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Phosphorylation of the ?-chain in the integrin LFA-1 enables ?2-chain phosphorylation and ?-actinin binding required for cell adhesion.

ABSTRACT: The integrin leukocyte function-associated antigen-1 (LFA-1) plays a pivotal role in leukocyte adhesion and migration, but the mechanism(s) by which this integrin is regulated has remained incompletely understood. LFA-1 integrin activity requires phosphorylation of its ?2-chain and interactions of its cytoplasmic tail with various cellular proteins. The ?-chain is constitutively phosphorylated and necessary for cellular adhesion, but how the ?-chain regulates adhesion has remained enigmatic. We now show that substitution of the ?-chain phosphorylation site (S1140A) in T cells inhibits the phosphorylation of the functionally important Thr-758 in the ?2-chain, binding of ?-actinin and 14-3-3 protein, and expression of an integrin-activating epitope after treatment with the stromal cell-derived factor-1?. The presence of this substitution resulted in a loss of cell adhesion and directional cell migration. Moreover, LFA-1 activation through the T-cell receptor in cells expressing the S1140A LFA-1 variant resulted in less Thr-758 phosphorylation, ?-actinin and talin binding, and cell adhesion. The finding that the LFA-1 ?-chain regulates adhesion through the ?-chain via specific phosphorylation at Ser-1140 in the ?-chain has not been previously reported and emphasizes that both chains are involved in the regulation of LFA-1 integrin activity.

SUBMITTER: Jahan F

PROVIDER: S-EPMC6093247 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Phosphorylation of the α-chain in the integrin LFA-1 enables β2-chain phosphorylation and α-actinin binding required for cell adhesion.

Jahan Farhana F Madhavan Sudarrshan S Rolova Taisia T Viazmina Larisa L Grönholm Mikaela M Gahmberg Carl G CG

The Journal of biological chemistry 20180614 32

The integrin leukocyte function-associated antigen-1 (LFA-1) plays a pivotal role in leukocyte adhesion and migration, but the mechanism(s) by which this integrin is regulated has remained incompletely understood. LFA-1 integrin activity requires phosphorylation of its β2-chain and interactions of its cytoplasmic tail with various cellular proteins. The α-chain is constitutively phosphorylated and necessary for cellular adhesion, but how the α-chain regulates adhesion has remained enigmatic. We ...[more]

PMID: 29903913

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Project description:BackgroundLeukocyte activation by anti-neutrophil cytoplasmic antibody (ANCA) and the subsequent leukocyte-endothelium interaction play a key role in the development of endothelial damage in ANCA-associated vasculitis (AAV). In contrast to that of leukocyte activation, the exact role of the leukocyte-endothelium interaction via integrin remains unclear. Here, we performed microarray and validation analyses to explore association between the expression levels of lymphocyte function-associated antigen-1 (LFA-1) and the clinical characteristics of patients with AAV.MethodsWe performed gene set enrichment analysis (GSEA) to identify the functional gene sets differentially expressed between patients with AAV and other types of vasculitis and the healthy controls (HCs). Flow cytometry was performed to validate the GSEA results. Treatment-naïve patients were monitored until 24 weeks of treatment. To examine the role of LFA-1 in the neutrophil-endothelium interaction, we performed a leukocyte adhesion and transmigration assay using peripheral blood and human umbilical vein endothelial cells (HUVECs).ResultsGSEA revealed that the molecular pathways involving integrin-related genes were significantly upregulated in patients with AAV compared to that in patients with other types of vasculitis and the HCs. Flow cytometry revealed that the percentage of neutrophils expressing LFA-1 was significantly higher in patients with AAV than in those with large-vessel vasculitis or polyarteritis nodosa and the HCs. LFA-1 levels in the neutrophils were higher in patients with MPO-ANCA-positive expression than in those with a positive PR3-ANCA expression and correlated with the peripheral eosinophil count, serum rheumatoid factor titre, serum C-reactive protein levels, and the vasculitis activity score of systemic and chest components. After 24 weeks of treatment, including prednisolone, cyclophosphamide, rituximab, azathioprine, methotrexate, and/or tacrolimus, neutrophil LFA-1 expression remained high in the non-responder patients, but decreased in the responder patients. The in vitro assay showed that leukocyte migration toward HUVECs was dependent on the interaction between LFA-1 and intercellular adhesion molecule-1 (ICAM1); the migration of leukocytes was inhibited by blocking the adhesion of LFA-1 to ICAM1.ConclusionsThe expression of LFA-1 in neutrophils is increased in patients with AAV. Neutrophil LFA-1 levels correlate with the clinical features of AAV. Inhibiting the adhesion of LFA-1 and ICAM1 impedes the neutrophil-endothelium interaction and may have a therapeutic role in AAV.

Dataset Information

Phosphorylation of the ?-chain in the integrin LFA-1 enables ?2-chain phosphorylation and ?-actinin binding required for cell adhesion.

Publications

Phosphorylation of the α-chain in the integrin LFA-1 enables β2-chain phosphorylation and α-actinin binding required for cell adhesion.

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