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The tetraspanin membrane protein CD151 has been suggested to regulate cancer invasion and metastasis by initiating signaling events. The CD151-mediated signaling pathways involved in this regulation remain to be revealed. In this study, we found that stable transfection of CD151 into MelJuSo human melanoma cells lacking CD151 expression significantly increased cell motility, matrix metalloproteinase-9 (MMP-9) expression, and invasiveness. The enhancement of cell motility and MMP-9 expression by CD151 overexpression was abrogated by inhibitors and small interfering RNAs targeted to focal adhesion kinase (FAK), Src, p38 MAPK, and JNK, suggesting an essential role of these signaling components in CD151 signaling pathways. Also, CD151-induced MMP-9 expression was shown to be mediated

CD99, a cell surface glycoprotein with a molecular mass of 32 kDa, was originally described as a human thymus leukemia antigen (1), a Ewing sarcoma-specific membrane marker molecule (2, 3), and a putative adhesion molecule (termed E2) involved in spontaneous rosette formation of T cells with erythrocytes (4 -7). CD99 is broadly distributed on many cell types, with particularly strong expression on human cortical thymocytes, Ewing sarcoma cells, and peripheral primitive neuroectodermal tumors (3,8). The functional role of CD99 is not fully understood, and most information about its functions is derived from triggering CD99-mediated signaling events with agonistic CD99 monoclonal antibodies (mAbs) 2 in hematopoietic cells. In normal cells, CD99 has been functionally implicated in cell adhesion, migration, apoptosis, differentiation, activation, and proliferation of lymphocytes and monocyte extravasation and transport of several transmembrane proteins (9 -19). In particular, the role of CD99 in the modulation of cell adhesion has been demonstrated by the ability of anti-CD99 mAbs to induce homotypic aggregation of CD4 ϩ CD8 ϩ thymocytes, whereas other anti-CD99 antibodies block spontaneous T cell-erythrocyte rosette formation (4,6,11,20). It was also shown that antibody ligation of CD99 molecules up-regulated the expression of LFA-1 (␣ L ␤ 2 integrin), and CD99-induced cell aggregation was blocked by the addition of mAbs to LFA-1 or intracellular adhesion molecule 1 (ICAM-1) in a B cell line (20). These results suggest that signal transduction via CD99 modulates cell adhesion of lymphocytes by regulating the expression level of the cell adhesion molecule, integrin LFA-1. Several signal transducing molecules, including MAPKs and protein kinase C, have been found to mediate CD99-dependent cell adhesion of T cells (21,22). In addition, it was found that CD99 on one cell binds to another neighboring CD99 on the next, indicating that CD99 is a homophilic cell surface interacting protein (18). However, the molecular mechanisms of CD99-mediated signal transduction remain largely unknown.

Background: CD81-associated tetraspanins influence the invasive and metastatic processes of various cancer cell types. Results: CD81-Akt signaling induces Sp1-mediated MT1-MMP expression, which enhances melanoma cell motility and invasiveness. Conclusion: CD81 functions as an inducer of MT1-MMP that plays a role in melanoma invasive processes. Significance: This study provides the first evidence that CD81 contributes to cancer malignant progression and elucidates the underlying mechanism.

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