FcαRI Dynamics Are Regulated by GSK-3 and PKCζ During Cytokine Mediated Inside-Out Signaling
| العنوان: | FcαRI Dynamics Are Regulated by GSK-3 and PKCζ During Cytokine Mediated Inside-Out Signaling |
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| المؤلفون: | Toine ten Broeke, Henk Honing, Arianne M. Brandsma, Shamir Jacobino, Jantine E. Bakema, Deon Kanters, Jan A. M. van der Linden, Madelon Bracke, Leo Koenderman, Jeanette H. W. Leusen |
| المصدر: | Frontiers in Immunology Frontiers in Immunology, 9. Frontiers Media S. A. Frontiers in Immunology, Vol 9 (2019) |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | lcsh:Immunologic diseases. Allergy, 0301 basic medicine, IgA binding, medicine.medical_treatment, Immunology, fluorescence recovery after photobleaching, Receptors, Fc, Models, Biological, Fc alpha receptor I, 03 medical and health sciences, Glycogen Synthase Kinase 3, Mice, 0302 clinical medicine, GSK-3, medicine, Animals, Humans, Immunology and Allergy, Phosphorylation, PI3K/AKT/mTOR pathway, