PTPRA Phosphatase Regulates GDNF-Dependent RET Signaling and Inhibits the RET Mutant MEN2A Oncogenic Potential

Leena Yadav; Elina Pietilä; Tiina Öhman; Xiaonan Liu; Arun K Mahato; Yulia Sidorova; Kaisa Lehti; Mart Saarma; Markku Varjosalo

doi:10.1016/j.isci.2020.100871

PTPRA Phosphatase Regulates GDNF-Dependent RET Signaling and Inhibits the RET Mutant MEN2A Oncogenic Potential

iScience. 2020 Feb 21;23(2):100871. doi: 10.1016/j.isci.2020.100871. Epub 2020 Jan 31.

Authors

Leena Yadav¹, Elina Pietilä², Tiina Öhman¹, Xiaonan Liu¹, Arun K Mahato³, Yulia Sidorova³, Kaisa Lehti⁴, Mart Saarma³, Markku Varjosalo⁵

Affiliations

¹ Systems Biology/Pathology Research Group and Proteomics Unit, Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00014, Finland.
² Research Programs Unit, Individualized Drug Therapy, Biomedicum, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland.
³ Laboratory of Molecular Neuroscience, Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00014, Finland.
⁴ Research Programs Unit, Individualized Drug Therapy, Biomedicum, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm 17177, Sweden.
⁵ Systems Biology/Pathology Research Group and Proteomics Unit, Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00014, Finland. Electronic address: markku.varjosalo@helsinki.fi.

Abstract

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 association. The PTPRA directly interacts with RET, and using the phosphoproteomic approach, we identify RET as a direct dephosphorylation substrate of PTPRA both in vivo and in 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.

Keywords: Biological Sciences; Cancer; Molecular Biology.