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

• Published in: Oncogene Vol. 18; no. 7; pp. 1435 - 1446
• Main Authors: OKAMOTO, I, KAWANO, Y, TSUIKI, H, SASAKI, J.-I, NAKAO, M, MATSUMOTO, M, SUGA, M, ANDO, M, NAKAJIMA, M, SAYA, H
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 18.02.1999; Nature Publishing Group
• Subjects: Amino Acid Sequence; Binding Sites; Biological and medical sciences; Cancer; CD44 antigen; Cell adhesion & migration; Cell migration; Cell Movement; Cell physiology; Cell surface; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cysteine Proteinase Inhibitors - pharmacology; Cytoplasm; Extracellular matrix; Fundamental and applied biological sciences. Psychology; Humans; Hyaluronan Receptors - immunology; Hyaluronan Receptors - metabolism; Hyaluronic Acid; Lung cancer; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - metabolism; Metalloproteinase; Metastases; Metastasis; Molecular and cellular biology; Molecular modelling; Molecular Sequence Data; Mutagenesis; Protease Inhibitors - pharmacology; Proteinase inhibitors; Proteolysis; Serine proteinase; Serine Proteinase Inhibitors - pharmacology; Tissue inhibitor of metalloproteinase 1; Tissue Inhibitor of Metalloproteinase-1 - pharmacology; Tumor Cells, Cultured; Tumors; Human; Enzyme; Induction; Metalloendopeptidases; Metastasis; Gene expression; Peptidases; Cell motility; Regulation(control); Cell line; Gene; Proteolysis; Tumor progression; Hydrolases; Tumor; Tumor cell
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1202447

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.