Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44

Daizo Murakami, Isamu Okamoto, Osamu Nagano, Yoshiaki Kawano, Taisuke Tomita, Takeshi Iwatsubo, Bart De Strooper, Eiji Yumoto, Hideyuki Saya

Research output: Contribution to journalArticlepeer-review

138 Citations (Scopus)


CD44 is the major adhesion molecule for the extracellular matrix components and is implicated in a wide variety of physiological and pathological processes including the regulation of tumor cell growth and metastasis. Our previous studies have shown that CD44 undergoes sequential proteolytic cleavages in the extracellular and transmembrane domains and the cleavage product derived from CD44 intramembranous cleavage acts as a signal transduction molecule. However, the underlying mechanism of the intramembranous cleavage of CD44 remains to be elucidated. In the present study, we report for the first time that CD44 is a substrate of the presenilin (PS)-dependent γ-secretase. We demonstrate that the intramembranous cleavage of CD44 induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) treatment or mechanical scraping is blocked by γ-secretase inhibitors in U251MG cells and that this cleavage is also inhibited in PS-deficient mouse embryonic fibroblasts. Furthermore, we showed that PSI is redistributed to ruffling areas of the plasma membrane similarly to CD44 after TPA treatment, supporting our biochemical observation that PS1 is involved in the intramembranous cleavage of CD44. Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/γ-secretase activity in the functional regulation of adhesion molecules.

Original languageEnglish
Pages (from-to)1511-1516
Number of pages6
Issue number10
Publication statusPublished - 2003 Mar 13
Externally publishedYes


  • CD44
  • Intramembranous cleavage
  • Presenilin
  • γ-secretase

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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