Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca2+ influx and PKC activation

Osamu Nagano, Daizo Murakami, Dieter Hartmann, Bart De Strooper, Paul Saftig, Takeshi Iwatsubo, Motowo Nakajima, Masanori Shinohara, Hideyuki Saya

Research output: Contribution to journalArticle

198 Citations (Scopus)

Abstract

CD44 is an adhesion molecule that interacts with hyaluronic acid (HA) and undergoes sequential proteolytic cleavages in its ectodomain and intramembranous domain. The ectodomain cleavage is triggered by extracellular Ca2+ influx or the activation of protein kinase C. Here we show that CD44-mediated cell-matrix adhesion is terminated by two independent ADAM family metalloproteinases, ADAM10 and ADAM17, differentially regulated in response to those stimuli. Ca2+ influx activates ADAM10 by regulating the association between calmodulin and ADAM10, leading to CD44 ectodomain cleavage. Depletion of ADAM10 strongly inhibits the Ca2+ influx-induced cell detachment from matrix. On the other hand, phorbol ester stimulation activates ADAM17 through the activation of PKC and small GTPase Rac, inducing proteolysis of CD44. Furthermore, depletion of ADAM10 or ADAM17 markedly suppressed CD44-dependent cancer cell migration on HA, but not on fibronectin. The spatio-temporal regulation of two independent signaling pathways for CD44 cleavage plays a crucial role in cell-matrix interaction and cell migration.

Original languageEnglish
Pages (from-to)893-902
Number of pages10
JournalJournal of Cell Biology
Volume165
Issue number6
DOIs
Publication statusPublished - 2004 Jun 21
Externally publishedYes

Fingerprint

Metalloproteases
Cell Communication
Hyaluronic Acid
Cell Movement
Cell-Matrix Junctions
Monomeric GTP-Binding Proteins
Phorbol Esters
Calmodulin
Fibronectins
Protein Kinase C
Proteolysis
ADAM17 Protein
Neoplasms

Keywords

  • ADAM10
  • ADAM17
  • Calmodulin
  • CD44
  • Rac

ASJC Scopus subject areas

  • Cell Biology

Cite this

Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca2+ influx and PKC activation. / Nagano, Osamu; Murakami, Daizo; Hartmann, Dieter; De Strooper, Bart; Saftig, Paul; Iwatsubo, Takeshi; Nakajima, Motowo; Shinohara, Masanori; Saya, Hideyuki.

In: Journal of Cell Biology, Vol. 165, No. 6, 21.06.2004, p. 893-902.

Research output: Contribution to journalArticle

Nagano, Osamu ; Murakami, Daizo ; Hartmann, Dieter ; De Strooper, Bart ; Saftig, Paul ; Iwatsubo, Takeshi ; Nakajima, Motowo ; Shinohara, Masanori ; Saya, Hideyuki. / Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca2+ influx and PKC activation. In: Journal of Cell Biology. 2004 ; Vol. 165, No. 6. pp. 893-902.
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AU - De Strooper, Bart

AU - Saftig, Paul

AU - Iwatsubo, Takeshi

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