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Receptor Heterodimerization: an Underappreciated Confounding Factor in Health and Disease?

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Most receptor tyrosine kinases exist as monomeric single-chain transmembrane polypeptides. When a ligand binds to the receptor this elicits either oligomerization or dimerization, resulting in activation of the kinase through transphosphorylation and triggering the signalling cascade. A potentially ...

Most receptor tyrosine kinases exist as monomeric single-chain transmembrane polypeptides. When a ligand binds to the receptor this elicits either oligomerization or dimerization, resulting in activation of the kinase through transphosphorylation and triggering the signalling cascade. A potentially underappreciated area of research centres on the role of hetero-dimerization of receptor tyrosine kinases.

Receptor heterodimerization was first associated with G protein–coupled receptors (GPCRs) in the 1980s. This has important implications not only for our basic understanding of receptor signalling in cellular processes, but also implications in the pharmacological setting with respect to the design and action of receptor agonists. Since then, diverse roles for receptor heterodimerization have been identified within the setting of disease. For example, well characterized roles have been identified for nuclear receptor heterodimers in diabetes, angiogenesis and neuronal settings (axonal guidance).

It is perhaps in the field of oncology however, that receptor heterodimerization may play critical roles, for example in resistance to chemotherapy. This Research Topic will explore (a) the potential role of receptor heterodimerization in cancer and discuss how tyrosine kinase inhibitors designed to target multiple RTKs (often termed multi-TKIs) may be superior to those designed to specifically target individual RTKs; and (b) the potential role of receptor heterodimerization in the drug resistance.

Topics to be covered:
_ Receptor Heterodimerization – Structure/Functional relationships with respect to health and disease
_ Receptor Heterodimerization – Role in drug resistance
_ Structural design and rationale for novel dual targeting or multi-TKIs to overcome Receptor Heterodimerization based chemotherapy resistance


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