Glycosynapses in cancer cell adhesion and signaling

描述（由申请人提供）：我们的研究由基金R 01 CA 80054支持，揭示了控制碳水化合物依赖性或碳水化合物调节的细胞粘附与信号转导偶联的膜微结构域的存在，称为“糖突触”（Glysyn）。Glysyn的结构和功能与某些肿瘤细胞的细胞生长控制和侵袭/转移特性密切相关：（i）Glysyn 1由GM 3、生长因子受体、CD 9或CD 81、Src家族激酶及其生理抑制剂Csk组成。其在转化细胞中的功能与生长控制的丧失（接触抑制）相关。（ii）Glysyn 3由与神经节苷脂（Gg）（特别是GM 3）复合的N-糖基化整联蛋白和四跨膜蛋白（TSP）组成，并抑制整联蛋白依赖性运动，如最初在IdID细胞模型中以及后来在各种人类癌细胞系中发现的。通过Glysyn 3的增加，这些细胞中可能发生恶性丧失或致癌表型的“逆转”。这项建议有两个主要的具体目标：1。阐明人正常上皮细胞与癌细胞系的生长控制机制，类似于先前研究的人肺成纤维细胞WI 38和致癌转化的VA 13细胞。研究的重点是：（a）与生长控制相关的Glysyn 1组合物，特别是Src激酶的Csk依赖性抑制;（B）Glysyn 1中TSP CD 9-CD 81在促进WI 38的接触抑制中的作用，相对于其在VA 13细胞中的损失;（c）相同Glysyn内GM 3与FGFR的相互作用（顺式相互作用）或界面Glysyn之间的相互作用（反式相互作用）。2.阐明Glysyn 3控制肿瘤细胞侵袭力的机制。研究的重点是：（a）组分的表征：TSP、Gg、N-糖基化整联蛋白;（B）它们之间的相互作用;（c）这种相互作用与细胞运动性的相关性;（d）Glysyn 3组分对整联蛋白信号传导的影响;（e）通过Glysyn 3组分的修饰从恶性表型逆转为非恶性表型。

DESCRIPTION (provided by applicant): Our studies supported by grant R01 CA80054 have revealed the presence of membrane microdomains that control carbohydrate-dependent or carbohydrate-modulated cell adhesion coupled with signal transduction, termed "glycosynapses" (Glysyn). Structure and function of Glysyn are correlated closely with cell growth control and invasive/ metastatic properties of certain tumor cells: (i) Glysyn 1 consists of GM3, growth factor receptor, CD9 or CD81, Src family kinase, and its physiological inhibitor Csk. Its function in transformed cells is associated with loss of growth control (contact inhibition), (ii) Glysyn 3 consists of N-glycosylated integrin and tetraspanin (TSP) complexed with ganglioside (Gg) (particularly GM3), and inhibits integrin-dependent motility, as found originally in IdID cell model and later in various human cancer cell lines. Loss of malignancy, or "reversion" of oncogenic phenotype, may occur in these cells through increased Glysyn 3. This proposal has two major Specific Aims: 1. Elucidate the growth control mechanism in human normal epithelial cells vs. cancer cell lines, in analogy to previously-studied human lung fibroblast WI38 and oncogenically transformed VA13 cells. Studies are focused on: (a) Glysyn 1 composition as related to growth control, particularly Csk-dependent inhibition of Src kinase; (b) role of TSP CD9-CD81 in Glysyn 1 in facilitating contact inhibition of WI38 vs. its loss in VA13 cells; (c) role of GM3-to-FGFR interaction within the same Glysyn (cis interaction) or between interfacing Glysyn (trans interaction). 2. Elucidate the mechanisms by which Glysyn 3 controls tumor cell invasiveness. Studies are focused on: (a) characterization of components: TSPs, Gg, N-glycosylated integrins; (b) interactions among them; (c) correlation of such interaction with cell motility; (d) effects of Glysyn 3 components on integrin signaling; (e) reversion from malignant to non-malignant phenotype by modification of Glysyn 3 components.