Keith E. Mostov
Professor and Vice Chairman
Department of Anatomy, Box 0452
University of California, San Francisco
San Francisco, CA 94143
1989 Searle Scholar
The Molecular Basis of Cell Polarity
All eukaryotic cells have a complex three dimensional organization.As a model system we are studying a simple cell type, epithelialcells, which form a layer lining a surface or cavity. The plasmamembrane of epithelial cells is divided into two surface: an apicalsurface facing the outside world, and a basolateral surface facingother cells and connective tissue. These two plasma membrane domainshave completely different protein compositions. To understandcell polarity we are studying how membrane proteins are sent tothe correct surface. Recent evidence suggests that the principlesunderlying these polarized sorting process apply generally toother cell types, such as neurons. As a model protein we are usingthe polymeric immunoglobulin receptor (pIgR), which transportsimmunoglobulins across epithelial cells. This protein makes twopolarized sorting decisions. Newly made pIgR travels through theGolgi and trans-Golgi network (TGN), where it is sorted into vesiclesthat deliver it to the basolateral surface. At that surface thepIgR is endocytosed into endosomes, where it is sorted into vesiclesthat transcytose it to the apical surface. Transcytosis is theonly universal pathway for apical delivery.
Basolateral sorting in the TGN is determined by a 17 amino acidsignal, whose central feature is a b turn. Mutations that disruptbasolateral sorting from the TGN also block basolateral sortingin endosomes, suggesting that the sorting signals and machineryoperating in the TGN and endosomes are similar or identical. Weare now using the two hybrid system and cross-linking to identifyproteins that interact with this signal and may be part of thesorting machinery.
Binding of the ligand, IgA, stimulates transcytosis by causingtyrosine phosphorylation of phospholipase C, with production ofinositol phosphates (IP3) and activation of protein kinase C (PKC).Activation of PKC, particularly the a and e isozymes, stimulatestranscytosis by acting on a vesicular coat protein. The IP3 causesa rise in intracellular Ca+2, which activates calmodulin. Ca+2-calmodulinbinds with high affinity to the basolateral targeting signal ofthe pIgR. In the absence of IgA binding, a basolateral targetingprotein binds to the basolateral targeting signal on the pIgRand causes the pIgR to be continually sent to the basolateralsurface. IgA binding to the pIgR leads to a Ca+2 increase, whichcauses calmodulin to bind to the basolateral targeting signal,thereby preventing it from interacting with the basolateral targetingprotein and allowing the pIgR to be transcytosed.
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