch for the class III PtdIns3K and autophagy. Autophagy 13:592-607

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