Mechanisms of Caveolae Membrane Traffic

Caveolae are lipid domains that are specialized for endocytosis as well as the compartmentalization of signal transduction at the cell surface. So far, caveolae have been found to participate in three types of endocytic pathways. One pathway is characterized by the formation of vesicles called cavicles that bud from the plasma membrane and travel on microtubules to endosomes deep within the cell. These Type I caveolae are able to carry cargo like viruses into the cell. A second caveolar pathway involves the cyclic budding and refusing of caveolae at the cell surface. These caveolae are specialized for delivering small molecules and ions to the cell. The final type of caveolae is one capable of forming tubules that extend several micrometers from the cell surface to the center of the cell. The function of Type 3 pathway is not known. Type I and II pathways are regulated by protein kinase C and tyrosine kinases, but the molecular machinery involved is not known.

Projects in the laboratory include:

1) identifying the molecules that mediate internalization
2) determining how caveolae become engaged in each type of endocytic pathway
3) establish the mechanism of cavicle targeting to specific endosomal compartments

Regulation of Receptor Clustering in Membrane Domains

The efficient operation of an endocytic pathway depends on the proper targeting of ligands to the site of endocytosis. Recent discoveries in or laboratory indicate that ligands can ride on receptors like the EGF receptor as it travels between caveolae and coated pits, suggesting that the receptors carry out domain specific functions. These findings raise the question of how the receptor is targeted to each domain, what is the stimulus that initiates movement and how does the receptor function at each site? Seeking the answers to these questions is a major goal of the laboratory.

The Structure and Function of Adiposomes

Scientists have variously designated sites of lipid accumulation in cells as lipid droplets, lipid bodies, lipid inclusions, oil droplets and oil bodies, which reflects the view that these are simple lipid storage compartments. Recent proteomic and genetic evidence suggests, however, that these sites are metabolically active organelles with essential roles in cell signaling, membrane traffic and lipid homeostasis. Nearly all prokaryotic and eukaryotic cells have the molecular capability to store lipids. Moreover, sites of lipid accumulation are associated with specific membrane systems. In eukaryotic cells lipid accumulation appears to be associated with ER membrane while in prokaryotic cells special regions of the plasma membrane are involved. Therefore, cells appear to have special compartments that contain the molecules necessary to synthesize and degrade specific classes of lipids as well as manage the traffic of these lipids among membrane systems. For this reason, we have proposed the name adiposome to designate this specialized cellular compartment.

Ongoing projects in the laboratory include:

1) determine the function of Rab GTPases in adiposomes
2) map the regulatory machinery that controls lipid accumulation
3) identify new protein motifs that target proteins to adiposomes