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PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain
- Source :
- Genes and Diseases, Vol 10, Iss 4, Pp 1702-1713 (2023)
- Publication Year :
- 2023
- Publisher :
- KeAi Communications Co., Ltd., 2023.
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 23523042
- Volume :
- 10
- Issue :
- 4
- Database :
- Directory of Open Access Journals
- Journal :
- Genes and Diseases
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.4990cf4cc5a949cb8f6fadeace638bc5
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.gendis.2022.11.003