Spatial regulation of receptor tyrosine kinases in development and cancer

Key Points 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. 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. 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. 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. 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). 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. This Review discusses the importance of spatial control of receptor tyrosine kinase (RTK) activity during development and tissue homeostasis, and how spatial deregulation of RTKs may contribute to tumorigenesis and affect the sensitivity and resistance of cancers to pharmacological RTK inhibitors. 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