Caveolae are well-known membrane domains found on the surface of most cells that are defined in part by a flask-shaped morphology, a filamentous coat on the cytoplasmic surface composed of caveolin and a high concentration of cholesterol relative to surrounding membrane. Caveolae engage in a distinctive endocytic activity capable of carrying molecules to the cytoplasm, to special endosomal compartments and to the ER. This domain is also critical for infection by pathogenic viruses and bacteria. Now that the caveolae pathway is better defined, important questions arise about the mechanism of invagination, budding and traffic, how caveolae achieve their unique protein and lipid composition, and the machinery involved in supplying structural lipids like cholesterol. This proposal outlines projects to address these three issues. The first project focuses on the mechanism of caveolae internalization. We have identified a new family of resident caveolae proteins that appear to regulate the internalization machinery by linking different isoforms of PKC to caveolin-1 and the internalization machinery. Experiments are planned to define how these caveolin adapters regulate internalization and identify the molecules involved. Caveolae contain a unique set of proteins that includes tyrosine kinase receptors and GPI anchored proteins.
In aim 2, we will look at three potential mechanisms for controlling the localization of proteins to caveolae. One mechanism we will explore is based on recent findings that proteins surrounded by a lipid shell composed of cholesterol and sphingolipid are specifically retained by caveolae. Recently we found that PDGF stimulates the ubiquitination of PDGFRB in caveolae, so experiments are planned to determine the role of ubiquitination in controlling the exit of PDGFRB from caveolae. In addition, we will determine if retention of proteins in caveolae is controlled by extramembrane and intramembrane proteolysis.
The third aim will focus on identifying the machinery that supplies cholesterol to caveolae and the mechanism cells use to sense the amount of cholesterol in caveolae and regulate delivery. These studies will focus on three proteins that have been implicated in maintaining caveolae cholesterol: caveolin, the cholesterol sensing molecule SR-BI and the cholesterol-regulated scaffolding protein OSBP. A better understanding of basic caveolae biology may lead to new strategies for treating human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Ainsztein, Alexandra M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Sw Medical Center Dallas
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Hernandez, Victor J; Weng, Jian; Ly, Peter et al. (2013) Cavin-3 dictates the balance between ERK and Akt signaling. Elife 2:e00905
Lee, Sungsoo; Wang, Ping-Yuan; Jeong, Yangsik et al. (2012) Sterol-dependent nuclear import of ORP1S promotes LXR regulated trans-activation of apoE. Exp Cell Res 318:2128-42
Mundy, Dorothy I; Li, Wei Ping; Luby-Phelps, Katherine et al. (2012) Caveolin targeting to late endosome/lysosomal membranes is induced by perturbations of lysosomal pH and cholesterol content. Mol Biol Cell 23:864-80
Asterholm, Ingrid Wernstedt; Mundy, Dorothy I; Weng, Jian et al. (2012) Altered mitochondrial function and metabolic inflexibility associated with loss of caveolin-1. Cell Metab 15:171-85
James, Christopher N; Horn, Patrick J; Case, Charlene R et al. (2010) Disruption of the Arabidopsis CGI-58 homologue produces Chanarin-Dorfman-like lipid droplet accumulation in plants. Proc Natl Acad Sci U S A 107:17833-8
McMahon, Kerrie-Ann; Zajicek, Hubert; Li, Wei-Ping et al. (2009) SRBC/cavin-3 is a caveolin adapter protein that regulates caveolae function. EMBO J 28:1001-15
Zehmer, John K; Bartz, Rene; Bisel, Blaine et al. (2009) Targeting sequences of UBXD8 and AAM-B reveal that the ER has a direct role in the emergence and regression of lipid droplets. J Cell Sci 122:3694-702
Zehmer, John K; Huang, Youguo; Peng, Gong et al. (2009) A role for lipid droplets in inter-membrane lipid traffic. Proteomics 9:914-21
Zehmer, John K; Bartz, Rene; Liu, Pingsheng et al. (2008) Identification of a novel N-terminal hydrophobic sequence that targets proteins to lipid droplets. J Cell Sci 121:1852-60
Wang, Ping-Yuan; Weng, Jian; Lee, Sungsoo et al. (2008) The N terminus controls sterol binding while the C terminus regulates the scaffolding function of OSBP. J Biol Chem 283:8034-45

Showing the most recent 10 out of 49 publications