Abstract

The Ras family small GTPases are molecular switch involved in controlling a wide range of cellular activities, including proliferation, growth, morphology, migration, intracellular trafficking, nuclear import/export. Post-translational modifications of the C-terminal CAAX motif are important for membrane association and biological functions of many Ras family proteins. Of particular importance is the isoprenylation of C-terminal cysteine in the CAAX motif. Isoprenylation is also present in many other proteins and is essential for their cellular functions. GCN2 is a multi-domain protein kinase involved in nutrient sensing and translation regulation. Our preliminary studies indicate that GCN2 affects the post-translational modifications of Ras and Rheb. The major goal of this proposal is to determine the molecular mechanism of GCN2 in regulation of the post-translational modifications and biological functions of the Ras family GTPases. Biochemical, cell biological, and genetic approaches will be used to achieve our goals.

Public Health Relevance

Ras is the most frequently mutated oncogene in human cancer. The Ras family GTPases regulate normal cell growth but dysregulation can cause diseases, such as cancer. Our goal is to understand how Ras function is regulated. These studies may lead to new therapeutic treatment for cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062694-12
Application #
7876671
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Maas, Stefan
Project Start
2000-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
12
Fiscal Year
2010
Total Cost
$290,615
Indirect Cost

  Institution

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

  Publications

Russell, Ryan C; Tian, Ye; Yuan, Haixin et al. (2013) ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 15:741-50
Zheng, Min; Wang, Yan-Hai; Wu, Xiao-Nan et al. (2011) Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1. Nat Cell Biol 13:263-72
Russell, Ryan C; Fang, Chong; Guan, Kun-Liang (2011) An emerging role for TOR signaling in mammalian tissue and stem cell physiology. Development 138:3343-56
Kang, Y J; Lu, M-K; Guan, K-L (2011) The TSC1 and TSC2 tumor suppressors are required for proper ER stress response and protect cells from ER stress-induced apoptosis. Cell Death Differ 18:133-44
Xie, Xiaoduo; Zhang, Denghong; Zhao, Bin et al. (2011) IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A 108:6474-9
Kim, Joungmok; Guan, Kun-Liang (2011) Amino acid signaling in TOR activation. Annu Rev Biochem 80:1001-32
Kim, Joungmok; Kundu, Mondira; Viollet, Benoit et al. (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132-41
Wang, Chenran; Yoo, Youngdong; Fan, Huaping et al. (2010) Regulation of Integrin ? 1 recycling to lipid rafts by Rab1a to promote cell migration. J Biol Chem 285:29398-405
Li, Li; Kim, Eunjung; Yuan, Haixin et al. (2010) Regulation of mTORC1 by the Rab and Arf GTPases. J Biol Chem 285:19705-9
Alexander, Angela; Cai, Sheng-Li; Kim, Jinhee et al. (2010) ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci U S A 107:4153-8

Showing the most recent 10 out of 16 publications