LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines
Abstract Leukocyte-associated immunoglobulin-like receptor-1 (LAIR1), an immune receptor containing immunoreceptor tyrosine-based inhibiory motifs (ITIMs), has emerged as an attractive target for cancer therapy. However, the intrinsic function of LAIR1 in gliomas remains unclear. In this study, the...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06199-9 |
| _version_ | 1797653549802323968 |
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| author | Xiaoqian Wei Shushan Pan Zirui Wang Jieru Chen Li Lu Qizhi Cao Shuling Song Huachang Zhang Xiaohui Liu Xianjun Qu Xiukun Lin Huanli Xu |
| author_facet | Xiaoqian Wei Shushan Pan Zirui Wang Jieru Chen Li Lu Qizhi Cao Shuling Song Huachang Zhang Xiaohui Liu Xianjun Qu Xiukun Lin Huanli Xu |
| author_sort | Xiaoqian Wei |
| collection | DOAJ |
| description | Abstract Leukocyte-associated immunoglobulin-like receptor-1 (LAIR1), an immune receptor containing immunoreceptor tyrosine-based inhibiory motifs (ITIMs), has emerged as an attractive target for cancer therapy. However, the intrinsic function of LAIR1 in gliomas remains unclear. In this study, the poor prognosis of glioma patients and the malignant proliferation of glioma cells in vitro and in vivo were found to be closely correlated with LAIR1. LAIR1 facilitates focal adhesion kinase (FAK) nuclear localization, resulting in increased transcription of cyclin D1 and chemokines/cytokines (CCL5, TGFβ2, and IL33). LAIR1 specifically supports in the immunosuppressive glioma microenvironment via CCL5-mediated microglia/macrophage polarization. SHP2Q510E (PTP domain mutant) or FAKNLM (non-nuclear localizing mutant) significantly reversed the LAIR1-induced growth enhancement in glioma cells. In addition, LAIR1Y251/281F (ITIMs mutant) and SHP2Q510E mutants significantly reduced FAK nuclear localization, as well as CCL5 and cyclin D1 expression. Further experiments revealed that the ITIMs of LAIR1 recruited SH2-containing phosphatase 2 (SHP2), which then interacted with FAK and induced FAK nuclear localization. This study uncovered a critical role for intrinsic LAIR1 in facilitating glioma malignant progression and demonstrated a requirement for LAIR1 and SHP2 to enhance FAK nuclear localization. |
| first_indexed | 2024-03-11T16:46:13Z |
| format | Article |
| id | doaj.art-58d7ae4e326a461c9d78334e6ea8bb72 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-11T16:46:13Z |
| publishDate | 2023-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-58d7ae4e326a461c9d78334e6ea8bb722023-10-22T11:29:04ZengNature Publishing GroupCell Death and Disease2041-48892023-10-01141011510.1038/s41419-023-06199-9LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokinesXiaoqian Wei0Shushan Pan1Zirui Wang2Jieru Chen3Li Lu4Qizhi Cao5Shuling Song6Huachang Zhang7Xiaohui Liu8Xianjun Qu9Xiukun Lin10Huanli Xu11Department of Pharmacology, School of Basic Medical Sciences, Capital Medical UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical UniversityDepartment of Immunology, School of Basic Medical Sciences, Binzhou Medical UniversitySchool of Gerontology, Binzhou Medical UniversityDepartment of Immunology, School of Basic Medical Sciences, Binzhou Medical UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical UniversityCollege of Marine Sciences, Beibu Gulf UniversityDepartment of Pharmacology, School of Basic Medical Sciences, Capital Medical UniversityAbstract Leukocyte-associated immunoglobulin-like receptor-1 (LAIR1), an immune receptor containing immunoreceptor tyrosine-based inhibiory motifs (ITIMs), has emerged as an attractive target for cancer therapy. However, the intrinsic function of LAIR1 in gliomas remains unclear. In this study, the poor prognosis of glioma patients and the malignant proliferation of glioma cells in vitro and in vivo were found to be closely correlated with LAIR1. LAIR1 facilitates focal adhesion kinase (FAK) nuclear localization, resulting in increased transcription of cyclin D1 and chemokines/cytokines (CCL5, TGFβ2, and IL33). LAIR1 specifically supports in the immunosuppressive glioma microenvironment via CCL5-mediated microglia/macrophage polarization. SHP2Q510E (PTP domain mutant) or FAKNLM (non-nuclear localizing mutant) significantly reversed the LAIR1-induced growth enhancement in glioma cells. In addition, LAIR1Y251/281F (ITIMs mutant) and SHP2Q510E mutants significantly reduced FAK nuclear localization, as well as CCL5 and cyclin D1 expression. Further experiments revealed that the ITIMs of LAIR1 recruited SH2-containing phosphatase 2 (SHP2), which then interacted with FAK and induced FAK nuclear localization. This study uncovered a critical role for intrinsic LAIR1 in facilitating glioma malignant progression and demonstrated a requirement for LAIR1 and SHP2 to enhance FAK nuclear localization.https://doi.org/10.1038/s41419-023-06199-9 |
| spellingShingle | Xiaoqian Wei Shushan Pan Zirui Wang Jieru Chen Li Lu Qizhi Cao Shuling Song Huachang Zhang Xiaohui Liu Xianjun Qu Xiukun Lin Huanli Xu LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines Cell Death and Disease |
| title | LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines |
| title_full | LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines |
| title_fullStr | LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines |
| title_full_unstemmed | LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines |
| title_short | LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines |
| title_sort | lair1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin d1 and immunosuppressive chemokines cytokines |
| url | https://doi.org/10.1038/s41419-023-06199-9 |
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