The eukaryotic plasma membrane forms a crucial interface between the cell and the external milieu. Rather than a simple homogeneous mixture of components, the plasma membrane is a complex dynamic heterogeneous structure. The origins of this heterogeneity are diverse and include several thousand species of lipid, compartmentalization by a sub-membrane actin cytoskeleton and the lateral assembly of sphingolipids and cholesterol. The overall aim of this research program is to dissect the function and composition of specific plasma membrane assemblies, including Ras signaling domains and caveolae, herein referred to as nanodomains. Caveolae are cell surface pits which are an abundant feature of mammalian cells. Caveolae have been implicated in signal transduction, lipid regulation, endocytosis, and mechanosensation. Caveolae dysfunction has been linked to cell transformation and to muscle disease. Ras proteins operate as molecular switches in many signal transduction pathways and are frequently mutated in human tumors. Different Ras isoforms occupy, distinct, non-overlapping nanodomains of the cell surface.
The aims of this project are to map structural components of Ras nanodomains and caveolae that are involved in the formation and function of these domains. The dynamic association of Ras isoforms with specific plasma membrane nanodomains will be dissected using a combination of novel electron and light microscopic methods, biochemical techniques, functional assays and by modeling in silico. The molecular mechanisms involved in caveolae formation will also be investigated. Newly identified components implicated in caveolae formation will be characterized in detail in order to understand how these components contribute to caveolae formation and caveolae function. These studies will provide new insights into fundamental aspects of membrane organization in eukaryotic cells and will lead to a new molecular understanding of the plasma membrane, relevant to numerous human diseases.

Public Health Relevance

This project seeks to understand how the surface of cells is organized at the molecular level. The proposed research will provide new insights into the way in which proteins and lipids come together to generate assemblies that have a crucial role in vital cellular processes such as the regulation of cell growth, a process perturbed in cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066717-07
Application #
8021000
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Chin, Jean
Project Start
2003-08-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
7
Fiscal Year
2011
Total Cost
$372,971
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Gambin, Yann; Ariotti, Nicholas; McMahon, Kerrie-Ann et al. (2014) Single-molecule analysis reveals self assembly and nanoscale segregation of two distinct cavin subcomplexes on caveolae. Elife 3:e01434
Zhou, Yong; Liang, Hong; Rodkey, Travis et al. (2014) Signal integration by lipid-mediated spatial cross talk between Ras nanoclusters. Mol Cell Biol 34:862-76
Ariotti, Nicholas; Fernández-Rojo, Manuel A; Zhou, Yong et al. (2014) Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling. J Cell Biol 204:777-92
Zhang, Feng; Wang, Ziqing; Lu, Maryia et al. (2014) Temporal production of the signaling lipid phosphatidic acid by phospholipase D2 determines the output of extracellular signal-regulated kinase signaling in cancer cells. Mol Cell Biol 34:84-95
Zhou, Yong; Maxwell, Kelsey N; Sezgin, Erdinc et al. (2013) Bile acids modulate signaling by functional perturbation of plasma membrane domains. J Biol Chem 288:35660-70
Cho, Kwang-Jin; Hancock, John F (2013) Ras nanoclusters: a new drug target? Small GTPases 4:57-60
Hocker, Harrison J; Cho, Kwang-Jin; Chen, Chung-Ying K et al. (2013) Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function. Proc Natl Acad Sci U S A 110:10201-6
Cho, Kwang-Jin; Park, Jin-Hee; Hancock, John F (2013) Staurosporine: A new tool for studying phosphatidylserine trafficking. Commun Integr Biol 6:e24746
Collins, Brett M; Davis, Melissa J; Hancock, John F et al. (2012) Structure-based reassessment of the caveolin signaling model: do caveolae regulate signaling through caveolin-protein interactions? Dev Cell 23:11-20
Janosi, Lorant; Li, Zhenlong; Hancock, John F et al. (2012) Organization, dynamics, and segregation of Ras nanoclusters in membrane domains. Proc Natl Acad Sci U S A 109:8097-102

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