PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain
How PD-L1 expression is regulated in cancer is poorly understood. Here, we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers (CRCs). ERBB3 is one of the four members of the EGF receptor family, all with protein tyrosine kinase domains. E...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
KeAi Communications Co., Ltd.
2023-07-01
|
| Series: | Genes and Diseases |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S235230422200304X |
| _version_ | 1797802164322566144 |
|---|---|
| author | Yamu Li Zhonghua Liu Yiqing Zhao Jie Yang Tsan Sam Xiao Ronald A. Conlon Zhenghe Wang |
| author_facet | Yamu Li Zhonghua Liu Yiqing Zhao Jie Yang Tsan Sam Xiao Ronald A. Conlon Zhenghe Wang |
| author_sort | Yamu Li |
| collection | DOAJ |
| description | How PD-L1 expression is regulated in cancer is poorly understood. Here, we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers (CRCs). ERBB3 is one of the four members of the EGF receptor family, all with protein tyrosine kinase domains. ERBB3 is a pseudokinase with a high binding affinity to ATP. We showed that ERBB3 ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft tumor growth of CRC cell lines. The ERBB3 ATP-binding mutant cells dramatically reduce IFN-γ-induced PD-L1 expression. Mechanistically, ERBB3 regulates IFN-γ-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis. CREB is the transcription factor that regulates PD-L1 gene expression in CRC cells. Knockin of a tumor-derived ERBB3 mutation located in the kinase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy, suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune checkpoint therapy. |
| first_indexed | 2024-03-13T05:01:37Z |
| format | Article |
| id | doaj.art-4990cf4cc5a949cb8f6fadeace638bc5 |
| institution | Directory Open Access Journal |
| issn | 2352-3042 |
| language | English |
| last_indexed | 2024-03-13T05:01:37Z |
| publishDate | 2023-07-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Genes and Diseases |
| spelling | doaj.art-4990cf4cc5a949cb8f6fadeace638bc52023-06-17T05:19:05ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422023-07-0110417021713PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domainYamu Li0Zhonghua Liu1Yiqing Zhao2Jie Yang3Tsan Sam Xiao4Ronald A. Conlon5Zhenghe Wang6Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Pathology, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Pathology, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA; Corresponding author. Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA.How PD-L1 expression is regulated in cancer is poorly understood. Here, we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers (CRCs). ERBB3 is one of the four members of the EGF receptor family, all with protein tyrosine kinase domains. ERBB3 is a pseudokinase with a high binding affinity to ATP. We showed that ERBB3 ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft tumor growth of CRC cell lines. The ERBB3 ATP-binding mutant cells dramatically reduce IFN-γ-induced PD-L1 expression. Mechanistically, ERBB3 regulates IFN-γ-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis. CREB is the transcription factor that regulates PD-L1 gene expression in CRC cells. Knockin of a tumor-derived ERBB3 mutation located in the kinase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy, suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune checkpoint therapy.http://www.sciencedirect.com/science/article/pii/S235230422200304XColon cancerERBB3ImmunotherapyPD-L1Pseudokinase |
| spellingShingle | Yamu Li Zhonghua Liu Yiqing Zhao Jie Yang Tsan Sam Xiao Ronald A. Conlon Zhenghe Wang PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain Genes and Diseases Colon cancer ERBB3 Immunotherapy PD-L1 Pseudokinase |
| title | PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain |
| title_full | PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain |
| title_fullStr | PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain |
| title_full_unstemmed | PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain |
| title_short | PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain |
| title_sort | pd l1 expression is regulated by atp binding of the erbb3 pseudokinase domain |
| topic | Colon cancer ERBB3 Immunotherapy PD-L1 Pseudokinase |
| url | http://www.sciencedirect.com/science/article/pii/S235230422200304X |
| work_keys_str_mv | AT yamuli pdl1expressionisregulatedbyatpbindingoftheerbb3pseudokinasedomain AT zhonghualiu pdl1expressionisregulatedbyatpbindingoftheerbb3pseudokinasedomain AT yiqingzhao pdl1expressionisregulatedbyatpbindingoftheerbb3pseudokinasedomain AT jieyang pdl1expressionisregulatedbyatpbindingoftheerbb3pseudokinasedomain AT tsansamxiao pdl1expressionisregulatedbyatpbindingoftheerbb3pseudokinasedomain AT ronaldaconlon pdl1expressionisregulatedbyatpbindingoftheerbb3pseudokinasedomain AT zhenghewang pdl1expressionisregulatedbyatpbindingoftheerbb3pseudokinasedomain |