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J Biol Chem, Vol. 274, Issue 36, 25525-25534, September 3, 1999

Regulated CD44 Cleavage under the Control of Protein Kinase C, Calcium Influx, and the Rho Family of Small G Proteins

Isamu OkamotoDagger §, Yoshiaki KawanoDagger , Mitsuhiro Matsumoto§, Moritaka Suga§, Kozo Kaibuchi, Masayuki Ando§, and Hideyuki SayaDagger

From the Dagger  Department of Tumor Genetics and Biology and the § First Department of Internal Medicine, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, the  Division of Signal Transduction, Nara Institute of Science and Technology, Ikoma, 630-0101, Japan

CD44 is a cell surface receptor for several extracellular matrix components and is implicated in tumor cell invasion and metastasis. Our previous studies have shown that CD44 expressed in cancer cells is proteolytically cleaved at the extracellular domain through membrane-associated metalloproteases and that CD44 cleavage plays a critical role in CD44-mediated tumor cell migration (Okamoto, I., Kawano, Y., Tsuiki, H., Sasaki, J., Nakao, M., Matsumoto, M., Suga, M., Ando, M., Nakajima, M., and Saya, H. (1999) Oncogene 18, 1435-1446). In the present study, we first demonstrate rapid degradation of the membrane-tethered CD44 cleavage product through intracellular proteolytic pathways, and it occurs only after CD44 extracellular cleavage. To address the mechanisms regulating CD44 cleavage at the extracellular domain, we show that 12-O-tetradecanoylphorbol 13-acetate (TPA) and the calcium ionophore ionomycin rapidly enhance metalloprotease-mediated CD44 cleavage in U251MG cells via protein kinase C-dependent and -independent pathways, respectively, suggesting the existence of multiple distinct pathways for regulation of CD44 cleavage. Concomitant with TPA-induced CD44 cleavage, TPA treatment induces redistribution of CD44 and ERM proteins (ezrin, radixin, and moesin) to newly generated membrane ruffling areas. Treatment with lysophosphatidic acid, which is known to activate the Rho-dependent pathway, inhibits TPA-induced CD44 redistribution and CD44 cleavage. Furthermore, overexpression of Rac dominant active mutants results in the redistribution of CD44 to the Rac-induced ruffling areas and the enhancement of CD44 cleavage. These results suggest that the Rho family proteins play a role in regulation of CD44 distribution and cleavage.

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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