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Lulu2 regulates the circumferential actomyosin tensile system in epithelial cells through p114RhoGEF.

Nakajima H, Tanoue T - J. Cell Biol. (2011)

Bottom Line: In its regulation of the belt, Lulu2 interacts with and activates p114RhoGEF, a Rho-specific guanine nucleotide exchanging factor (GEF), at apical cell-cell junctions.This interaction is negatively regulated via phosphorylation events in the FERM-adjacent domain of Lulu2 catalyzed by atypical protein kinase C.We further found that Patj, an apical cell polarity regulator, recruits p114RhoGEF to apical cell-cell boundaries via PDZ (PSD-95/Dlg/ZO-1) domain-mediated interaction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Global Centers of Excellence Program for Integrative Membrane Biology, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japan.

ABSTRACT
Myosin II-driven mechanical forces control epithelial cell shape and morphogenesis. In particular, the circumferential actomyosin belt, which is located along apical cell-cell junctions, regulates many cellular processes. Despite its importance, the molecular mechanisms regulating the belt are not fully understood. In this paper, we characterize Lulu2, a FERM (4.1 protein, ezrin, radixin, moesin) domain-containing molecule homologous to Drosophila melanogaster Yurt, as an important regulator. In epithelial cells, Lulu2 is localized along apical cell-cell boundaries, and Lulu2 depletion by ribonucleic acid interference results in disorganization of the circumferential actomyosin belt. In its regulation of the belt, Lulu2 interacts with and activates p114RhoGEF, a Rho-specific guanine nucleotide exchanging factor (GEF), at apical cell-cell junctions. This interaction is negatively regulated via phosphorylation events in the FERM-adjacent domain of Lulu2 catalyzed by atypical protein kinase C. We further found that Patj, an apical cell polarity regulator, recruits p114RhoGEF to apical cell-cell boundaries via PDZ (PSD-95/Dlg/ZO-1) domain-mediated interaction. These findings therefore reveal a novel molecular system regulating the circumferential actomyosin belt in epithelial cells.

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Schematic representation of Lulu2 involvement in regulation of the circumferential actomyosin belt. Lulu2 activates p114RhoGEF, thereby regulating the circumferential actomyosin belt. Lulu2 is phosphorylated in the FA domain and negatively regulated by aPKC. p114RhoGEF is recruited to apical cell–cell boundaries by Patj via PDZ domain–mediated interaction. Par3 regulates Patj accumulation at apical cell–cell boundaries. P, phosphorylation; DH, Dbl homology domain; PH, pleckstrin homology domain; CC, coiled-coil region.
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fig9: Schematic representation of Lulu2 involvement in regulation of the circumferential actomyosin belt. Lulu2 activates p114RhoGEF, thereby regulating the circumferential actomyosin belt. Lulu2 is phosphorylated in the FA domain and negatively regulated by aPKC. p114RhoGEF is recruited to apical cell–cell boundaries by Patj via PDZ domain–mediated interaction. Par3 regulates Patj accumulation at apical cell–cell boundaries. P, phosphorylation; DH, Dbl homology domain; PH, pleckstrin homology domain; CC, coiled-coil region.

Mentions: We previously reported that Lulu2 overexpression in epithelial cells caused strong accumulation of actomyosin bundles at the cell cortex and induced apical constriction (Nakajima and Tanoue, 2010). Here, we characterized Lulu2 as a regulator of the circumferential actomyosin belt in epithelial cells by studying Lulu2 in more detail at the molecular level. One of the main findings of our present study is that Lulu2 interacts with and activates p114RhoGEF in its regulation of the circumferential actomyosin belt (Fig. 9). p114RhoGEF was recently shown to be an essential regulator of RhoA at apical junctions: it activates RhoA at apical junctions, thereby regulating the circumferential actomyosin belt and participating in tight junction formation in Ca2+ switch experiments (Terry et al., 2011). Our results here also confirm the importance of p114RhoGEF in organization of the circumferential actomyosin belt. Its role in tight junction organization, however, might be cell-type dependent: without Ca2+ switch, p114RhoGEF depletion resulted in disruption of tight junctions in human corneal epithelial cells but not in Caco2 and DLD-1 cells (Fig. 4; Terry et al., 2011).


