Over‐expression of PAR‐3 suppresses contact‐mediated inhibition of cell migration in MDCK cells

Mishima, Aki; Suzuki, Atsushi; Enaka, Makiko; Hirose, Tomonori; Mizuno, Keiko; Ohnishi, Tetsuo; Mohri, Hiroshi; Ishigatsubo, Yoshiaki; Ohno, Shigeo

doi:10.1046/j.1365-2443.2002.00540.x

Cited by 21 publications

(15 citation statements)

References 51 publications

(102 reference statements)

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“…2B,E,F) NC cells, without affecting NC induction ( Fig. 2A) One way in which Par3 could affect dispersion is through controlling cell-cell adhesion, as has been shown in other cell types (Chen and Macara, 2005;Mertens et al, 2005;Mishima et al, 2002). We analysed the effect of Par3MO on the level and localisation of various cell adhesion proteins.…”

Section: Research Articlementioning

confidence: 86%

“…Par3 promotes the maturation of the cell adhesion complex and has been linked to the regulation of microtubule dynamics and Rac1 activity through interaction with the Rac-GEF Tiam1 (Chen et al, 2013;Chen and Macara, 2005;Mack et al, 2012;Mertens et al, 2005;Mishima et al, 2002;Xue et al, 2013). In epithelial cells, Par3 associates with cell-cell adhesion complexes and appears to be important for establishing apicobasal polarity; however, whether Par3 controls PCP during CIL remains to be investigated.…”

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confidence: 99%

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Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion

et al. 2013

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There is growing evidence that contact inhibition of locomotion (CIL) is essential for morphogenesis and its failure is thought to be responsible for cancer invasion; however, the molecular bases of this phenomenon are poorly understood. Here we investigate the role of the polarity protein Par3 in CIL during migration of the neural crest, a highly migratory mesenchymal cell type. In epithelial cells, Par3 is localised to the cell-cell adhesion complex and is important in the definition of apicobasal polarity, but the localisation and function of Par3 in mesenchymal cells are not well characterised. We show in Xenopus and zebrafish that Par3 is localised to the cell-cell contact in neural crest cells and is essential for CIL. We demonstrate that the dynamics of microtubules are different in different parts of the cell, with an increase in microtubule catastrophe at the collision site during CIL. Par3 loss-of-function affects neural crest migration by reducing microtubule catastrophe at the site of cell-cell contact and abrogating CIL. Furthermore, Par3 promotes microtubule catastrophe by inhibiting the Rac-GEF Trio, as double inhibition of Par3 and Trio restores microtubule catastrophe at the cell contact and rescues CIL and neural crest migration. Our results demonstrate a novel role of Par3 during neural crest migration, which is likely to be conserved in other processes that involve CIL such as cancer invasion or cell dispersion.

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Section: Research Articlementioning

confidence: 86%

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confidence: 99%

Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion

et al. 2013

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“…In addition, a JAM-A deletion mutant lacking the PDZ-binding residues redistributes Par3 from cell contacts in the cytosol (Ebnet et al, 2001). Finally, Par3 overexpression causes the loss of contact-dependent inhibition of cell motility (Mishima et al, 2002), and soluble Par3 inhibits PKCζ activity (Lin et al, 2000). On the basis of this evidence, we surmised that, in the absence of JAM-A, increased availability of Par3 might result in PKCζ inactivation and, consequently, in GSK-3β activation.…”

Section: Jam-a and The Pkcζ/gsk-3β Axismentioning

confidence: 90%

Expression of junctional adhesion molecule-A prevents spontaneous and random motility

Bazzoni

Tonetti

Manzi

et al. 2005

Journal of Cell Science

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Junctional adhesion molecule-A (JAM-A) is a cell-surface glycoprotein that localizes to intercellular junctions and associates with intracellular proteins via PSD95-Dlg-ZO1-binding residues. To define the functional consequences of JAM-A expression, we have produced endothelial cells from JAM-A-deficient mice. We report here that the absence of JAM-A enhanced spontaneous and random motility. In turn, the enhanced motility of JAM-A-negative cells was abrogated either on transfection of exogenous JAM-A or on treatment with inhibitors of glycogen synthase kinase-3β (GSK-3β). In addition, in JAM-A-positive cells, motility was enhanced on inactivation of protein kinase Cζ (PKCζ), which is an inhibitor of GSK-3β. Although these findings suggested that JAM-A might inhibit GSK-3β, we found that expression per se of JAM-A did not change the levels of inactive GSK-3β. Thus, JAM-A expression may regulate effectors of motility that are also downstream of the PKCζ/GSK-3β axis. In support of this view, we found that JAM-A absence increased the number of actin-containing protrusions, reduced the stability of microtubules and impaired the formation of focal adhesions. Notably, all the functional consequences of JAM-A absence were reversed either on treatment with GSK-3β inhibitors or on transfection of full-length JAM-A, but not on transfection of a JAM-A deletion mutant devoid of the PSD95-Dlg-ZO1-binding residues. Thus, by regulating cytoskeletal and adhesive structures, JAM-A expression prevents cell motility, probably in a PSD95-Dlg-ZO1-dependent manner.

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“…These cDNAs were subcloned into the EpsteinBarr virus (EBV)-based expression vector pEB6-CAG, or its derivative pOSTet14, which can autonomously replicate in MDCK cells (Mishima et al, 2004;. Adenovirus expression vectors encoding β-galactosidase or the long isoform of PAR-3 were described previously (Mishima et al, 2002). An adenovirus expression vector encoding the long isoform of PAR-3 S827/829A was newly generated, as described previously ), using pAxCAwt (TaKaRa).…”

Section: Expression Vectorsmentioning

confidence: 99%

Interaction between PAR-3 and the aPKC–PAR-6 complex is indispensable for apical domain development of epithelial cells

Horikoshi

Suzuki

Yamanaka

et al. 2009

Journal of Cell Science

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The evolutionarily conserved polarity proteins PAR-3, atypical protein kinase C (aPKC) and PAR-6 critically regulate the apical membrane development required for epithelial organ development. However, the molecular mechanisms underlying their roles remain to be clarified. We demonstrate that PAR-3 knockdown in MDCK cells retards apical protein delivery to the plasma membrane, and eventually leads to mislocalized apical domain formation at intercellular regions in both twodimensional and three-dimensional culture systems. The defects in PAR-3 knockdown cells are efficiently rescued by wild-type PAR-3, but not by a point mutant (S827/829A) that lacks the ability to interact with aPKC, indicating that formation of the PAR-3-aPKC-PAR-6 complex is essential for apical membrane development. This is in sharp contrast with tight junction maturation, which does not necessarily depend on the aPKC-PAR-3 interaction, and indicates that the two fundamental processes essential for epithelial polarity are differentially regulated by these polarity proteins. Importantly, highly depolarized cells accumulate aPKC and PAR-6, but not PAR-3, on apical protein-containing vacuoles, which become targeted to PAR-3-positive primordial cell-cell contact sites during the initial stage of the repolarization process. Therefore, formation of the PAR-3-aPKC-PAR-6 complex might be required for targeting of not only the aPKC-PAR-6 complex but also of apical protein carrier vesicles to primordial junction structures. Supplementary material available online at

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Over‐expression of PAR‐3 suppresses contact‐mediated inhibition of cell migration in MDCK cells

Cited by 21 publications

References 51 publications

Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion

Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion

Expression of junctional adhesion molecule-A prevents spontaneous and random motility

Interaction between PAR-3 and the aPKC–PAR-6 complex is indispensable for apical domain development of epithelial cells

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