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Abstract
SummaryReceptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains. Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the tyrosine kinase domain and specific patterns of autophosphorylation sites. Here, we show that the juxtamembrane (JM) segment enhances RET catalytic domain activity through Y687. This phospho-site is also required by the JM region to rescue an otherwise catalytically deficient RET activation-loop mutant lacking tyrosines. Structure-function analyses identified interactions between the JM hinge, αC helix, and an unconventional activation-loop serine phosphorylation site that engages the HRD motif and promotes phospho-tyrosine conformational accessibility and regulatory spine assembly. We demonstrate that this phospho-S909 arises from an intrinsic RET dual-specificity kinase activity and show that 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 direct implications for drug discovery.
Highlights
Vertebrates have close to 60 receptor tyrosine kinases (RTKs) that respond to a diverse set of extracellular polypeptide ligands by stimulating their intrinsic tyrosine kinase function
Receptor tyrosine kinases exhibit a variety of activation mechanisms despite highly homologous catalytic domains
Such diversity arises through coupling of extracellular ligand-binding portions with highly variable intracellular sequences flanking the tyrosine kinase domain and specific patterns of autophosphorylation sites
Summary
Vertebrates have close to 60 receptor tyrosine kinases (RTKs) that respond to a diverse set of extracellular polypeptide ligands by stimulating their intrinsic tyrosine kinase function. For other RTKs, such as the IR and FGFR2, ligand-dependent stimulation leads to kinase activation and phosphorylation of specific tyrosine residues, which relieve repressive cis-inhibitory interactions to enhance catalytic activity and to promote binding of phosphotyrosine-binding domain (PTB)- and Src homology 2 (SH2)domain-containing proteins to transmit downstream signals (Chen et al, 2007; Hubbard, 1997). While the latter role for phosphorylation has been demonstrated for RET, its effect on catalytic activation has been only recently elucidated. Allosteric mechanisms have been identified to stimulate receptor activity independent of activation segment phosphorylation
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