T-cadherin enhances cell-matrix adhesiveness by regulating beta1 integrin trafficking in cutaneous squamous carcinoma cells.
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 beta1 integrin, which functioned as extracellular matrix (ECM) receptor. Involvement of T-cadherin in beta1 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 beta1 integrin mainly internalized via caveolae. Over-expression of T-cadherin suppressed the internalization of both beta1 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 beta1 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 beta1 integrin.
Mukoyama
Yohei
Y
Department of Dermatology, Graduate School of Medicine, Kyoto University, 54 kawahara-cho, Shogo-in, Sakyo-ku, Kyoto 606-8317, Japan. mukoyama_bux@mii.maruho.co.jp
Utani
Atsushi
A
Matsui
Seiya
S
Zhou
Shuxia
S
Miyachi
Yoshiki
Y
Matsuyoshi
Norihisa
N
D015820:Cadherins / Q000096:biosynthesis* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D017261:Glycosylphosphatidylinositols / Q000737:chemistry; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism*
D015820:Cadherins; D017261:Glycosylphosphatidylinositols; C099972:H-cadherin; D019012:Integrin beta1; D066246:ErbB Receptors