Ephrin receptor (Eph)–ephrin signalling is important for cell positioning and tissue patterning during development and in oncogenic contexts, controlling cell morphology and cell–cell adhesion through cytoskeletal remodelling. PTP-PEST, a ubiquitous protein tyrosine phosphatase that interacts with focal adhesion proteins and coordinates cell movement, has been shown to be recruited to EphA3-signalling complexes, but its role in the Eph-mediated effects is unclear. On page 277, Mariam Mansour, Eva Nievergall and colleagues thus thoroughly investigate the role of PTP-PEST in EphA3 function using cell fractionation to isolate cell-surface Eph-signalling clusters, which contain key focal adhesion and cytoskeletal proteins. They show that an N-terminal fragment of PTP-PEST, which is generated by localised caspase-3-mediated cleavage in response to ephrin-A5, is recruited to EphA3 clusters and controls EphA3 activation by directly affecting its phosphorylation status. This inhibits receptor internalisation and cell retraction. Interestingly, inhibiting actin cytoskeletal dynamics reduces the levels of EphA3 phosphorylation, similar to the effect of PTP-PEST overexpression, suggesting that the cytoskeletal reorganisation is not only a consequence of Eph activation but is also required for Eph clustering and activation. As EphA3 and PTP-PEST are known to promote tumour formation, the role of PTP-PEST in controlling Eph-induced cytoskeletal remodelling described here also has important implications for our understanding of cancer cell motility.
- © 2016. Published by The Company of Biologists Ltd
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