Roles of glycosphinglipids in converging process of the cell signals of proliferation and adhesion in cancer cells.

在本研究中，我们研究了神经节苷脂GD3在GD3+人黑色素瘤细胞中通过在细胞膜附近形成分子复合物，参与癌细胞增殖和粘附细胞信号的汇聚过程。我们报道了神经节苷脂GD3在胎牛血清刺激后促进细胞增殖和黑色素瘤侵袭，导致FAK、p130Cas和paxillin的酪氨酸磷酸化增强。除了通过生长因子/受体的信号外，通过整合素的粘附信号也可能被GD3增强。本研究考察了整合素介导的信号通路在细胞增殖和侵袭中的作用，以及在接头分子激活中的作用，表明整合素β1在细胞生长和侵袭中也很重要。在无血清的情况下，FAK、p130Cas和paxillin在GD3+细胞中酪氨酸磷酸化比在GD3-细胞中更强。此外，在膜附近寻找由GD3激活的分子。在黑色素瘤细胞系中表达的Src家族激酶（SFKs），即Yes、Src和Fyn中，只有Yes参与细胞增殖和侵袭等恶性特性。因此，在GD3+细胞中，研究表明整合素参与细胞生长和侵袭，并且在细胞粘附过程中观察到FAK， p130Cas和paxillin的活化与fcs处理细胞中检测到的相似。这些结果表明，神经节苷脂GD3在细胞增殖和粘附两大信号通路的聚合过程中起重要作用，导致GD3+人黑色素瘤细胞细胞膜附近FAK、p130Cas和paxillin的强烈激活。现在，我们正在研究GD3在细胞膜附近触发细胞增殖和粘附信号转换的分子机制。

In this study, we have investigated the roles of ganglioside GD3 in converging process of the cell signals of proliferation and adhesion in cancer cells by forming molecular complex in the vicinity of cell membrane in GD3+human melanoma cells.We reported that ganglioside GD3 enhances cell proliferation and invasion of melanomas causing stronger tyrosine-phosphorylation of FAK, p130Cas and paxillin after stimulation with fetal calf serum. Besides signals via growth factor/receptor, adhesion signals via integrin might be also enhanced by GD3. Here, roles of integrin-mediated signaling in the cell proliferation and invasion, and in the activation of adaptor molecules were examined, showing that integrin β1 was also important for the cell growth and invasion. FAK, p130Cas and paxillin underwent stronger tyrosine-phosphorylation in GD3+ cells than in GD3- cells during the adhesion to collagen type I in the absence of serum. Furthermore, molecules activated by GD3 in the vicinity of membranes were searched. Among Src family kinases (SFKs), i.e. Yes, Src and Fyn expressed in the melanoma cell lines, only Yes was involved in the malignant properties such as cell proliferation and invasion.Consequently, in GD3+ cells, it was demonstrated that integrins are involved in cell growth and invasion, and similar activation of FAK, p130Cas and paxillin during cell adhesion to those detected in FCS-treated cells was observed. These results suggest that ganglioside GD3 is important for converging process of the two major signaling pathways for cell proliferation and adhesion leading to strong activation of FAK, p130Cas and paxillin in the vicinity of cell membrane in GD3+ human melanoma cells.Now, we are investigating the molecular mechanisms for the triggering of the conversion of the signals for cell proliferation and adhesion by GD3, in the vicinity of cell membrane.