小分子探针对肿瘤细胞表面整合素 (Integrin) 胞外蛋白质配体的标记与识别

Integrin is a family of membrane proteins widely distributed in numerous cell and tissue types. By binding to specific protein ligands in the extracellular matrix or on the membrane of neighboring cells, integrins regulate many key aspects of cell adhesion properties and related signaling transductions. Consequently, integrins play important roles in numerous cellular activities including cell migration, proliferation, angiogenesis, etc. Many tumor cells over-express integrins in order to improve their motility and invasiveness, therefore enhancing tumor’s ability in metastasis and angiogenesis. Indeed, integrins have been intensively pursued as a major class of anti-cancer drug targets. In addition, imaging probes based on integrin-specific ligands are extensively used in cancer diagnostics to detect metastasis and to evaluate efficacy of treatment. However, due to integrin’s nature as a family of membrane proteins, comprehensive profiling and accurate characterization of its extracellular protein ligands has been proved to be extremely challenging. Herein we propose a novel DNA-programmed small-molecule probe strategy, which can enable the direct interrogation of protein-protein interactions on the surface of live cells. We propose to use this strategy to label and identify extracellular ligand proteins for a variety of integrins in cancer cells. We expect the proposed research will provide novel and useful tools for studying integrin’s molecular mechanisms, discovering drug candidates, and developing versatile imaging probes targeting integrin in various forms of cancers.

整合素 (integrin) 是一类通过结合多种蛋白质配体，实现细胞内外信号传导的重要膜蛋白。整合素调控细胞与环境、细胞与细胞之间的相互作用，影响细胞增殖、分化、迁移、形态变化、免疫应答等重要生命活动。整合素在多种恶性肿瘤中高度表达，促进肿瘤血管生成和癌转移，是抗肿瘤药物研发和疾病诊断的一类重要靶标。由于整合素作为膜蛋白的性质，当今尚缺乏对其细胞外所结合的配体蛋白质进行准确、全面、特异性的识别和分析方法。本申请提出一种新颖的基于DNA模板控制的分子探针方法，以实现在活细胞表面对“蛋白质-蛋白质”相互作用的表征，从而能够用于肿瘤细胞整合素胞外配体蛋白的标记与识别。由于整合素与胞外配体的相互作用对其在细胞中的生物功能至关重要，因此本申请的研究内容对探索癌症分子机理、抗肿瘤药物研发、以及疾病诊断成像方面，具有重要的科学和实际意义。

整合素 (integrin) 是一类通过结合多种蛋白质配体，实现细胞内外信号传导的重要膜蛋白。由于整合素作为膜蛋白的性质，当今尚缺乏对其细胞外配体蛋白质进行准确、全面、特异性分析的有效方法。在本项目的执行中，我们拓展了基于DNA模板控制的分子探针方法 (DNA-Programmed Affinity Labeling, DPAL)，实现了在活细胞表面对膜蛋白的特异性标记，从而本方法能够用于对膜蛋白的胞外配体蛋白的标记与识别，以及用于细胞内复杂复合体的蛋白质成分解析。在膜蛋白DNA标记的基础之上，本项目进一步实现了对整合素的胞外配体蛋白的识别工作。.本项目研究成果一方面发展了新颖的膜蛋白和蛋白质复合体标记技术，一方面发现了众多新颖的的整合素胞外配体蛋白。例如，在膜蛋白方面，我们发现了多个潜在的新颖整合素配体蛋白，并且发现了integrin-LRC15-MT2A 的蛋白质复合体，有潜力成为一种新颖的细胞传导通路，从而为进一步的细胞分子机理的基础研究，以及相应的靶点识别和药物研发等应用研究，提供了重要的科学基础和技术手段。

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