Key Points
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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.
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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.
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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.
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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.
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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).
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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.
Abstract
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.
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Acknowledgements
The authors would like to thank J. Engelman for thoughtful comments on the manuscript, and members of the McClatchey laboratory for many creative discussions. This work was supported by US NIH R01 CA113733 to A.I.M.
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FURTHER INFORMATION
Glossary
- Autocrine
-
A mode of signalling in which a secreted substance acts on surface receptors that are present on the same cell from which the substance was produced.
- Cell cortex
-
The outer margin of a cell containing the plasma membrane and underlying cortical cytoskeleton (a contractile, mesh-like structure that is rich in contractile actin–myosin filaments and other cytoskeletal components). Can also be used to refer to the cortical cytoskeleton alone.
- Clathrin
-
A major protein component of the vesicular coat of specialized pits and vesicles involved in receptor-mediated endocytosis.
- Adherens junctions
-
Macromolecular complexes containing adhesive transmembrane receptors (cadherins and nectins) and cytoplasmic regulators (catenins) that link the complexes to the actin cytoskeleton. Adherens junctions undergo continuous remodelling and are necessary for cell–cell adhesion and the polarization of epithelial and endothelial cells.
- Tight junctions
-
Cell–cell adhesion complexes that form a semi-permeable barrier between the apical and basolateral surfaces of epithelial cells and that contribute to cell polarity and signalling.
- Apical–basal polarity
-
Epithelial cells are polarized, with an apical membrane that faces the external environment or a lumen and a spatially opposed basolateral membrane that functions in cell–cell interactions and contacts the basement membrane.
- Paracrine
-
A mode of signalling in which a secreted substance acts on surface receptors present on other cells.
- PDZ domain
-
A structural, protein–protein interaction domain of ∼80–90 amino acids in length that often serves as a scaffold for signalling complexes and/or as a cytoskeletal anchor for transmembrane proteins.
- Crypt–villus axis
-
The longitudinal or vertical axis formed by a villus and its corresponding crypts in the small intestine.
- Dynamin
-
A large GTPase that forms a helix around the neck of nascent endocytic vesicles to separate them from parent membranes.
- Axon terminal
-
The distal termination of a presynaptic neuron.
- Cell body
-
The part of a neuron containing the nucleus and surrounding cytoplasm, but not the axonal and dendritic extensions.
- Epithelial-to-mesenchymal transition
-
(EMT). A programme by which cells convert from an epithelial to a mesenchymal phenotype. This process, which is enacted during normal embryonic development, can be abnormally activated in carcinomas, resulting in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.
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Casaletto, J., McClatchey, A. Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer 12, 387–400 (2012). https://doi.org/10.1038/nrc3277
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DOI: https://doi.org/10.1038/nrc3277
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