Identifying Regulatory Posttranslational Modifications of PD-L1: A Focus on Monoubiquitinaton
A set of high-affinity, high-specificity posttranslational modification (PTM) enrichment tools was developed to generate an unbiased snapshot of four key PTM profiles (tyrosine phosphorylation, acetylation, ubiquitination, and SUMOylation 2/3) for the clinically important protein programmed cell dea...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-04-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558617300295 |
| _version_ | 1811268090144489472 |
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| author | Henrick Horita Andy Law Soonjin Hong Kim Middleton |
| author_facet | Henrick Horita Andy Law Soonjin Hong Kim Middleton |
| author_sort | Henrick Horita |
| collection | DOAJ |
| description | A set of high-affinity, high-specificity posttranslational modification (PTM) enrichment tools was developed to generate an unbiased snapshot of four key PTM profiles (tyrosine phosphorylation, acetylation, ubiquitination, and SUMOylation 2/3) for the clinically important protein programmed cell death ligand 1 (PD-L1). The results showed that epidermal growth factor (EGF) treatment induced tyrosine phosphorylation, acetylation, and ubiquitination of PD-L1. Further characterization of EGF-induced PD-L1 ubiquitination revealed a significant increase in mono- and multiubiquitination of PD-L1 that occurred on glycosylated PD-L1. EGF induced mono- and multiubiquitination of PD-L1 preceded EGF-induced increases in PD-L1 protein levels. Chemical inhibitors of the EGFR pathway, gefitnib and SCH772984, suppressed PD-L1 mono- and multiubiquitination, and inhibition of the ubiquitin E1 activating enzyme, with the chemical inhibitor PYR41, was sufficient to block EGF-stimulated increases in PD-L1 protein levels. This study highlights the significance of identifying novel PTMs for PD-L1 and reveals potentially critical regulatory mechanisms that may be valuable therapeutic targets. In a broader context, this report validates an approach whereby one can gain insight into novel mechanisms of action by a simple and unbiased analysis of a PTM profile of potentially any endogenous protein of interest. |
| first_indexed | 2024-04-12T21:15:31Z |
| format | Article |
| id | doaj.art-f8e1c662e1aa433e80ab8a8cc9b9e6a4 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-04-12T21:15:31Z |
| publishDate | 2017-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-f8e1c662e1aa433e80ab8a8cc9b9e6a42022-12-22T03:16:28ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862017-04-01194346353Identifying Regulatory Posttranslational Modifications of PD-L1: A Focus on MonoubiquitinatonHenrick Horita0Andy Law1Soonjin Hong2Kim Middleton3Address all correspondence to: Henrick Horita, R&D Department, Cytoskeleton Inc., Denver, CO, 80223, USA.; R&D Department, Cytoskeleton Inc., Denver, CO, 80223, USAR&D Department, Cytoskeleton Inc., Denver, CO, 80223, USAR&D Department, Cytoskeleton Inc., Denver, CO, 80223, USAR&D Department, Cytoskeleton Inc., Denver, CO, 80223, USAA set of high-affinity, high-specificity posttranslational modification (PTM) enrichment tools was developed to generate an unbiased snapshot of four key PTM profiles (tyrosine phosphorylation, acetylation, ubiquitination, and SUMOylation 2/3) for the clinically important protein programmed cell death ligand 1 (PD-L1). The results showed that epidermal growth factor (EGF) treatment induced tyrosine phosphorylation, acetylation, and ubiquitination of PD-L1. Further characterization of EGF-induced PD-L1 ubiquitination revealed a significant increase in mono- and multiubiquitination of PD-L1 that occurred on glycosylated PD-L1. EGF induced mono- and multiubiquitination of PD-L1 preceded EGF-induced increases in PD-L1 protein levels. Chemical inhibitors of the EGFR pathway, gefitnib and SCH772984, suppressed PD-L1 mono- and multiubiquitination, and inhibition of the ubiquitin E1 activating enzyme, with the chemical inhibitor PYR41, was sufficient to block EGF-stimulated increases in PD-L1 protein levels. This study highlights the significance of identifying novel PTMs for PD-L1 and reveals potentially critical regulatory mechanisms that may be valuable therapeutic targets. In a broader context, this report validates an approach whereby one can gain insight into novel mechanisms of action by a simple and unbiased analysis of a PTM profile of potentially any endogenous protein of interest.http://www.sciencedirect.com/science/article/pii/S1476558617300295 |
| spellingShingle | Henrick Horita Andy Law Soonjin Hong Kim Middleton Identifying Regulatory Posttranslational Modifications of PD-L1: A Focus on Monoubiquitinaton Neoplasia: An International Journal for Oncology Research |
| title | Identifying Regulatory Posttranslational Modifications of PD-L1: A Focus on Monoubiquitinaton |
| title_full | Identifying Regulatory Posttranslational Modifications of PD-L1: A Focus on Monoubiquitinaton |
| title_fullStr | Identifying Regulatory Posttranslational Modifications of PD-L1: A Focus on Monoubiquitinaton |
| title_full_unstemmed | Identifying Regulatory Posttranslational Modifications of PD-L1: A Focus on Monoubiquitinaton |
| title_short | Identifying Regulatory Posttranslational Modifications of PD-L1: A Focus on Monoubiquitinaton |
| title_sort | identifying regulatory posttranslational modifications of pd l1 a focus on monoubiquitinaton |
| url | http://www.sciencedirect.com/science/article/pii/S1476558617300295 |
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