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

Eph和EGFR受体酪氨酸激酶是细胞间通讯的关键介质，在正常发育和癌性转化中发挥重要作用。在其他功能中，它们通过引导迁移细胞来控制细胞定位。在其他rtk中，Eph和EGFR的信号是由ADAM家族的跨膜锌金属蛋白酶调节的。在细胞间排斥和EGFR配体脱落过程中，ADAM蛋白水解释放Eph/ephrin介导的细胞接触是EGFR激活的先决条件。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，脱落可能通过ADAM对完整受体/配体复合物的识别以及RTK细胞质结构域的活性和构象来控制。拟议的研究将检查Eph和EGFR信号复合物在adam介导的配体切割和随后的受体介导的内吞作用的背景下的命运。我们建议对adam控制的Eph和EGF受体信号通路进行全面调查，特别是在内吞过程中继续进行的信号通路，对于更全面地了解细胞-细胞通信机制至关重要。在肿瘤生物学的背景下，这些关于ADAMcontrolled RTK信号传导的新见解将有助于开发或优化针对RTK功能去调控的治疗方法。

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.