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¹ Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 kawahara-cho, Shogo-in, Sakyo-ku, Kyoto 606-8317, Japan
² Drug Discovery Research, Research Laboratories, Kyoto R&D Center, Maruho Co., Ltd., 92 Awata-cho, Chudoji, Shimogyo-ku, Kyoto 600-8815, Japan
³ Life Sciences, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

T-cadherin is a glycosyl-phosphatidylinositol (GPI) anchored cadherin molecule. We previously reported that T-cadherin is normally expressed on the basal keratinocytes of the epidermis and is down-regulated in cutaneous squamous cell carcinoma (SCC). We found that expression of T-cadherin in cutaneous squamous carcinoma cells regulated level of surface ß1 integrin, which functioned as extracellular matrix (ECM) receptor. Involvement of T-cadherin in ß1 integrin trafficking was studied using three different stable cell lines with cytomegalovirus (CMV)-driven over-expression, tetracycline (Tet)-inducible expression and RNAi-mediated suppressed expression of T-cadherin. Pulse–chase analysis using a cholesterol-depleting reagent and a tyrosine kinase inhibitor showed that ß1 integrin mainly internalized via caveolae. Over-expression of T-cadherin suppressed the internalization of both ß1 integrin and cholera toxin (CTX), a marker of caveolae-mediated endocytosis. By Western blot analysis of tyrosine-kinase target molecules, we demonstrated a reduced level of EGF receptor (EGFR)-phosphorylation in T-cadherin over-expressing cells. In addition, studies using EGF and EGFR specific inhibitors revealed that EGFR activation stimulated ß1 integrin internalization. Taking these results together, T-cadherin may modulate cell–matrix adhesion in basal keratinocytes as well as invasive potency in SCC by regulating surface level of ß1 integrin.

^* Correspondence: E-mail: mukoyama_bux{at}mii.maruho.co.jp

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