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    RET functions as a dual-specificity kinase that requires allosteric inputs from juxtamembrane elements

    McDonald, Neil Q. (2016) RET functions as a dual-specificity kinase that requires allosteric inputs from juxtamembrane elements. Cell Reports 17 (12), pp. 3319-3332. ISSN 2211-1247.

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    Receptor tyrosine kinases exhibit a plethora of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of their respective extracellular ligand-binding portions with highly variable intracellular sequences flanking their tyrosine kinase domains and specific patterns of autophosphorylayion sites. Here we show that the juxtamembrane (JM) segment enhances RET catalytic domain activity through Y687, which is also required by the JM-region to rescue an otherwise catalytically-deficient RET Y900/905F activationloop mutant. Structure-function analyses identified interactions between the JMhinge, aC helix and an unconventional activation-loop serine phosphorylation site that by engaging the HRD motif promotes conformational accessibility to phosphotyrosine binding modules and regulatory-spine assembly. We demonstrate that this previously unreported phospho-S909 arises from an intrinsic RET dual-specificity kinase activity, and show an equivalent serine is required for RET signaling in Drosophila. Our findings reveal dual-specificity and allosteric components for the mechanism of RET activation and signaling with important drug-discovery implications.


    Item Type: Article
    Keyword(s) / Subject(s): receptor tyrosine kinase, RTK, structure-function, phosphorylation, dual-specificity, signaling, oncogene, Drosophila
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Neil Mcdonald
    Date Deposited: 16 Jan 2017 14:01
    Last Modified: 02 Aug 2023 17:28


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