The signalling output of many transmembrane receptors that mediate cell-cell communication is restricted by the endosomal sorting complex required for transport (ESCRT), but the impact of this machinery on Eph tyrosine kinase receptor function is unknown. We identified the ESCRT-associated adaptor protein HD-PTP as part of an EphB2 BioID interactome, and confirmed this association using co-immunoprecipitation. Although HD-PTP loss does not change EphB2 expression, it attenuates the ephrin-B2:EphB2 signalling-induced collapse of cultured cells and axonal growth cones, and results in aberrant guidance of chick spinal motor neuron axons in vivo. HD-PTP depletion abrogates ligand-induced EphB2 clustering, and EphB2 and Src family kinase activation. HD-PTP deficiency also accelerates ligand-induced EphB2 degradation, contrasting the phenotypes reported for other cell surface receptors. Our results link Eph signalling to the ESCRT machinery and demonstrate a role for HD-PTP in the earliest steps of ephrin-B:EphB signalling, as well as in obstructing premature receptor depletion.

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