title: Regulation of myosin activation during cell-cell contact formation by Par3-Lgl antagonism: entosis without matrix detachment.
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.
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Wan
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zheng
authors.forename: Huabin
authors.initials: H
authors.lastname: Zhu
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Chu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Du
mesh_terms: D000818:Animals; D002450:Cell Communication; D002460:Cell Line; D004285:Dogs; D004705:Endocytosis; D057691:Entosis; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D024462:Myosin Type II / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D018994:Myosin Light Chains; D025521:Tumor Suppressor Proteins; D054460:rho-Associated Kinases; D024462:Myosin Type II; D020741:rho GTP-Binding Proteins