ABSTRACT
Polarized epithelia develop distinct cell surface domains, with the apical membrane acquiring characteristic morphological features such as microvilli. Cell polarization is driven by polarity determinants including the evolutionarily conserved partitioning-defective (PAR) proteins that are separated into distinct cortical domains. PAR protein segregation is thought to be a consequence of asymmetric actomyosin contractions. The mechanism of activation of apically polarized actomyosin contractility is unknown. Here we show that the Cdc42 effector MRCK activates myosin-II at the apical pole to segregate aPKC-Par6 from junctional Par3, defining the apical domain. Apically polarized MRCK-activated actomyosin contractility is reinforced by cooperation with aPKC-Par6 downregulating antagonistic RhoA-driven junctional actomyosin contractility, and drives polarization of cytosolic brush border determinants and apical morphogenesis. MRCK-activated polarized actomyosin contractility is required for apical differentiation and morphogenesis in vertebrate epithelia and Drosophila photoreceptors. Our results identify an apical origin of actomyosin-driven morphogenesis that couples cytoskeletal reorganization to PAR polarity signalling.
Subject(s)
Cell Membrane/enzymology , Cell Polarity , Epithelial Cells/enzymology , Myotonin-Protein Kinase/metabolism , Actomyosin/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Animals , Animals, Genetically Modified , Caco-2 Cells , Cell Cycle Proteins/metabolism , Cell Differentiation , Dogs , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/cytology , Drosophila melanogaster/enzymology , Genotype , Guanine Nucleotide Exchange Factors/metabolism , Humans , Madin Darby Canine Kidney Cells , Membrane Proteins/metabolism , Morphogenesis , Myosin Type II/metabolism , Myotonin-Protein Kinase/genetics , Phenotype , Photoreceptor Cells, Invertebrate/enzymology , Protein Kinase C/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , RNA Interference , Signal Transduction , Time Factors , Transfection , cdc42 GTP-Binding Protein/metabolismABSTRACT
Tight junctions are components of the junctional complex linking neighbouring epithelial cells and are important for barrier formation. Recent evidence suggests that tight junctions also participate in signal transduction mechanisms that regulate epithelial cell proliferation, gene expression, differentiation and morphogenesis. One important class of tight-junction-associated signal transduction mechanism is based on dual localisation of certain proteins both at junctions and in the nucleus. These proteins and their partners participate in various steps of gene expression, ranging from regulation of transcription and chromatin structure to mRNA processing and translation. In cancer tissues, their expression is often deregulated in a manner that suggests that tight junctions function as suppressors of proliferation and transformation.
