RESUMO
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.
Assuntos
Membrana Celular/enzimologia , Polaridade Celular , Células Epiteliais/enzimologia , Miotonina Proteína Quinase/metabolismo , Actomiosina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Animais Geneticamente Modificados , Células CACO-2 , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Cães , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/enzimologia , Genótipo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Células Madin Darby de Rim Canino , Proteínas de Membrana/metabolismo , Morfogênese , Miosina Tipo II/metabolismo , Miotonina Proteína Quinase/genética , Fenótipo , Células Fotorreceptoras de Invertebrados/enzimologia , Proteína Quinase C/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Transfecção , Proteína cdc42 de Ligação ao GTP/metabolismoRESUMO
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.
