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First published online June 28, 2004
doi: 10.1242/10.1242/jcs.01201

Journal of Cell Science 117, 3379-3388 (2004)
Published by The Company of Biologists 2004
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Research Article

CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells

Yoko Murayama1,*, Jun-ichiro Miyagawa1, Kenji Oritani1, Hitoshi Yoshida1, Katsumi Yamamoto1, Osamu Kishida1, Tamana Miyazaki1, Shusaku Tsutsui1, Tatsuya Kiyohara1, Yoshiji Miyazaki1, Shigeki Higashiyama2, Yuji Matsuzawa1 and Yasuhisa Shinomura1

1 Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 B5, Yamadaoka, Suita 565-0871, Japan
2 Department of Medical Biochemistry, Ehime University School of Medicine, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan

* Author for correspondence (e-mail: yokom{at}imed2.med.osaka-u.ac.jp)

Accepted 8 March 2004

CD9, a member of the tetraspanin family, has been shown to be involved in a range of cellular activities, including migration, proliferation and adhesion, but the molecular mechanisms by which it mediates such events is unclear. Here, we found that anti-CD9 monoclonal antibody ALB6 inhibited cell proliferation, reduced cell viability and induced not only morphological changes specific to apoptosis but also molecular changes, as evidenced by TUNEL and annexin-V staining. For the possible mechanism of ALB6-induced apoptosis, ALB6 activated the c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 mitogen-activated-protein kinase (MAPK) within 5-15 minutes, as well as caspase-3 within 24-48 hours. It is noteworthy that ALB6 induced tyrosine phosphorylation of the p46 Shc isoform specifically and that the overexpression of its dominant-negative form completely suppressed the ALB6-induced activation of JNK/SAPK, p38 MAPK and caspase-3, resulting in the inhibition of apoptotic cell death. These results suggest that CD9 might regulate apoptosis through the specialized signals in human cancer cell lines.

Key words: CD9, Tetraspanin, Apoptosis, Shc, Cancer cells




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