GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells
NKG2D ligands play a relevant role in Natural Killer (NK) cell -mediated immune surveillance of multiple myeloma (MM). Different levels of regulation control the expression of these molecules at cell surface. A number of oncogenic proteins and miRNAs act as negative regulators of NKG2D ligand transc...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.942640/full |
| _version_ | 1818002362489372672 |
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| author | Andrea Kosta Abdelilah Mekhloufi Lorenzo Lucantonio Alessandra Zingoni Alessandra Soriani Marco Cippitelli Angela Gismondi Francesca Fazio Maria Teresa Petrucci Angela Santoni Angela Santoni Angela Santoni Helena Stabile Cinzia Fionda |
| author_facet | Andrea Kosta Abdelilah Mekhloufi Lorenzo Lucantonio Alessandra Zingoni Alessandra Soriani Marco Cippitelli Angela Gismondi Francesca Fazio Maria Teresa Petrucci Angela Santoni Angela Santoni Angela Santoni Helena Stabile Cinzia Fionda |
| author_sort | Andrea Kosta |
| collection | DOAJ |
| description | NKG2D ligands play a relevant role in Natural Killer (NK) cell -mediated immune surveillance of multiple myeloma (MM). Different levels of regulation control the expression of these molecules at cell surface. A number of oncogenic proteins and miRNAs act as negative regulators of NKG2D ligand transcription and translation, but the molecular mechanisms sustaining their basal expression in MM cells remain poorly understood. Here, we evaluated the role of the growth arrest specific 6 (GAS6)/TAM signaling pathway in the regulation of NKG2D ligand expression and MM recognition by NK cells. Our data showed that GAS6 as well as MERTK and AXL depletion in MM cells results in MICA downregulation and inhibition of NKG2D-mediated NK cell degranulation. Noteworthy, GAS6 derived from bone marrow stromal cells (BMSCs) also increases MICA expression at both protein and mRNA level in human MM cell lines and in primary malignant plasma cells. NF-kB activation is required for these regulatory mechanisms since deletion of a site responsive for this transcription factor compromises the induction of mica promoter by BMSCs. Accordingly, knockdown of GAS6 reduces the capability of BMSCs to activate NF-kB pathway as well as to enhance MICA expression in MM cells. Taken together, these results shed light on molecular mechanism underlying NKG2D ligand regulation and identify GAS6 protein as a novel autocrine and paracrine regulator of basal expression of MICA in human MM cells. |
| first_indexed | 2024-04-14T03:45:49Z |
| format | Article |
| id | doaj.art-25869058e7b14f3b8801c581e1b362a1 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-14T03:45:49Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-25869058e7b14f3b8801c581e1b362a12022-12-22T02:14:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-07-011310.3389/fimmu.2022.942640942640GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cellsAndrea Kosta0Abdelilah Mekhloufi1Lorenzo Lucantonio2Alessandra Zingoni3Alessandra Soriani4Marco Cippitelli5Angela Gismondi6Francesca Fazio7Maria Teresa Petrucci8Angela Santoni9Angela Santoni10Angela Santoni11Helena Stabile12Cinzia Fionda13Department of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Biomedical Engineering, Emory University, Atlanta, GA, United StatesDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDivision of Hematology, Department of Translational Medicine and Precision, Sapienza University of Rome, Rome, ItalyDivision of Hematology, Department of Translational Medicine and Precision, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyIstituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, ItalyIstituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyDepartment of Molecular Medicine, Sapienza University of Rome, Rome, ItalyNKG2D ligands play a relevant role in Natural Killer (NK) cell -mediated immune surveillance of multiple myeloma (MM). Different levels of regulation control the expression of these molecules at cell surface. A number of oncogenic proteins and miRNAs act as negative regulators of NKG2D ligand transcription and translation, but the molecular mechanisms sustaining their basal expression in MM cells remain poorly understood. Here, we evaluated the role of the growth arrest specific 6 (GAS6)/TAM signaling pathway in the regulation of NKG2D ligand expression and MM recognition by NK cells. Our data showed that GAS6 as well as MERTK and AXL depletion in MM cells results in MICA downregulation and inhibition of NKG2D-mediated NK cell degranulation. Noteworthy, GAS6 derived from bone marrow stromal cells (BMSCs) also increases MICA expression at both protein and mRNA level in human MM cell lines and in primary malignant plasma cells. NF-kB activation is required for these regulatory mechanisms since deletion of a site responsive for this transcription factor compromises the induction of mica promoter by BMSCs. Accordingly, knockdown of GAS6 reduces the capability of BMSCs to activate NF-kB pathway as well as to enhance MICA expression in MM cells. Taken together, these results shed light on molecular mechanism underlying NKG2D ligand regulation and identify GAS6 protein as a novel autocrine and paracrine regulator of basal expression of MICA in human MM cells.https://www.frontiersin.org/articles/10.3389/fimmu.2022.942640/fullGAS6AXLMERTKMICANKG2D ligandmultiple myeloma |
| spellingShingle | Andrea Kosta Abdelilah Mekhloufi Lorenzo Lucantonio Alessandra Zingoni Alessandra Soriani Marco Cippitelli Angela Gismondi Francesca Fazio Maria Teresa Petrucci Angela Santoni Angela Santoni Angela Santoni Helena Stabile Cinzia Fionda GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells Frontiers in Immunology GAS6 AXL MERTK MICA NKG2D ligand multiple myeloma |
| title | GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells |
| title_full | GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells |
| title_fullStr | GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells |
| title_full_unstemmed | GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells |
| title_short | GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells |
| title_sort | gas6 tam signaling pathway controls mica expression in multiple myeloma cells |
| topic | GAS6 AXL MERTK MICA NKG2D ligand multiple myeloma |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.942640/full |
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