Microtubule remodelling is required for the front–rear polarity switch during contact inhibition of locomotion

Kadir, Shereen; Astin, Jonathan W.; Tahtamouni, Lubna H.; Martin, Paul; Nobes, Catherine D.

doi:10.1242/jcs.087965

Cited by 57 publications

(77 citation statements)

References 40 publications

(50 reference statements)

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“…Accordingly, our data can be interpreted as showing preferential recruitment and increased growth rate of MTs at cell-extracellular-matrix contacts versus cell-cell contacts, in relation to the establishment of a front-rear cell polarity required for migration (Kadir et al, 2011). These data are consistent with previous observations of a clear bias of MT growth towards the free edge of cells at the border of cell islands (Dupin et al, 2009;Jaulin and Kreitzer, 2010).…”

Section: Discussionsupporting

confidence: 92%

Adhesive interactions of N-cadherin limit the recruitment of microtubules to cell–cell contacts through organization of actomyosin

Plestant¹,

Strale²,

Seddiki³

et al. 2014

Development

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Adhesive interactions of cadherins induce crosstalk between adhesion complexes and the actin cytoskeleton, allowing strengthening of adhesions and cytoskeletal organization. The underlying mechanisms are not completely understood, and microtubules (MTs) might be involved, as for integrin-mediated cell-extracellular-matrix adhesions. Therefore, we investigated the relationship between N-cadherin and MTs by analyzing the influence of N-cadherin engagement on MT distribution and dynamics. MTs progressed less, with a lower elongation rate, towards cadherin adhesions than towards focal adhesions. Increased actin treadmilling and the presence of an actomyosin contractile belt, suggested that actin relays inhibitory signals from cadherin adhesions to MTs. The reduced rate of MT elongation, associated with reduced recruitment of end-binding (EB) proteins to plus ends, was alleviated by expression of truncated N-cadherin, but was only moderately affected when actomyosin was disrupted. By contrast, destabilizing actomyosin fibers allowed MTs to enter the adhesion area, suggesting that tangential actin bundles impede MT growth independently of MT dynamics. Blocking MT penetration into the adhesion area strengthened cadherin adhesions. Taken together, these results establish a crosstalk between N-cadherin, Factin and MTs. The opposing effects of cadherin and integrin engagement on actin organization and MT distribution might induce bias of the MT network during cell polarization.

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Section: Discussionsupporting

confidence: 92%

Adhesive interactions of N-cadherin limit the recruitment of microtubules to cell–cell contacts through organization of actomyosin

Plestant¹,

Strale²,

Seddiki³

et al. 2014

Development

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“…When fibroblasts with normal motility collide, they undergo temporary paralysis of movement and then divert their paths to avoid contact in a phenomenon known as contact inhibition of locomotion, which was first described by Michael Abercrombie and Joan Heaysman in the early 1950s [90,91]. The cell overlap shown by IRM here indicates that ROCK inhibition causes a release from contact inhibition of locomotion, as reported before [92][93][94], and reviewed by Mayor and Carmona-Fontaine [95]. A consequence of contact inhibition of locomotion is that sparse cells will translocate faster than more numerous cells due to a lesser number of collisions [90].…”

Section: Functional Consequences Of Irs-1 Inhibitionsupporting

confidence: 66%

Calreticulin affects cell adhesiveness through differential phosphorylation of insulin receptor substrate-1

Czarnowski

Papp

Száraz

et al. 2014

Cellular and Molecular Biology Letters

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Cellular adhesion to the underlying substratum is regulated through numerous signaling pathways. It has been suggested that insulin receptor substrate 1 (IRS-1) is involved in some of these pathways, via association with and activation of transmembrane integrins. Calreticulin, as an important endoplasmic reticulum-resident, calcium-binding protein with a chaperone function, plays an obvious role in proteomic expression. Our previous work showed that calreticulin mediates cell adhesion not only by affecting protein expression but also by affecting the state of regulatory protein phosphorylation, such as that of c-src. Here, we demonstrate that calreticulin affects the abundance of IRS-1 such that the absence of calreticulin is paralleled by a decrease in IRS-1 levels and the unregulated overexpression of calreticulin is accompanied by an increase in IRS-1 levels. These changes in the abundance of calreticulin and IRS-1 are accompanied by changes in cell-substratum adhesiveness and phosphorylation, such that increases in the expression of calreticulin and IRS-1 are paralleled by an increase in focal contact-based cellsubstratum adhesiveness, and a decrease in the expression of these proteins brings about a decrease in cell-substratum adhesiveness. Wild type and calreticulin-null mouse embryonic fibroblasts (MEFs) were cultured and the IRS-1 isoform profile was assessed. Differences in morphology and motility were also quantified. While no substantial differences in the speed of locomotion were found, the directionality of cell movement was greatly promoted by the presence of calreticulin. Calreticulin expression was also found to have a dramatic effect on the phosphorylation state of serine 636 of IRS-1, such that phosphorylation of IRS-1 on serine 636 increased radically in the absence of calreticulin. Most importantly, treatment of cells with the RhoA/ROCK inhibitor, Y-27632, which among its many effects also inhibited serine 636 phosphorylation of IRS-1, had profound effects on cell-substratum adhesion, in that it suppressed focal contacts, induced extensive close contacts, and increased the strength of adhesion. The latter effect, while counterintuitive, can be explained by the close contacts comprising labile bonds but in large numbers. In addition, the lability of bonds in close contacts would permit fast locomotion. An interesting and novel finding is that Y-27632 treatment of MEFs releases them from contact inhibition of locomotion, as evidenced by the invasion of a cell's underside by the thin lamellae and filopodia of a cell in close apposition.

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“…Thus, by the selective stabilization of microtubules at the leading edge, cell polarity is established, and cells can move directionally up a chemical gradient or toward an open wound. In the latter assay, it is unclear whether selective stabilization occurs at the leading edge because of molecules released by cells damaged during the formation of the wound or whether there is selective destabilization (increased dynamicity) at the rear of the cell caused by cell-to-cell contact as has been reported in other studies (41).…”

Section: Discussionmentioning

confidence: 85%

The Role of Microtubules and Their Dynamics in Cell Migration

Ganguly

Yang

Sharma

et al. 2012

Journal of Biological Chemistry

110

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Background: Microtubule effects on cell migration are poorly understood. Results: Tubulin mutations or drug treatments that suppress microtubule dynamics impede cell locomotion. Depolymerizing microtubules does not inhibit movement, but it becomes random. Conclusion: Microtubules act to restrain cell movement and specify directionality. Significance: Drugs have dose-dependent effects on microtubule behavior, cell migration, and mitosis. Understanding these actions will lead to more effective drug use.

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Microtubule remodelling is required for the front–rear polarity switch during contact inhibition of locomotion

Cited by 57 publications

References 40 publications

Adhesive interactions of N-cadherin limit the recruitment of microtubules to cell–cell contacts through organization of actomyosin

Adhesive interactions of N-cadherin limit the recruitment of microtubules to cell–cell contacts through organization of actomyosin

Calreticulin affects cell adhesiveness through differential phosphorylation of insulin receptor substrate-1

The Role of Microtubules and Their Dynamics in Cell Migration

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