Research in my lab focuses on the molecular mechanisms regulating the cell polarity. Specifically, epithelial cells develop apical-basal polarity by partitioning the cell surface into distinct apical and basolateral domains through polarized formation of cell junctions. Establishing and maintaining apical-basal polarity is crucial for the function and structure of epithelia, while disruption of such polarity often accompanies the malignant transformation or stress-induced damage of epithelial cells.
To date a dozen of so-called "polarity proteins" have been identified for their conserved and essential roles in regulating the cell polarity in both vertebrates and invertebrates. A key feature of these polarity proteins is that they must localize to specific apical or basolateral membrane domains to regulate cell polarity, a process generally assumed to be achieved by physical interactions with other polarity proteins or cytoskeleton etc. However, we recently discovered that polarity protein Lgl is targeted to plasma membrane through direct binding between its positively charged polybasic domain and the negative charged inositol phospholipids PIP2 and PI4P on the plasma membrane. Using both Drosophila and cultured mammalian cells as model systems, we are investigating how direct interactions between polarity proteins and plasma membrane lipids may act as a crucial molecular mechanism regulating the subcellular localizations and functions of polarity proteins. The ongoing projects focus on:
1) Mechanisms regulating the polarized membrane targeting of polarity proteins: Direct binding between Lgl and plasma membrane would localize Lgl to both apical and basolateral membrane domain, rather than exclusively to the basolateral domains. Thus, additional molecular mechanisms must function to fine tune the membrane targeting of polarity proteins. For instance, we are investigating how Lgl membrane targeting is spatially regulated through phosphorylation of Lgl by polarity protein complex aPKC/Par-6.
2) Role of phospholipids in regulating cell polarity: our discovery that hypoxia acutely and reversibly inhibits Lgl plasma membrane targeting through depleting membrane phospholipids suggests that phospholipid turn-over dynamics and homeostasis play significant role to conserve cell polarity and promote cell survival under cellular stress such as hypoxia/ischemia.
3) Plasma membrane targeting of polarity proteins in tumorigenesis: many polarity proteins, such as Lgl, also function as tumor suppressors. Loss of Lgl membrane targeting is a hallmark in both Drosophila and human tumor cells. We are investigating the mechanism contribute to loss of membrane targeting of polarity proteins and progressive disruption of cell polarity during tumorigenesis.
To carry out the above projects, we have developed genomic engineering tools that allow efficient generation of knock-in alleles of Drosophila genes. We have also developed comprehensive imaging tools for visualizing the dynamic subcellular localizations of polarity proteins under various physiological conditions including hypoxia.
University of Pittsburgh
Department of Cell Biology