Regulation of myosin activation during cell-cell contact formation by Par3-Lgl antagonism: entosis without matrix detachment.

Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
Molecular biology of the cell (Impact Factor: 5.98). 04/2012; 23(11):2076-91. DOI: 10.1091/mbc.E11-11-0940
Source: PubMed

ABSTRACT Cell-cell contact formation following cadherin engagement requires actomyosin contraction along the periphery of cell-cell contact. The molecular mechanisms that regulate myosin activation during this process are not clear. In this paper, we show that two polarity proteins, partitioning defective 3 homologue (Par3) and mammalian homologues of Drosophila Lethal (2) Giant Larvae (Lgl1/2), antagonize each other in modulating myosin II activation during cell-cell contact formation in Madin-Darby canine kidney cells. While overexpression of Lgl1/2 or depletion of endogenous Par3 leads to enhanced myosin II activation, knockdown of Lgl1/2 does the opposite. Intriguingly, altering the counteraction between Par3 and Lgl1/2 induces cell-cell internalization during early cell-cell contact formation, which involves active invasion of the lateral cell-cell contact underneath the apical-junctional complexes and requires activation of the Rho-Rho-associated, coiled-coil containing protein kinase (ROCK)-myosin pathway. This is followed by predominantly nonapoptotic cell-in-cell death of the internalized cells and frequent aneuploidy of the host cells. Such effects are reminiscent of entosis, a recently described process observed when mammary gland epithelial cells were cultured in suspension. We propose that entosis could occur without matrix detachment and that overactivation of myosin or unbalanced myosin activation between contacting cells may be the driving force for entosis in epithelial cells.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Distributing junctional components around the cell periphery is key for epithelial tissue morphogenesis and homeostasis. We discovered that positioning of dynamic microtubules controls the asymmetric accumulation of E-cadherin. Microtubules are oriented preferentially along the dorso-ventral axis in Drosophila melanogaster embryonic epidermal cells, and thus more frequently contact E-cadherin at dorso-ventral cell-cell borders. This inhibits RhoGEF2, reducing membrane recruitment of Rho-kinase, and increasing a specific E-cadherin pool that is mobile when assayed by fluorescence recovery after photobleaching. This mobile E-cadherin is complexed with Bazooka/Par-3, which in turn is required for normal levels of mobile E-cadherin. Mobile E-cadherin-Bazooka prevents formation of multicellular rosette structures and cell motility across the segment border in Drosophila embryos. Altogether, the combined action of dynamic microtubules and Rho signaling determines the level and asymmetric distribution of a mobile E-cadherin-Bazooka complex, which regulates cell behavior during the generation of a patterned epithelium.
    The Journal of Cell Biology 06/2013; 201(6):887-901. · 10.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although cell-in-cell structure was noted 100 years ago, the molecular mechanisms of 'entering' and the destination of cell-in-cell remain largely unclear. It takes place among the same type of cells (homotypic cell-in-cell) or different types of cells (heterotypic cell-in-cell). Cell-in-cell formation affects both effector cells and their host cells in multiple aspects, while cell-in-cell death is under more intensive investigation. Given that cell-in-cell has an important role in maintaining homeostasis, aberrant cell-in-cell process contributes to the etiopathology in humans. Indeed, cell-in-cell is observed in many pathological processes of human diseases. In this review, we intend to discuss the biological models of cell-in-cell structures under physiological and pathological status.
    Cell Death & Disease 01/2013; 4:e630. · 6.04 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Spindle positioning is believed to be governed by the interaction between astral microtubules and the cell cortex, and involve cortically anchored motor protein dynein. How dynein is recruited to and regulated at the cell cortex to generate forces on astral microtubules is not clear. Here, we show that LGN, a Gα(i)-binding protein that is critical for spindle positioning in different systems, associates withcytoplasmic dynein heavy chain (DYNC1H1) in a Gα(i)-regulated manner. LGN is required for the mitotic cortical localization of DYNC1H1, which, in turn, also modulates the cortical accumulation of LGN. Using FRAP analysis, we show that cortical LGN is dynamic and the turnover of LGN relies, at least partially, on astral microtubules and DYNC1H1. We provide evidence for dynein and astral microtubule-mediated transport of Gα(i)/LGN/NuMA complexfrom cell cortex to spindle poles and show that actin filaments counteract such transport by maintaining Gα(i)/LGN/NuMAand dynein at the cell cortex. Our results indicate that astral microtubules are required for establishing bipolar, symmetric cortical LGN distribution during metaphase.We propose that regulated cortical release and transport of LGN complex along astral microtubules may contribute to spindle positioning in mammalian cells.
    Molecular biology of the cell 02/2013; · 5.98 Impact Factor


Available from