Lulu2 regulates the circumferential actomyosin tensile system in epithelial cells through p114RhoGEF.

Nakajima H, Tanoue T - J. Cell Biol. (2011)

Schematic representation of Lulu2 involvement in regulation of the circumferential actomyosin belt. Lulu2 activates p114RhoGEF, thereby regulating the circumferential actomyosin belt. Lulu2 is phosphorylated in the FA domain and negatively regulated by aPKC. p114RhoGEF is recruited to apical cell–cell boundaries by Patj via PDZ domain–mediated interaction. Par3 regulates Patj accumulation at apical cell–cell boundaries. P, phosphorylation; DH, Dbl homology domain; PH, pleckstrin homology domain; CC, coiled-coil region.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3198159&req=5

fig9: Schematic representation of Lulu2 involvement in regulation of the circumferential actomyosin belt. Lulu2 activates p114RhoGEF, thereby regulating the circumferential actomyosin belt. Lulu2 is phosphorylated in the FA domain and negatively regulated by aPKC. p114RhoGEF is recruited to apical cell–cell boundaries by Patj via PDZ domain–mediated interaction. Par3 regulates Patj accumulation at apical cell–cell boundaries. P, phosphorylation; DH, Dbl homology domain; PH, pleckstrin homology domain; CC, coiled-coil region.
Mentions: We previously reported that Lulu2 overexpression in epithelial cells caused strong accumulation of actomyosin bundles at the cell cortex and induced apical constriction (Nakajima and Tanoue, 2010). Here, we characterized Lulu2 as a regulator of the circumferential actomyosin belt in epithelial cells by studying Lulu2 in more detail at the molecular level. One of the main findings of our present study is that Lulu2 interacts with and activates p114RhoGEF in its regulation of the circumferential actomyosin belt (Fig. 9). p114RhoGEF was recently shown to be an essential regulator of RhoA at apical junctions: it activates RhoA at apical junctions, thereby regulating the circumferential actomyosin belt and participating in tight junction formation in Ca2+ switch experiments (Terry et al., 2011). Our results here also confirm the importance of p114RhoGEF in organization of the circumferential actomyosin belt. Its role in tight junction organization, however, might be cell-type dependent: without Ca2+ switch, p114RhoGEF depletion resulted in disruption of tight junctions in human corneal epithelial cells but not in Caco2 and DLD-1 cells (Fig. 4; Terry et al., 2011).

Bottom Line: In its regulation of the belt, Lulu2 interacts with and activates p114RhoGEF, a Rho-specific guanine nucleotide exchanging factor (GEF), at apical cell-cell junctions.This interaction is negatively regulated via phosphorylation events in the FERM-adjacent domain of Lulu2 catalyzed by atypical protein kinase C.We further found that Patj, an apical cell polarity regulator, recruits p114RhoGEF to apical cell-cell boundaries via PDZ (PSD-95/Dlg/ZO-1) domain-mediated interaction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Global Centers of Excellence Program for Integrative Membrane Biology, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japan.

ABSTRACT
Myosin II-driven mechanical forces control epithelial cell shape and morphogenesis. In particular, the circumferential actomyosin belt, which is located along apical cell-cell junctions, regulates many cellular processes. Despite its importance, the molecular mechanisms regulating the belt are not fully understood. In this paper, we characterize Lulu2, a FERM (4.1 protein, ezrin, radixin, moesin) domain-containing molecule homologous to Drosophila melanogaster Yurt, as an important regulator. In epithelial cells, Lulu2 is localized along apical cell-cell boundaries, and Lulu2 depletion by ribonucleic acid interference results in disorganization of the circumferential actomyosin belt. In its regulation of the belt, Lulu2 interacts with and activates p114RhoGEF, a Rho-specific guanine nucleotide exchanging factor (GEF), at apical cell-cell junctions. This interaction is negatively regulated via phosphorylation events in the FERM-adjacent domain of Lulu2 catalyzed by atypical protein kinase C. We further found that Patj, an apical cell polarity regulator, recruits p114RhoGEF to apical cell-cell boundaries via PDZ (PSD-95/Dlg/ZO-1) domain-mediated interaction. These findings therefore reveal a novel molecular system regulating the circumferential actomyosin belt in epithelial cells.

Show MeSH
Related in: MedlinePlus