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• W2988885903 abstract "Receptor protein tyrosine phosphatases (RPTPs) play critical regulatory roles in mammalian signal transduction. However, the structural basis for the regulation of their catalytic activity is not fully understood, and RPTPs are generally not therapeutically targetable. This knowledge gap is partially due to the lack of known natural ligands or selective agonists of RPTPs. Contrary to what is known from structure–function studies of receptor tyrosine kinases (RTKs), RPTP activities have been reported to be suppressed by dimerization, which may prevent RPTPs from accessing their RTK substrates. We report here that homodimerization of protein tyrosine phosphatase receptor J (PTPRJ, also known as DEP-1) is regulated by specific transmembrane (TM) residues. We found that disrupting these interactions destabilizes homodimerization of full-length PTPRJ in cells, reduces the phosphorylation of the known PTPRJ substrate epidermal growth factor receptor (EGFR) and of other downstream signaling effectors, antagonizes EGFR-driven cell phenotypes, and promotes substrate access. We demonstrate these observations in human cancer cells using mutational studies and identified a peptide that binds to the PTPRJ TM domain and represents the first example of an allosteric agonist of RPTPs. The results of our study provide fundamental structural and functional insights into how PTPRJ activity is tuned by TM interactions in cells. Our findings also open up opportunities for developing peptide-based agents that could be used as tools to probe RPTPs’ signaling mechanisms or to manage cancers driven by RTK signaling. Receptor protein tyrosine phosphatases (RPTPs) play critical regulatory roles in mammalian signal transduction. However, the structural basis for the regulation of their catalytic activity is not fully understood, and RPTPs are generally not therapeutically targetable. This knowledge gap is partially due to the lack of known natural ligands or selective agonists of RPTPs. Contrary to what is known from structure–function studies of receptor tyrosine kinases (RTKs), RPTP activities have been reported to be suppressed by dimerization, which may prevent RPTPs from accessing their RTK substrates. We report here that homodimerization of protein tyrosine phosphatase receptor J (PTPRJ, also known as DEP-1) is regulated by specific transmembrane (TM) residues. We found that disrupting these interactions destabilizes homodimerization of full-length PTPRJ in cells, reduces the phosphorylation of the known PTPRJ substrate epidermal growth factor receptor (EGFR) and of other downstream signaling effectors, antagonizes EGFR-driven cell phenotypes, and promotes substrate access. We demonstrate these observations in human cancer cells using mutational studies and identified a peptide that binds to the PTPRJ TM domain and represents the first example of an allosteric agonist of RPTPs. The results of our study provide fundamental structural and functional insights into how PTPRJ activity is tuned by TM interactions in cells. Our findings also open up opportunities for developing peptide-based agents that could be used as tools to probe RPTPs’ signaling mechanisms or to manage cancers driven by RTK signaling. Correction: Disrupting the transmembrane domain–mediated oligomerization of protein tyrosine phosphatase receptor J inhibits EGFR-driven cancer cell phenotypesJournal of Biological ChemistryVol. 298Issue 9PreviewIt was determined via STR profiling that cell line UMSCC2 should have been labeled as HSC3 cells. Like UMSCC2 cells, HSC3 cells are squamous cell carcinoma cells that express wild type EGFR, the primary substrate of PTPRJ/DEP1 investigated in this publication. Therefore, this correction does not affect the results and conclusions of the paper. Full-Text PDF Open AccessCorrection: A novel NF-κB-inducing kinase-MAPK signaling pathway up-regulates NF-κB activity in melanoma cellsJournal of Biological ChemistryVol. 298Issue 8PreviewIn the original version of Figure 3A(ii) the first three lanes for the actin loading control were mistakenly duplicated in the last three lanes of the image panel. A representative data from several repeated experiments is now provided in corrected Figure 3A(ii). The revised figure shows results obtained with new NIK antibody because initial antibody is no longer available. In two cell lines (BEAS2B and H358) the new antibody revealed better NIK expression than it was shown with original antibody. Full-Text PDF Open Access" @default.
• W2988885903 created "2019-11-22" @default.
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• W2988885903 date "2019-12-01" @default.
• W2988885903 modified "2023-10-04" @default.
• W2988885903 title "Disrupting the transmembrane domain–mediated oligomerization of protein tyrosine phosphatase receptor J inhibits EGFR-driven cancer cell phenotypes" @default.
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• W2988885903 doi "https://doi.org/10.1074/jbc.ra119.010229" @default.
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