Abstract
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 language | English |
|---|---|
| Pages (from-to) | 1511-1516 |
| Number of pages | 6 |
| Journal | Oncogene |
| Volume | 22 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2003 Mar 13 |
| Externally published | Yes |
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Keywords
- γ-secretase
- CD44
- Intramembranous cleavage
- Presenilin
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44. / Murakami, Daizo; Okamoto, Isamu; Nagano, Osamu; Kawano, Yoshiaki; Tomita, Taisuke; Iwatsubo, Takeshi; De Strooper, Bart; Yumoto, Eiji; Saya, Hideyuki.
In: Oncogene, Vol. 22, No. 10, 13.03.2003, p. 1511-1516.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44
AU - Murakami, Daizo
AU - Okamoto, Isamu
AU - Nagano, Osamu
AU - Kawano, Yoshiaki
AU - Tomita, Taisuke
AU - Iwatsubo, Takeshi
AU - De Strooper, Bart
AU - Yumoto, Eiji
AU - Saya, Hideyuki
PY - 2003/3/13
Y1 - 2003/3/13
N2 - 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.
AB - 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.
KW - γ-secretase
KW - CD44
KW - Intramembranous cleavage
KW - Presenilin
UR - http://www.scopus.com/inward/record.url?scp=0037435016&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037435016&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1206298
DO - 10.1038/sj.onc.1206298
M3 - Article
VL - 22
SP - 1511
EP - 1516
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 10
ER -