ADAM10 as a gatekeeper of receptor tyrosine kinase activation and trafficking: comparative analysis of cell-morphogenetic and mitogenic Eph and EGF receptor signalling pathways

ADAM10 作为受体酪氨酸激酶激活和运输的看门人：细胞形态发生和促有丝分裂 Eph 和 EGF 受体信号通路的比较分析

• 批准号: 72455513
• 负责人: Dr. Carolin Stegmayer
• 金额: --
• 依托单位: Department of Biochemistry and Molecular Biology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/72455513?language=en
• 关键词: ADAM10; gatekeeper; receptor; tyrosine; kinase

Eph and EGFR receptor tyrosine kinases are key mediators of cell-cell communication, with important roles in normal development and oncogenic transformation. Amongst other functions, they control cell positioning by directing migrating cells. Signalling by Eph and EGFR, amongst other RTKs, is regulated by transmembrane zinc metalloproteases of the ADAM family. ADAM proteolysis releases Eph/ephrin-mediated cell contacts during cell-cell repulsion and shedding of EGFR ligands is a prerequisite for EGFR activation. We propose that ADAMs are gatekeepers for these signalling pathways. Recent findings indicate that shedding may be controlled both through recognition by ADAM of an intact receptor/ligand complex and by the activity and conformation of the RTK cytoplasmic domain. The proposed studies will examine the fate of Eph and EGFR signalling complexes in the context of ADAM-mediated ligand cleavage and subsequent receptor-mediated endocytosis. We propose a comprehensive survey of ADAM-controlled Eph and EGF receptor signalling pathways, in particular those continuing during endocytosis, is essential for achieving a more complete understanding of cell-cell communication mechanisms. In the context of tumour biology, these new insights into ADAMcontrolled RTK signalling will aid development or optimisation of therapeutic approaches targeting de-regulated RTK function.

Eph和EGFR受体酪氨酸激酶是细胞间通讯的关键介质，在正常发育和致癌转化中具有重要作用。在其他功能中，它们通过引导迁移细胞来控制细胞定位。通过Eph和EGFR以及其他RTK的信号传导受ADAM家族的跨膜锌金属蛋白酶调节。ADAM蛋白水解在细胞-细胞排斥期间释放Eph/肝配蛋白介导的细胞接触，并且EGFR配体的脱落是EGFR活化的先决条件。我们认为亚当斯是这些信号通路的守门人。最近的研究结果表明，脱落可能是通过识别一个完整的受体/配体复合物的ADAM和RTK胞质结构域的活性和构象控制。拟议的研究将检查Eph和EGFR信号复合物在ADAM介导的配体裂解和随后的受体介导的内吞作用的背景下的命运。我们提出了一个全面的调查ADAM控制的Eph和EGF受体信号通路，特别是那些持续在胞吞作用，是必不可少的实现更完整的理解细胞间的通信机制。在肿瘤生物学的背景下，这些对ADAM控制的RTK信号传导的新见解将有助于开发或优化针对失调RTK功能的治疗方法。