Differentiated epithelial cells are characterized by an apical-basolateral polarity and specialized cell-cell contacts. Depolarization, loss of adhesiveness and invasion of epithelial cells occur in normal processes (i.e. organ development and remodeling, wound healing) and in a deregulated manner during carcinogenesis.
Simple epithelia are organized into sheets of contiguous cells that cover surfaces of organs to separate external from internal compartments. Junctional complexes such as adherens and tight junctions promote cell-cell adhesion. Epithelial cells exhibit a structural asymmetry of the cytoplasm and the plasma membrane is compartmentalized into distinct apical and basolateral domains with characteristic lipid and protein compositions.
Newly synthesized proteins are sorted at the trans-Golgi network into distinct
carrier vesicles for delivery either to the apical or basolateral cell surface,
or to endosomes/lysosomes. In the endocytic route, internalized proteins are either recycled back to the surface of internalization (apical or basolateral),
transported across the cell to the opposite plasma membrane domain (transcytosis),
or delivered to endosomes/lysosomes. Targeting of proteins to the basolateral surface requires specific sorting signals in the form of short
amino acid sequences in their cytosolic domain. This group have shown that AP-4,
a protein complex related to clathrin adaptors, interacts with basolateral sorting
signals. Depletion of endogenous AP-4 in MDCK cells using an antisense approach
results in the missorting of several basolateral proteins to the apical domain,
consistent with a role of AP-4 in basolateral sorting. The lab is also studying
epithelial receptors for IgG which mediate the transport of IgG across different
epithelia (i.e. the small intestine, the mammary gland and the placental syncytiotrophoblast)
and which are critical for fetal and neonatal immunity and the maintenance of
IgG homeostasis.
Tight junctions (TJ) restrict the diffusion of membrane proteins and certain lipids from the apical to the basolateral plasma membrane domain and vice versa. Furthermore, they mediate adhesion between neighboring cells and regulate the paracellular permeability of the epithelial monolayer. TJ may also be involved in signal transduction events. Dr. Hunziker and colleagues recently showed that the PDZ-domains of the TJ protein zonula occludens-1 (ZO-1) can induce the conversion of epithelial MDCKI cells into tumorigenic, fibroblastoid cells via the activation of the transcriptional activity of b-catenin, a downstream component of the Wnt-signaling pathway. Wnt-signaling plays a role in modulating epithelial cell polarity in normal processes (i.e. organ development and remodeling, wound healing) and its deregulation promotes carcinogenesis.
The group expects to obtain insights into cancer development by understanding
how epithelial cell polarity is regulated.