摘要：SummaryThe RET proto-oncogene encodes receptor tyrosine kinase, expressed primarily in tissues of neural crest origin. De-regulation of RET signaling is implicated in several human cancers. Recent phosphatome interactome analysis identified PTPRA interacting with the neurotrophic factor (GDNF)-dependent RET-Ras-MAPK signaling-axis. Here, by identifying comprehensive interactomes of PTPRA and RET, we reveal their close physical and functional association. The PTPRA directly interacts with RET, and using the phosphoproteomic approach, we identify RET as a direct dephosphorylation substrate of PTPRA bothin vivoandin vitro. The protein phosphatase domain-1 is indispensable for the PTPRA inhibitory role on RET activity and downstream Ras-MAPK signaling, whereas domain-2 has only minor effect. Furthermore, PTPRA also regulates the RET oncogenic mutant variant MEN2A activity and invasion capacity, whereas the MEN2B is insensitive to PTPRA. In sum, we discern PTPRA as a novel regulator of RET signaling in both health and cancer.Graphical AbstractDisplay OmittedHighlights•PTPRA inhibits ligand (GDNF-GFRα1)-mediated RET activity on Ras-MAPK signaling axis•PTPRA dephosphorylate RET on key functional phosphotyrosine sites•PTPRA catalytic (PTPase) domain 1 regulates RET-driven signaling•PTPRA suppresses RET oncogenic mutant MEN2A in both Ras-MAPK and cell invasion modelsBiological Sciences; Molecular Biology; Cancer
