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

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 PS1 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.

We are grateful to Dr Yasuo Ihara (University of Tokyo) for providing antibody C4; Dr WG Stetler-Stevenson for providing BB94; and members of the Gene Technology Center in Kumamoto

University for their important contributions to the experiments. We wish to thank Yoshimi Fukushima for secretarial assistance. This work was supported by a grant for cancer research from

the Ministry of Education, Science and Culture of Japan (HS) and ‘Research for the Future’ program of the Japan Society for the Promotion of Science (HS).

Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto, 860-0811, Japan

Daizo Murakami, Osamu Nagano, Yoshiaki Kawano & Hideyuki Saya

Department of Otolaryngology-Head and Neck Surgery, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

First Department of Internal Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

Center for Human Genetics, KU Leuven and Flanders Interuniversity Institute for Biotechnology (VIB), Herestraat 49, Leuven, 3000, Belgium

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