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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 cellmatrix 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 cellmatrix interaction and cell migration.
Key Words: CD44; ADAM10; ADAM17; calmodulin; Rac
Abbreviations used in this paper: HA, hyaluronic acid; HB-EGF, heparin-binding epidermal growth factorlike growth factor; MEF, mouse embryonic fibroblast; MMP, matrix metalloproteinase; TFP, trifluoperazine.
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