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Summary 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. 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., Graphical Abstract, Highlights • The JM segment enhances RET catalytic domain activity • Structural visualization of activation-loop phospho-S909 engaging the HRD motif • Phospho-S909 arises from an intrinsic RET dual-specificity kinase activity • RET αC hydrophobic pocket is a potential drug-targetable allosteric site, Receptor tyrosine kinases exhibit a plethora of activation mechanisms despite highly homologous catalytic domains. Plaza-Menacho et al. find that RET tyrosine kinase activation and signaling require allosteric inputs from juxtamembrane elements as well as dual-specificity activity.