文章：

受体酪氨酸激酶在发育和癌症中的空间调控

Spatial regulation of receptor tyrosine kinases in development and cancer

原文发布日期：2012-05-24

DOI: 10.1038/nrc3277

类型: Review Article

开放获取: 否

要点：

1. The deregulation of receptor tyrosine kinases (RTKs) has been implicated in nearly all forms of human cancer. As such, RTKs are the subject of major ongoing efforts to develop targeted cancer therapies.
2. Because of their broad roles in many crucial cellular processes, RTKs are subject to tight regulation. The regulation of RTK production has been well studied; mounting evidence indicates that spatial regulation of RTKs is also important.
3. RTKs are spatially regulated in two dimensions — lateral and axial. The heterogeneous nature of the plasma membrane yields lateral compartmentalization of RTKs to both nanometre-scale and much larger macrodomains. Axial control of RTKs via endocytosis enables differential signalling from the plasma membrane and/or endosomes.
4. The spatial distribution of RTKs is important for many developmental processes, including directed cell migration and branching morphogenesis. Regulated RTK distribution is also necessary for spatial patterning during cell fate specification and tissue homeostasis.
5. There are many ways in which deregulated spatial control of RTKs may contribute to tumorigenesis. For example, increased RTK production can yield altered plasma membrane distribution and clustering, defective tissue architecture can promote abnormal receptor–receptor and/or receptor–ligand interactions, and defects in vesicular trafficking can increase surface RTK levels and affect the location from which signalling occurs (for example, the plasma membrane versus the endosome).
6. Despite accumulating evidence, the effect of spatial RTK signalling in tumorigenesis and therapeutic response is underappreciated. A three-dimensional view of RTK activity in tumour cells and tissues could yield a more complete understanding of the mechanisms of tumour progression and therapeutic resistance, leading to altered treatment strategies.

要点翻译：

1. 受体酪氨酸激酶（RTK）的失调与几乎所有类型的人类癌症都密切相关。因此，RTK已成为开发靶向癌症疗法的主要研究方向。
2. 由于RTK在众多关键细胞过程中发挥广泛作用，其活性受到严格调控。RTK的合成调控已得到深入研究，而越来越多的证据表明RTK的空间调控同样至关重要。
3. RTK的空间调控存在于两个维度——横向与轴向。质膜的非均质特性使RTK在纳米尺度和更大宏观尺度上形成横向分区。通过内吞作用实现的轴向调控，使得RTK能够从质膜和/或内体发出差异化信号。
4. RTK的空间分布对许多发育过程至关重要，包括定向细胞迁移和分支形态发生。在细胞命运特化和组织稳态过程中，受调控的RTK分布对于空间模式构建同样不可或缺。
5. RTK空间调控失衡促进肿瘤发生的方式多种多样。例如：RTK合成增加可能导致质膜分布改变和簇集；组织结构缺陷可能促进异常受体-受体和/或受体-配体相互作用；囊泡运输缺陷会提高表面RTK水平并影响信号传导位点（如质膜与内体的差异）。
6. 尽管证据不断积累，空间维度RTK信号传导在肿瘤发生和治疗反应中的作用仍未受到足够重视。从三维视角解析肿瘤细胞和组织中的RTK活性，可更全面地理解肿瘤进展和治疗抵抗机制，从而推动治疗策略的革新。

英文摘要：

During development and tissue homeostasis, patterns of cellular organization, proliferation and movement are highly choreographed. Receptor tyrosine kinases (RTKs) have a crucial role in establishing these patterns. Individual cells and tissues exhibit tight spatial control of the RTKs that they express, enabling tissue morphogenesis and function, while preventing unwarranted cell division and migration that can contribute to tumorigenesis. Indeed, RTKs are deregulated in most human cancers and are a major focus of targeted therapeutics. A growing appreciation of the essential role of spatial RTK regulation during development prompts the realization that spatial deregulation of RTKs is likely to contribute broadly to cancer development and may affect the sensitivity and resistance of cancer to pharmacological RTK inhibitors.

摘要翻译： 

在发育和组织稳态过程中，细胞组织、增殖和迁移的模式是高度协调的。受体酪氨酸激酶（RTKs）在建立这些模式中起着关键作用。单个细胞和组织对其表达的RTKs表现出严格的空间控制，从而实现组织形态发生和功能，同时防止可能导致肿瘤发生的异常细胞分裂和迁移。事实上，RTKs在大多数人类癌症中都存在失调，并且是靶向治疗的主要焦点。对RTKs空间调控在发育中重要作用的日益认识促使人们意识到，RTKs的空间失调可能广泛地促进癌症的发展，并可能影响癌症对药理学RTK抑制剂的敏感性和耐药性。

原文链接：

Spatial regulation of receptor tyrosine kinases in development and cancer