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 journalArticle

108 Citations (Scopus)

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 languageEnglish
Pages (from-to)1511-1516
Number of pages6
JournalOncogene
Volume22
Issue number10
DOIs
Publication statusPublished - 2003 Mar 13
Externally publishedYes

Fingerprint

Presenilins
Amyloid Precursor Protein Secretases
Tetradecanoylphorbol Acetate
Signal Transduction
Physiological Phenomena
Pathologic Processes
Extracellular Matrix
Fibroblasts
Cell Membrane
Neoplasm Metastasis
Growth
Neoplasms

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 journalArticle

Murakami, D, Okamoto, I, Nagano, O, Kawano, Y, Tomita, T, Iwatsubo, T, De Strooper, B, Yumoto, E & Saya, H 2003, 'Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44', Oncogene, vol. 22, no. 10, pp. 1511-1516. https://doi.org/10.1038/sj.onc.1206298
Murakami, Daizo ; Okamoto, Isamu ; Nagano, Osamu ; Kawano, Yoshiaki ; Tomita, Taisuke ; Iwatsubo, Takeshi ; De Strooper, Bart ; Yumoto, Eiji ; Saya, Hideyuki. / Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44. In: Oncogene. 2003 ; Vol. 22, No. 10. pp. 1511-1516.
@article{4e8b845467654284b55cba822ec2b625,
title = "Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44",
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.",
keywords = "γ-secretase, CD44, Intramembranous cleavage, Presenilin",
author = "Daizo Murakami and Isamu Okamoto and Osamu Nagano and Yoshiaki Kawano and Taisuke Tomita and Takeshi Iwatsubo and {De Strooper}, Bart and Eiji Yumoto and Hideyuki Saya",
year = "2003",
month = "3",
day = "13",
doi = "10.1038/sj.onc.1206298",
language = "English",
volume = "22",
pages = "1511--1516",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "10",

}

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 -