文章：

致癌III类受体酪氨酸激酶的细胞外组装和激活原理

Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases

原文发布日期：2012-10-18

DOI: 10.1038/nrc3371

类型: Review Article

开放获取: 否

要点：

1. Receptor tyrosine kinases (RTKs) are known to be mutated in human tumours.
2. Functioning as molecular antennae that ultimately transduce downstream signalling, all RTKs exhibit a modular architecture that projects an extracellular ligand-binding domain to capture incoming molecular signals, a single membrane-spanning helix facilitating their localization in the membrane and a conserved intracellular tyrosine kinase domain (TKD) that undergoes chemical modification to trigger associations with other intracellular proteins.
3. Originally grouped under the umbrella of the platelet-derived growth factor receptor (PDGFR) family, the class III RTK (RTK-III) family includes five members: the KIT receptor, the colony-stimulating factor 1 receptor (CSF1R), the Fms-like tyrosine kinase 3 receptor (FLT3), PDGFRα and PDGFRβ.
4. The recent application of hybrid methods in structural biology to provide structural views of nearly all RTK-III complexes, including three complete ectodomain complexes, has offered an unprecedented plethora of structural and mechanistic insights that now decisively address a host of long-standing questions.
5. The wealth of structural information on RTK-III ectodomains provides the opportunity to map confirmed somatic mutations that are associated with cancer to specific extracellular segments of RTK-IIIs in order to rationalize their role in abberant receptor activation in cancer development and progression.
6. These structural and mechanistic insights also open avenues for the development of new drugs that target these receptors outside of the TKD domain. For example, the structure of PDGF in complex with a regulatory propeptide might provide a good starting point for the rational design of antagonists for PDGF signalling.

要点翻译：

1. 受体酪氨酸激酶（RTK）已知在人类肿瘤中存在突变。
2. 作为最终转导下游信号的分子天线，所有RTK均采用模块化结构：突出胞外的配体结合域用于捕获外来分子信号，单个跨膜螺旋帮助其定位于细胞膜，以及一个保守的胞内酪氨酸激酶结构域（TKD）通过化学修饰触发与其他胞内蛋白的相互作用。
3. III类RTK家族最初被归为血小板衍生生长因子受体（PDGFR）家族，包含五个成员：KIT受体、集落刺激因子1受体（CSF1R）、Fms样酪氨酸激酶3受体（FLT3）、PDGFRα和PDGFRβ。
4. 近期杂交方法在结构生物学中的应用，几乎揭示了所有RTK-III复合物的结构全貌（包括三个完整的胞外域复合物），为我们提供了前所未有的丰富结构和机制见解，最终解答了大量长期悬而未决的问题。
5. RTK-III胞外域的大量结构信息使得将癌症相关体细胞突变精确定位到RTK-III特定胞外段成为可能，从而有助于理解这些突变在癌症发生发展过程中异常受体激活的作用机制。
6. 这些结构与机制的突破性认知也为开发靶向TKD结构域之外受体区域的新药开辟了道路。例如，PDGF与其调节性前肽的复合物结构可能为合理设计PDGF信号通路拮抗剂提供重要切入点。

英文摘要：

Intracellular signalling cascades initiated by class III receptor tyrosine kinases (RTK-IIIs) and their cytokine ligands contribute to haematopoiesis and mesenchymal tissue development. They are also implicated in a wide range of inflammatory disorders and cancers. Recent snapshots of RTK-III ectodomains in complex with cognate cytokines have revealed timely insights into the structural determinants of RTK-III activation, evolution and pathology. Importantly, candidate 'driver' and 'passenger' mutations that have been identified in RTK-IIIs can now be collectively mapped for the first time to structural scaffolds of the corresponding RTK-III ectodomains. Such insights will generate a renewed interest in dissecting the mechanistic effects of such mutations and their therapeutic relevance.

摘要翻译： 

III类受体酪氨酸激酶（RTK-IIIs）及其细胞因子配体启动的细胞内信号级联反应参与造血和间充质组织发育，也与多种炎症性疾病和癌症相关。近期捕捉到的RTK-III胞外区与相应细胞因子复合物的“快照”，及时揭示了RTK-III激活、进化及病理的结构决定因素。重要的是，首次可在相应RTK-III胞外区结构支架上集体映射已发现的候选“驱动”和“乘客”突变。这些见解将重新激发人们剖析这些突变的机制效应及其治疗相关性的兴趣。

原文链接：

Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases