Figure 9.

A model of the dual role of HD-PTP in EphB signalling. (a) Under basal conditions, EphB2 receptors exist at the membrane as unclustered molecules and HD-PTP does not associate with them. During signalling initiation, HD-PTP forms a molecular complex with ligand-activated EphB2, and promotes receptor multimerisation. HD-PTP loss results in dampened ligand-induced receptor phosphorylation, Src family kinase activation, and repulsive cellular responses in vitro and in vivo. (b) Ligand-bound EphB2 complexes are internalised in early endosomes, from where the receptor can be recycled back to the membrane or sorted to the endocytic pathway for lysosomal degradation. Our data shows that internalised EphB2 complexes are protected from lysosomal degradation in an HD-PTP-dependent manner. HD-PTP’s deubiquitylase-recruiting function may play a role in this process.