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

Key Points

  • Receptor tyrosine kinases (RTKs) are known to be mutated in human tumours.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

Abstract

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.

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Figure 1: Structural diversity of RTK-III cytokine ligands and RTK-III complexes.
Figure 2: Distinct and consensus features of cytokine recognition by RTK-IIIs.
Figure 3: General mechanism for cytokine-dependent activation of RTK-IIIs.
Figure 4: Possible structural consequences of oncogenic RTK-III mutations.
Figure 5: Strategies for targeted therapeutic intervention.

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Acknowledgements

The authors gratefully acknowledge financial support from the Research Foundation Flanders, Belgium (FWO) in terms of a pre-doctoral fellowship to K.V. and research grants (3G064307, G059710 and 3G0B7912W) to S.N.S. They offer their sincere apologies to colleagues whose work could not be cited owing to space limitations.

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Correspondence to Kenneth Verstraete or Savvas N. Savvides.

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K.V. and S.N.S. are co-applicants in a patent filing (EP10196039.1) focusing on the druggability of the FLT3 ligand–receptor interaction epitope.

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Glossary

Short-chain α-helical bundle

A protein fold adopted by several cytokines (such as granulocyte–macrophage- colony-stimulating factor, interleukin-4 and interleukin-2) featuring a core of four α-helices 10–20 amino acids each in length with 'up-up-down-down' topology.

Cystine-knot fold

An all β-strand protein fold featuring the pairing of four cysteines into two disulphide bonds, forming a loop through which a third disulphide bond passes.

Somatic mutations

Genetic mutations that occur in somatic cells after conception. Such mutations may contribute to the development of various medical conditions such as chronic diseases and cancer. Somatic mutations can be identified by comparing the genetic material in cells from a tissue of interest and with that from cells elsewhere in the body.

Hybrid methods in structural biology

The combination of methods such as X-ray crystallography, small-angle X-ray scattering (SAXS), electron microscopy (EM) and nuclear magnetic resonance (NMR) to obtain diverse structural information about the structure and dynamics of proteins and their assembly into complexes with other macromolecules.

Bundle axis

Refers to the principal direction of the α-helices in the helical bundle fold.

Twofold axis

An element of rotational symmetry that generates equivalent positions by rotating 180° around the axis.

Protomers

Subunits of a multimeric protein assembly.

Cooperative binding

In the context of complex formation, a multivalent macromolecule (for example, an oligomeric protein) can exhibit allosteric binding behaviour with positive or negative cooperativity when the binding of a first cognate binding partner increases or decreases the affinity of a second binding event by an additional binder or binders.

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Verstraete, K., Savvides, S. Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases. Nat Rev Cancer 12, 753–766 (2012). https://doi.org/10.1038/nrc3371

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