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

Kiyoharu Ito, Isamu Okamoto, Norie Araki, Yoshiaki Kawano, Mitsuyoshi Nakao, Shigetoshi Fujiyama, Kimio Tomita, Tatsuyuki Mimori, Hideyuki Saya

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

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 membrane-tethered cleavage product is subsequently degraded by intracellular proteolytic pathway. Futhermore, we show that extracellular calcium influx, 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 influx results in translocation of β-catenin from the cell-cell contacts to cytoplasm. Our data suggest that calcium influx-induced proteolysis of E-cadherin not only disrupts the cell-cell adhesion but also activates β-catenin-mediated intracellular signaling pathway, potentially leading to alterations in motility and proliferation activity of cells.

Original languageEnglish
Pages (from-to)7080-7090
Number of pages11
JournalOncogene
Volume18
Issue number50
Publication statusPublished - 1999 Nov 25
Externally publishedYes

Fingerprint

Catenins
Cadherins
Proteolysis
Calcium
Metalloproteases
Neoplasms
Ionomycin
Cell Adhesion Molecules
Cell Adhesion
Healthy Volunteers
Cytoplasm
Cell Proliferation
Cell Membrane
Membranes
Serum

Keywords

  • β-catenin
  • Calcium ionophore
  • E-cadherin
  • Mechanical stimulation
  • Metalloprotease

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Calcium influx triggers the sequential proteolysis of extracellular and cytoplasmic domains of E-cadherin, leading to loss of β-catenin from cell-cell contacts. / Ito, Kiyoharu; Okamoto, Isamu; Araki, Norie; Kawano, Yoshiaki; Nakao, Mitsuyoshi; Fujiyama, Shigetoshi; Tomita, Kimio; Mimori, Tatsuyuki; Saya, Hideyuki.

In: Oncogene, Vol. 18, No. 50, 25.11.1999, p. 7080-7090.

Research output: Contribution to journalArticle

Ito, K, Okamoto, I, Araki, N, Kawano, Y, Nakao, M, Fujiyama, S, Tomita, K, Mimori, T & Saya, H 1999, 'Calcium influx triggers the sequential proteolysis of extracellular and cytoplasmic domains of E-cadherin, leading to loss of β-catenin from cell-cell contacts', Oncogene, vol. 18, no. 50, pp. 7080-7090.
Ito, Kiyoharu ; Okamoto, Isamu ; Araki, Norie ; Kawano, Yoshiaki ; Nakao, Mitsuyoshi ; Fujiyama, Shigetoshi ; Tomita, Kimio ; Mimori, Tatsuyuki ; Saya, Hideyuki. / Calcium influx triggers the sequential proteolysis of extracellular and cytoplasmic domains of E-cadherin, leading to loss of β-catenin from cell-cell contacts. In: Oncogene. 1999 ; Vol. 18, No. 50. pp. 7080-7090.
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