Orthologues of the serine/threonine kinase Par-1, a polarity determinant in the C. elegans one-cell embryo, have been identified as microtubule (MT)-regulating proteins in several systems. We have established that the mammalian PAR1-homologue EMK1 promotes the development of a non-centrosomal, apico-basolateral MT-array in kidney (MDCK) and hepatic (WIFB) epithelial cells at the time they are undergoing polarization. This change in MT-organization is essential for the generation of epithelial lumina, likely because of a key role of MTs in polarized targeting of luminal proteins. Kidney and liver epithelial cells differ in their lumen polarity and in the mechanisms they use to target luminal proteins. Kidney cells (e.g.MDCK) generate apical lumina and target proteins directly from the Golgi to the apical surface while hepatocytes form lumina at cell-cell contact sites (bile canaliculi) and target their luminal markers proteins by transcytosis via the basolateral domain. We have conclusively demonstrated that EMK1 -overexpression induced the appearance of intercellular lumina and an indirect apical targeting mode in MDCK cells. Thus, EMK1 is the first protein assigned the role of regulating the developmental branching decision between the hepatic and columnar epithelial phenotypes. The goals of this proposal are 1. to gain insight into the signaling mechanisms that underlie the role of the EMK1 in epithelial MT- and lumen organization and 2. to elucidate the EMK1 -mediated differences in the apical protein trafficking pathways that contribute to different lumen polarity in kidney epithelia and hepatocytes.
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