Signaling mechanisms of RTKs with membrane-proximal fibronectin type III domains

描述（由申请人提供）：受体酪氨酸激酶（rtk）是用于治疗癌症和其他疾病的许多治疗剂的靶标。这些药物包括抑制rtk细胞内催化活性的小分子酪氨酸激酶抑制剂（TKIs）和靶向细胞外配体结合域的抗体疗法。人类蛋白质组中58种rtk中的许多现已与癌症和其他疾病有关-要么作为致癌驱动因素，要么作为对现有靶向治疗的抗性机制。因此，人们正在努力将EGFR的成功方法推广到其他rtk。在这里，我们将重点放在rtk的Tie1/2和Tyro3/Axl/Mer （TAM）家族上，作为40%的人类rtk在其细胞外区域含有膜近端纤维连接蛋白III型（FNIII）结构域的例子。这两个家族的配体诱导激活机制尚不清楚。现有的结构研究未能揭示配体诱导受体激活的机制。对于Tie2，我们发现膜近端FNIII结构域在受体二聚化和激活中起关键作用。在本研究中，我们将研究rtk的Tie1/2和TAM家族中的膜近端FNIII结构域是否具有共同的机制作用。在我们的具体目标中，我们将处理这些问题：Tie2的膜-近端纤维连接蛋白III型（FNIII）结构域如何调节受体激活状态？2. rtk中膜近端FNIII结构域是否有共同的功能？这些研究将为这两个RTKs家族的调控提供重要的见解，丰富我们对RTKs一般细胞外调控的认识，并为这些受体在癌症和其他疾病状态中异常激活的干预开辟潜在的新途径。

DESCRIPTION (provided by applicant): Receptor tyrosine kinases (RTKs) are the targets of numerous therapeutic agents used in the treatment of cancer and other diseases. These agents include small molecule tyrosine kinase inhibitors (TKIs) that inhibit the intracellular catalytic activity of RTKs and antibody therapeutics that target the extracellular ligand-binding domain. Many of the 58 RTKs in the human proteome have now been implicated in cancer and other diseases - either as oncogenic drivers or in mechanisms of resistance to existing targeted therapies. Accordingly, efforts are underway to extend approaches that have been successful for EGFR, for example, to other RTKs. Here we focus on the Tie1/2 and the Tyro3/Axl/Mer (TAM) families of RTKs as examples of the 40% of human RTKs that contain membrane proximal fibronectin type III (FNIII) domains in their extracellular region. The mechanisms of ligand-induced activation for these two families is poorly characterized. Existing structural studies have failed to reveal the mechanism of ligand- induced receptor activation. For Tie2 we find that the membrane-proximal FNIII domains play a key role in receptor dimerization and activation. In this proposal, we will investigate whether the membrane proximal FNIII domains in the Tie1/2 and TAM families of RTKs share a common mechanistic role. In our specific aims we will address these questions: 1. How do the membrane-proximal fibronectin type III (FNIII) domains of Tie2 regulate receptor activation states? 2. Is there a common function for membrane proximal FNIII domains in RTKs? These studies will provide important insight into the regulation of these two families of RTKs, enriching our appreciation of extracellular regulation of RTKs in general, and opening potential new avenues for intervention where these receptors are aberrantly activated in cancer and other disease states.