PTPRA Phosphatase Regulates GDNF-Dependent RET Signaling and Inhibits the RET Mutant MEN2A Oncogenic Potential
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Published on: July 17, 2020
Leena Yadav1, Elina Pietilä2, Tiina Öhman1
1Systems Biology/Pathology Research Group and Proteomics Unit, Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki 00014, Finland.
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.
Insights
Protein tyrosine phosphatase receptor type A (PTPRA) directly dephosphorylates and inhibits RET receptor tyrosine kinase signaling. This interaction is crucial for regulating RET activity in both normal tissues and cancers like MEN2A.
Area of Science:
- Molecular Biology
- Cancer Research
- Signal Transduction
Background:
- The RET proto-oncogene encodes a receptor tyrosine kinase vital for neural crest development.
- Dysregulated RET signaling is a known driver in various human cancers.
- Previous studies suggested a link between PTPRA and the GDNF-RET-Ras-MAPK pathway.
Purpose of the Study:
- To elucidate the physical and functional association between PTPRA and RET.
- To identify RET as a dephosphorylation substrate of PTPRA.
- To investigate PTPRA's role in regulating RET activity and oncogenic variants.
Main Methods:
- Comprehensive interactome analysis of PTPRA and RET.
- Phosphoproteomic approaches to identify dephosphorylation events.
- In vitro and in vivo assays to assess PTPRA's functional impact on RET signaling.
Main Results:
- PTPRA directly interacts with RET, with domain-1 being critical for inhibition.
- PTPRA dephosphorylates RET, thereby inhibiting RET activity and downstream Ras-MAPK signaling.
- PTPRA suppresses the activity and invasion capacity of the MEN2A RET mutant, but not MEN2B.
Conclusions:
- PTPRA acts as a direct, inhibitory regulator of RET receptor tyrosine kinase signaling.
- PTPRA's phosphatase activity is essential for controlling RET-mediated oncogenic processes.
- PTPRA is identified as a novel player in both physiological RET signaling and cancer.
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