Interactions of CD147 Involved in MMP Induction

CD147 参与 MMP 诱导的相互作用

• 批准号: 6875392
• 负责人: MARTIN E HEMLER
• 金额: $ 27.61万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875392
• 关键词: binding sites; carcinogenesis; cell line; collagenase; gene induction /repression; human tissue; integrins; intermolecular interaction; laboratory mouse; membrane proteins; metalloendopeptidases; neoplasm /cancer invasiveness; neoplastic cell; neoplastic growth; oncoproteins; protein protein interaction; protein structure function; receptor binding

DESCRIPTION (provided by applicant): The cell surface IgSF protein CD147/EMMPRIN/basigin, binds to peritumor stromal cells or to other tumor cells, leading to MMP production, extracellular matrix degradation, and elevated tumor invasion and metastasis. Despite the growing CD 147 literature (300 papers in Medline), relevant counter-receptors remain to be identified, and mechanisms for MMP induction and tumor regulatory functions need to be established. We now define six molecular targets likely to be important for CD 147 function. These targets include novel CD 147 counter-receptor molecules, the homophilic ligand binding site (within the first Ig domain of CD 147), integrin association site (first Ig domain), the site required for caveolin-1 association (second Ig domain), a potential transmembrane domain interaction site, and a cytoplasmic domain site involved in MMP "induction. We propose to rigorously test the importance of each of these target sites for coordinated associations with other proteins, for MMP production in vitro, and for tumorigenicity in vivo. First, we will identify and characterize the CD 147 counter-receptors utilized during MMP-1 and MMP-2 induction. Second, we will determine CD 147 domain 1 sites required for counter-receptor binding and association with o3j81 integrin, and then we will evaluate the role of these sites during MMP-1 and MMP-2 production. Third, we will utilize domain 2 mutants to test the hypothesis that CD147-caveolin-l complexes suppress MMP induction by preventing CD 147 glycosylation and multimerization. Fourth, we will investigate the role of a highly conserved transmembrane glutamic residue (E218) with respect to protein-protein associations (including monocarboxylate transporter association), and CD147 MMP-inducing functions. Fifth, the CD147 cytoplasmic tail will be used as a probe to search for associated intracellular molecules critical for CD147 functions. Sixth, key mutants defined and characterized in Aims 2-5 will be expressed in breast cancer cell lines and tested for effects on tumor cells in vitro and in orthotopic mouse models in vivo. Our new insights into the coordination of counter-receptor binding, MMP induction, cell adhesion, lactate utilization, and caveolin/microdomain organization should provide an integrated framework in which to better understand the dramatic effects of CD 147 on the invasive behavior of tumor cells.

描述（申请人提供）：细胞表面IgSF蛋白CD147/EMMPRIN/basigin与肿瘤周围基质细胞或其他肿瘤细胞结合，导致MMP产生、细胞外基质降解以及肿瘤侵袭和转移增加。尽管 CD 147 文献不断增加（Medline 中有 300 篇论文），但相关的反受体仍有待确定，并且需要建立 MMP 诱导和肿瘤调节功能的机制。我们现在定义了可能对 CD 147 功能重要的 6 个分子靶点。这些靶标包括新型 CD 147 反受体分子、同源配体结合位点（CD 147 的第一个 Ig 结构域内）、整联蛋白关联位点（第一个 Ig 结构域）、caveolin-1 关联所需的位点（第二个 Ig 结构域）、潜在的跨膜结构域相互作用位点以及参与 MMP“诱导”的细胞质结构域位点。我们建议严格测试 这些靶位点中的每一个都与其他蛋白质协调关联、体外产生 MMP 以及体内致瘤性。首先，我们将鉴定并表征 MMP-1 和 MMP-2 诱导过程中使用的 CD 147 反受体。其次，我们将确定反受体结合和与 o3j81 整联蛋白关联所需的 CD 147 结构域 1 位点，然后我们将评估这些位点的作用 MMP-1 和 MMP-2 生产过程中的位点。第三，我们将利用结构域 2 突变体来检验 CD147-caveolin-1 复合物通过阻止 CD 147 糖基化和多聚化来抑制 MMP 诱导的假设。第四，我们将研究高度保守的跨膜谷氨酸残基（E218）在蛋白质-蛋白质关联（包括单羧酸 转运蛋白协会）和 CD147 MMP 诱导功能。第五，CD147细胞质尾部将用作探针来寻找对CD147功能至关重要的相关细胞内分子。第六，目标 2-5 中定义和表征的关键突变体将在乳腺癌细胞系中表达，并在体外和原位小鼠模型体内测试对肿瘤细胞的影响。我们的新 对反受体结合、MMP 诱导、细胞粘附、乳酸利用和小窝蛋白/微结构域组织协调的深入了解应该提供一个综合框架，以便更好地理解 CD 147 对肿瘤细胞侵袭行为的显着影响。