Regulated CD44 cleavage under the control of protein kinase C, calcium influx, and the rho family of small G proteins

Isamu Okamoto, Yoshiaki Kawano, Mitsuhiro Matsumoto, Moritaka Suga, Kozo Kaibuchi, Masayuki Ando, Hideyuki Saya

研究成果: Article

88 引用 (Scopus)

抜粋

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.

元の言語English
ページ(範囲)25525-25534
ページ数10
ジャーナルJournal of Biological Chemistry
274
発行部数36
DOI
出版物ステータスPublished - 03-09-1999
外部発表Yes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

フィンガープリント Regulated CD44 cleavage under the control of protein kinase C, calcium influx, and the rho family of small G proteins' の研究トピックを掘り下げます。これらはともに一意のフィンガープリントを構成します。

  • これを引用