CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration

Isamu Okamoto, Yoshiaki Kawano, Hiromasa Tsuiki, Ji Ichiro Sasaki, Mitsuyoshi Nakao, Mitsuhiro Matsumoto, Moritaka Suga, Masayuki Ando, Motowo Nakajima, Hideyuki Saya

Research output: Contribution to journalArticle

190 Citations (Scopus)

Abstract

CD44 is a cell surface receptor for hyaluronate, a component of the extracellular matrix (ECM). Although CD44 has been implicated in tumor invasion and metastasis, the molecular mechanisms remain to be elucidated. Here we find that CD44 expressed in cancer cells is cleaved at the membrane-proximal region of the ectodomain and the membrane-bound cleavage product can be detected using an antibody against the cytoplasmic domain of CD44. Furthermore, we report that CD44 cleavage is mediated by a membrane-associated metalloprotease expressed in cancer cells. A tissue inhibitor of metalloproteases-1 (TIMP-1), as well as metalloprotease inhibitors, inhibit CD44 cleavage in the cell-free assay. Contrary, serine protease inhibitors enhance CD44 cleavage, and the enhancement can be prevented by pretreatment with a metalloprotease inhibitor. Thus, CD44 cleavage is regulated by an intricate balance between some proteases and their inhibitors. Interestingly, treatment with the metalloprotease blocker 1,10-phenanthroline, which strongly prevent the CD44 cleavage, suppressed RERF-LC-OK lung cancer cell migration on a hyaluronate substrate, but not on several other substrates. These results suggest that CD44 cleavage plays a critical role in an efficient cell-detachment from a hyaluronate substrate during the cell migration and consequently promotes CD44-mediated cancer cell migration. Our present data indicate that CD44, not only ECM per se, is one of the targets of pericellular proteolysis involved in tumor invasion and metastasis.

Original languageEnglish
Pages (from-to)1435-1446
Number of pages12
JournalOncogene
Volume18
Issue number7
Publication statusPublished - 1999 Feb 18
Externally publishedYes

Fingerprint

Metalloproteases
Cell Movement
Membranes
Neoplasms
Extracellular Matrix
Neoplasm Metastasis
Serine Proteinase Inhibitors
Cell Surface Receptors
Protease Inhibitors
Proteolysis
Lung Neoplasms
Antibodies

Keywords

  • CD44
  • Cleavage
  • Hyaluronic acid
  • Metalloprotease
  • Tumor cell migration

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Okamoto, I., Kawano, Y., Tsuiki, H., Sasaki, J. I., Nakao, M., Matsumoto, M., ... Saya, H. (1999). CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration. Oncogene, 18(7), 1435-1446.

CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration. / Okamoto, Isamu; Kawano, Yoshiaki; Tsuiki, Hiromasa; Sasaki, Ji Ichiro; Nakao, Mitsuyoshi; Matsumoto, Mitsuhiro; Suga, Moritaka; Ando, Masayuki; Nakajima, Motowo; Saya, Hideyuki.

In: Oncogene, Vol. 18, No. 7, 18.02.1999, p. 1435-1446.

Research output: Contribution to journalArticle

Okamoto, I, Kawano, Y, Tsuiki, H, Sasaki, JI, Nakao, M, Matsumoto, M, Suga, M, Ando, M, Nakajima, M & Saya, H 1999, 'CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration', Oncogene, vol. 18, no. 7, pp. 1435-1446.
Okamoto I, Kawano Y, Tsuiki H, Sasaki JI, Nakao M, Matsumoto M et al. CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration. Oncogene. 1999 Feb 18;18(7):1435-1446.
Okamoto, Isamu ; Kawano, Yoshiaki ; Tsuiki, Hiromasa ; Sasaki, Ji Ichiro ; Nakao, Mitsuyoshi ; Matsumoto, Mitsuhiro ; Suga, Moritaka ; Ando, Masayuki ; Nakajima, Motowo ; Saya, Hideyuki. / CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration. In: Oncogene. 1999 ; Vol. 18, No. 7. pp. 1435-1446.
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