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

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206 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

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Keywords

  • ADAM10
  • ADAM17
  • CD44
  • Calmodulin
  • Rac

ASJC Scopus subject areas

  • Cell Biology

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