Interactions of CD147 Involved in MMP Induction

CD147 参与 MMP 诱导的相互作用

• 批准号: 7109287
• 负责人: MARTIN E HEMLER
• 金额: $ 29.24万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7109287
• 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（由申请人提供）：细胞表面IgSF蛋白CD 147/EMMPRIN/basigin与瘤周基质细胞或其他肿瘤细胞结合，导致MMP产生、细胞外基质降解和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鉴定，MMP诱导和肿瘤调节功能的机制需要建立。我们现在定义了可能对CD 147功能重要的六个分子靶点。这些靶点包括新的CD 147反受体分子、嗜同性配体结合位点（在CD 147的第一个IG结构域内）、整联蛋白结合位点（第一个IG结构域）、小窝蛋白-1结合所需的位点（第二个IG结构域）、潜在的跨膜结构域相互作用位点和参与MMP-1诱导的胞质结构域位点.我们建议严格测试的重要性，这些目标网站协调协会与其他蛋白质，MMP生产在体外，在体内致瘤性。首先，我们将鉴定和表征MMP-1和MMP-2诱导过程中使用的CD 147反受体。第二，我们将确定CD 147结构域1与α 3 β 81整联蛋白结合和结合所需的位点，然后我们将评估这些位点在MMP-1和MMP-2产生过程中的作用。第三，我们将利用结构域2突变体来检验CD 147-小窝蛋白-I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-蛋白质结合（包括单羧酸转运蛋白结合）和CD 147 MMP诱导功能中的作用。第五，CD 147胞质尾区将用作探针，以寻找对CD 147功能至关重要的相关细胞内分子。第六，在目的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，并在体外和体内原位小鼠模型中测试对肿瘤细胞的作用。我们对反受体结合、MMP诱导、细胞粘附、乳酸盐利用和小窝蛋白/微区组织的协调的新见解应该提供一个综合框架，以更好地理解CD 147对肿瘤细胞侵袭行为的显著影响。