Novel Tumor Suppressor PTPRA Regulates GDNF-Dependent RET Signaling and Inhibits the RET Mutant MEN2A Oncogenic Potential

The 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 role. The PTPRA directly interacts with RET and using an in vitro phosphatase assay coupled to mass spectrometry we identify RET as a direct dephosphorylation substrate of PTPRA. The protein phosphatase domain-1 is indispensable for the PTPRA inhibitory role on RET activity and 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 identify PTPRA as novel tumor suppressor regulating the RET signaling in both health and cancer.