A Wound-Induced [Ca2+]iIncrease and Its Transcriptional Activation of Immediate Early Genes Is Important in the Regulation of Motility

Tran, Phuong Oanh T.; Hinman, Lee E.; Unger, Gretchen M.; Sammak, Paul J.

doi:10.1006/excr.1998.4239

Cited by 70 publications

(82 citation statements)

References 23 publications

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“…In particular, Ca 2ϩ influx is recognized as a critical event in the stimulation of wound healing, leading to increased migration and proliferation (31,32). Our results, which demonstrate that Ca 2ϩ influx induces the cleavage of E-cadherin depending on ADAM10 activity, offer valuable clues to understanding these processes.…”

Section: Adam10-mediated E-cadherin Shedding Cannot Be Compensated Inmentioning

confidence: 65%

ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and β-catenin translocation

Maretzky

Reiß²,

Ludwig³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

609

576

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E-cadherin controls a wide array of cellular behaviors, including cell-cell adhesion, differentiation, and tissue development. We show here that E-cadherin is cleaved specifically by ADAM (a disintegrin and metalloprotease) 10 in its ectodomain. Analysis of ADAM10-deficient fibroblasts, inhibitor studies, and RNA interference-mediated down-regulation of ADAM10 demonstrated that ADAM10 is responsible not only for the constitutive shedding but also for the regulated shedding of this adhesion molecule in fibroblasts and keratinocytes. ADAM10-mediated E-cadherin shedding affects epithelial cell-cell adhesion as well as cell migration. Furthermore, the shedding of E-cadherin by ADAM10 modulates the ␤-catenin subcellular localization and downstream signaling. ADAM10 overexpression in epithelial cells increased the expression of the ␤-catenin downstream gene cyclin D1 dose-dependently and enhanced cell proliferation. In ADAM10-deficient mouse embryos, the C-terminal E-cadherin fragment is not generated, and the full-length protein accumulates, highlighting the in vivo relevance for ADAM10 in E-cadherin shedding. Our data strongly suggest that this protease constitutes a major regulatory element for the multiple functions of E-cadherin under physiological as well as pathological conditions. ADAM ͉ cadherin ͉ metalloproteinases ͉ shedding

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Section: Adam10-mediated E-cadherin Shedding Cannot Be Compensated Inmentioning

confidence: 65%

ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and β-catenin translocation

Maretzky

Reiß²,

Ludwig³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

609

576

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“…Disrupting an endothelial cell monolayer with a fine scratch results in a wave of Ca 2ϩ excitation from the injured/surviving cells adjacent to the wound to distal cells that is critical for motility (26) and proliferation (27). In addition to this, we find a positive feed-forward loop involving the prostanoid PGE 2 after mechanical disruption of endothelial cell monolayers that aids recovery of monolayer integrity.…”

Section: Figmentioning

confidence: 74%

Endothelial Cell Confluence Regulates Cyclooxygenase-2 and Prostaglandin E2 Production That Modulate Motility

Jiang

Weyrich

Zimmerman

et al. 2004

Journal of Biological Chemistry

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Endothelial cells line the vasculature and, after mechanical denudation during invasive procedures or cellular loss from natural causes, migrate to reestablish a confluent monolayer. We find confluent monolayers of human umbilical vein endothelial cells were quiescent and expressed low levels of cyclooxygenase-2, but expressed cyclooxygenase-2 at levels comparable with cytokine-stimulated cells when present in a subconfluent culture. Mechanically wounding endothelial cell monolayers stimulated rapid cyclooxygenase-2 expression that increased with the level of wounding. Cyclooxygenase-2 re-expression occurred throughout the culture, suggesting signaling from cells proximal to the wound to distal cells. Media from wounded monolayers stimulated cyclooxygenase-2 expression in confluent monolayers, which correlated with the level of wounding of the donor monolayer. Wounded monolayers and cells in subconfluent cultures secreted enhanced levels of prostaglandin (PG) E 2 that depended on cyclooxygenase-2 activity, and PGE 2 stimulated cyclooxygenase-2 expression in confluent endothelial cell monolayers. Cells from subconfluent monolayers migrated through filters more readily than those from confluent monolayers, and the cyclooxygenase-2-selective inhibitor NS-398 suppressed migration. Adding PGE 2 to NS-398-treated cells augmented migration. Endothelial cells also migrated into mechanically denuded areas of confluent monolayers, and this too was suppressed by NS-398. We conclude that endothelial cells not in contact with neighboring cells express cyclooxygenase-2 that results in enhanced release of PGE 2 , and that this autocrine and paracrine loop enhances endothelial cell migration to cover denuded areas of the endothelium.

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“…Upon mechanical wounding of quiescent cells, a transient increase in the concentration of intracellular free Ca 2+ is induced in cells at the wound edge (Tran et al, 1999). Furthermore, it was reported that proliferation of vascular smooth muscle cells following balloon catheter injury was signi®cantly reduced by administration of calcium antagonists (Reidy and Jackson, 1990).…”

Section: Discussionmentioning

confidence: 99%

Calcium influx triggers the sequential proteolysis of extracellular and cytoplasmic domains of E-cadherin, leading to loss of β-catenin from cell – cell contacts

et al. 1999

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Cadherins are major cell ± cell adhesion molecules in both tumor and normal tissues. Although serum levels of soluble E-cadherin have been shown to be higher in the cancer patients than in healthy volunteers, the detail mechanism regulating release of soluble E-cadherin remains to be elucidated. Here we show that the ectodomain of E-cadherin is proteolytically cleaved from some cancer cells by a membrane-bound metalloprotease to yield soluble form, and the residual membranetethered cleavage product is subsequently degraded by intracellular proteolytic pathway. Futhermore, we show that extracellular calcium in¯ux, that is induced by mechanical scraping of cells or ionomycin treatment, enhances the metalloprotease-mediated E-cadherin cleavage and the subsequent degradation of the cytoplasmic domain. Immunocytochemical analysis demonstrates that the sequential proteolysis of E-cadherin triggered by the calcium in¯ux results in translocation of b-catenin from the cell ± cell contacts to cytoplasm. Our data suggest that calcium in¯ux-induced proteolysis of E-cadherin not only disrupts the cell ± cell adhesion but also activates bcatenin-mediated intracellular signaling pathway, potentially leading to alterations in motility and proliferation activity of cells.

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A Wound-Induced [Ca2+]iIncrease and Its Transcriptional Activation of Immediate Early Genes Is Important in the Regulation of Motility

Cited by 70 publications

References 23 publications

ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and β-catenin translocation

ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and β-catenin translocation

Endothelial Cell Confluence Regulates Cyclooxygenase-2 and Prostaglandin E2 Production That Modulate Motility

Calcium influx triggers the sequential proteolysis of extracellular and cytoplasmic domains of E-cadherin, leading to loss of β-catenin from cell – cell contacts

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