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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Epithelial cells require attachment to the extracellular matrix (ECM) for survival. However, during tumour progression and metastasis, cancerous epithelial cells must adapt to and survive in the absence of ECM. During the past 20 years, several cellular changes, including anoikis, have been shown to regulate cell viability when cells become detached from the ECM. In this Opinion article, we review in detail how cancer cells can overcome or take advantage of these specific processes. Gaining a better understanding of how cancer cells survive during detachment from the ECM will be instrumental in designing chemotherapeutic strategies that aim to eliminate ECM-detached metastatic cells.
    Nature reviews. Cancer 08/2014; 14(9). DOI:10.1038/nrc3789 · 37.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Entosis, a cell-in-cell process, has been implicated in the formation of aneuploidy associated with an aberrant cell division control. Microtubule plus-end-tracking protein TIP150 facilitates the loading of MCAK onto the microtubule plus ends and orchestrates microtubule plus-end dynamics during cell division. Here we show that TIP150 cooperates with MCAK to govern entosis via a regulatory circuitry that involves Aurora A-mediated phosphorylation of MCAK. Our biochemical analyses show that MCAK forms an intra-molecular association, which is essential for TIP150 binding. Interestingly, Aurora A-mediated phosphorylation of MCAK modulates its intra-molecular association, which perturbs the MCAK-TIP150 interaction in vitro and inhibits entosis in vivo. To probe if MCAK-TIP150 interaction regulates microtubule plasticity to affect the mechanical properties of cells during entosis, we used an optical trap to measure the mechanical rigidity of live MCF7 cells. We find that the MCAK cooperates with TIP150 to promote microtubule dynamics and modulate the mechanical rigidity of the cells during entosis. Our results show that a dynamic interaction of MCAK-TIP150 orchestrated by Aurora A-mediated phosphorylation governs entosis via regulating microtubule plus-end dynamics and cell rigidity. These data reveal a previously unknown mechanism of Aurora A regulation in the control of microtubule plasticity during cell-in-cell processes.
    Journal of Molecular Cell Biology 05/2014; DOI:10.1093/jmcb/mju016 · 8.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: eLife digest Entosis is the invasion of one cell by another and can be observed in aggressive cancers. Although the invading cell is usually killed, the surviving cell is sometimes left with the wrong number of chromosomes. This suggests that entosis may help cancer to progress because cells with an abnormal number of chromosomes are common in cancers. For entosis to occur, the invading cell must be released from the tissue that surrounds it, so it can move towards and attach to the cell it is about to invade. Very little is currently known about the cellular and molecular events that enable these processes to occur. Purvanov et al. studied entosis in cells grown in the laboratory and observed that invading cells produce bulges and projections at their rear end for invasion. These projections contain a protein called mDia1. This protein is involved in controlling the growth of the cytoskeleton—the structure that helps cells to both maintain their shape and to move. Adding the signaling molecule lysophosphatidic acid, which is present in human serum, increased the likelihood that cells would invade others. From this, Purvanov et al. established the identities of the proteins involved in transmitting the lysophosphatidic acid signal that controls mDia1 activity during entosis. Changes to this signaling pathway have been associated with cancer and how it spreads between different organs and its involvement in entosis lends further support to the notion that there may be a link between cell-in-cell invasion and the advancement of cancer. DOI:
    eLife Sciences 06/2014; 3:e02786. DOI:10.7554/eLife.02786 · 8.52 Impact Factor


Available from