Defining functional interactions during biogenesis of epithelial junctions

Erasmus, Jennifer C.; Bruche, Susann; Pizarro, Luis; Maimari, Nataly; Pogglioli, T; Tomlinson, Chris; Lees, Jonathan G.; Zalivina, Irina; Wheeler, Ann; Alberts, Arthur S.; Russo, Antonella; Braga, Vania

doi:10.1038/ncomms13542

Cited by 18 publications

(17 citation statements)

References 63 publications

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“…1G , Figure S1 ). These results are in line with previous reports that cadherin junctional levels are not a bona-fide predictor of the strength or stability of cell-cell adhesion 26 . Thus, the smaller sized initial aggregates formed in suspension are more resistant to disruption by mechanical stress.…”

Section: Resultssupporting

confidence: 93%

The scaffold protein Ajuba suppresses CdGAP activity in epithelia to maintain stable cell-cell contacts

McCormack

Bruche

Ouadda

et al. 2017

Sci Rep

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Levels of active Rac1 at epithelial junctions are partially modulated via interaction with Ajuba, an actin binding and scaffolding protein. Here we demonstrate that Ajuba interacts with the Cdc42 GTPase activating protein CdGAP, a GAP for Rac1 and Cdc42, at cell-cell contacts. CdGAP recruitment to junctions does not require Ajuba; rather Ajuba seems to control CdGAP residence at sites of cell-cell adhesion. CdGAP expression potently perturbs junctions and Ajuba binding inhibits CdGAP activity. Ajuba interacts with Rac1 and CdGAP via distinct domains and can potentially bring them in close proximity at junctions to facilitate activity regulation. Functionally, CdGAP-Ajuba interaction maintains junctional integrity in homeostasis and diseases: (i) gain-of-function CdGAP mutants found in Adams-Oliver Syndrome patients strongly destabilize cell-cell contacts and (ii) CdGAP mRNA levels are inversely correlated with E-cadherin protein expression in different cancers. We present conceptual insights on how Ajuba can integrate CdGAP binding and inactivation with the spatio-temporal regulation of Rac1 activity at junctions. Ajuba provides a novel mechanism due to its ability to bind to CdGAP and Rac1 via distinct domains and influence the activation status of both proteins. This functional interplay may contribute towards conserving the epithelial tissue architecture at steady-state and in different pathologies.

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Section: Resultssupporting

confidence: 93%

The scaffold protein Ajuba suppresses CdGAP activity in epithelia to maintain stable cell-cell contacts

McCormack

Bruche

Ouadda

et al. 2017

Sci Rep

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“…eEF1A1 rather than eEF1A2 interacted with calmodulin in Ca 2+dependent way [75]. eEF1A is known to interact with actin [76] probably due to its dimeric form [77]. Interestingly, the eEF1A1 and eEF1A2 isoforms induced the formation of differently shaped actin bundles [75] which could be important for a supposed role of eEF1A2 in oncogenesis.…”

Section: Functions Of the Eef1a Isoformsmentioning

confidence: 97%

Protein isoforms. Origin, structure and functions.

Новосильная

2017

Biopolym. Cell

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“…Rosi highly upregulated CD36, FABP4, and GPD1 (Figure 4B), which are involved in fatty acid and glycerol metabolism (Hotamisligil and Bernlohr 2015;Kiskinis et al 2014). TPhP highly upregulated CNN2, VASP, and SEC13 (Figure 4B), which are involved in actin polymerization (Erasmus et al 2016).…”

Section: Analysis Of the Tphp-induced Proteome In 3t3 L1 Adipocytesmentioning

confidence: 99%

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

Kim

Rabhi

Blum

et al. 2019

Preprint

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Background: Triphenyl phosphate (TPhP) is an environmental PPARγ ligand, and growing evidence suggests that it is a metabolic disruptor. We have shown previously that the structurally similar ligand, tributyltin, does not induce brite adipocyte gene expression.Objectives: First, we tested whether TPhP also fails to induce brite adipogenesis in vivo, in human primary preadipocytes and in 3T3 L1 cells. Second, we tested the hypothesis that TPhP is a selective PPARγ modulator that is unable to protect PPARγ from phosphorylation at serine 273.Methods: C57BL/6J male mice were fed either a low or very high fat diet for 13 weeks. From weeks 7-13, mice were injected intraperitoneally, daily, with vehicle, rosiglitazone (Rosi), or TPhP (10 mg/kg). Mature adipocytes were isolated from inguinal adipose tissue to assess adipocyte gene expression. Adipocyte genotype and phenotype were assessed in human primary preadipocytes differentiated in the presence of Rosi, or TPhP. Adipocyte gene and protein expression were determined in 3T3 L1 cells differentiated in the presence of Rosi or TPhP. Swiss 3T3 cell lines expressing wild-type PPARγ2 or PPARγ2 with alanine substitute for serine at position 273 were used to determine effects of PPARγ phosphorylation on Rosiand TPhP-induced gene expression.Results: Compared to Rosi, TPhP did not induce browning of mature adipocytes. TPhP also did not induce expression of brite adipocyte genes, mitochondrial biogenesis or cellular respiration in primary human adipocytes. Rosi and TPhP induced distinct proteomic and phosphoproteomic profiles; Rosi enriched more regulatory pathways related to fatty acid oxidation and mitochondrial proteins. Furthermore, TPhP maintained phosphorylation of PPARγ at ser273. Upon inhibition of phosphorylation at ser273, TPhP was able to induce brite adipocyte genes.Discussion: Here, we show that TPhP acts via a novel mechanism of action. TPhP disrupts brite adipocyte differentiation by failing to protect PPARγ from phosphorylation at ser273, in contrast to the therapeutic PPARγ ligand Rosi.

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Defining functional interactions during biogenesis of epithelial junctions

Cited by 18 publications

References 63 publications

The scaffold protein Ajuba suppresses CdGAP activity in epithelia to maintain stable cell-cell contacts

The scaffold protein Ajuba suppresses CdGAP activity in epithelia to maintain stable cell-cell contacts

Protein isoforms. Origin, structure and functions.

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

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