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Published online 14 June 2004. doi:10.1083/jcb.200310024
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 6, 893-902
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Article

Cell–matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca2+ influx and PKC activation



Osamu Nagano1,2, Daizo Murakami1, Dieter Hartmann3, Bart de Strooper3, Paul Saftig4, Takeshi Iwatsubo5, Motowo Nakajima6, Masanori Shinohara2, and Hideyuki Saya1

1 Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
2 Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan
3 Center for Human Genetics, KU Leuven and Flanders Interuniversity Institute for Biotechnology (VIB), 3000 Leuven, Belgium
4 Biochemical Institute, Christian-Albrechts-University, D-24118 Kiel, Germany
5 Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Science, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
6 Tsukuba Research Institute, Novartis Pharma K.K., Ohkubo 8, Tsukuba, Ibaraki 300-2611, Japan

Address correspondence to Hideyuki Saya, Dept. of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Tel.: 81-96-373-5116. Fax: 81-96-373-5120. email: hsaya{at}gpo.kumamoto-u.ac.jp

CD44 is an adhesion molecule that interacts with hyaluronic acid (HA) and undergoes sequential proteolytic cleavages in its ectodomain and intramembranous domain. The ectodomain cleavage is triggered by extracellular Ca2+ influx or the activation of protein kinase C. Here we show that CD44-mediated cell–matrix adhesion is terminated by two independent ADAM family metalloproteinases, ADAM10 and ADAM17, differentially regulated in response to those stimuli. Ca2+ influx activates ADAM10 by regulating the association between calmodulin and ADAM10, leading to CD44 ectodomain cleavage. Depletion of ADAM10 strongly inhibits the Ca2+ influx-induced cell detachment from matrix. On the other hand, phorbol ester stimulation activates ADAM17 through the activation of PKC and small GTPase Rac, inducing proteolysis of CD44. Furthermore, depletion of ADAM10 or ADAM17 markedly suppressed CD44-dependent cancer cell migration on HA, but not on fibronectin. The spatio-temporal regulation of two independent signaling pathways for CD44 cleavage plays a crucial role in cell–matrix interaction and cell migration.

Key Words: CD44; ADAM10; ADAM17; calmodulin; Rac

The online version of this article contains supplemental material.

Abbreviations used in this paper: HA, hyaluronic acid; HB-EGF, heparin-binding epidermal growth factor–like growth factor; MEF, mouse embryonic fibroblast; MMP, matrix metalloproteinase; TFP, trifluoperazine.


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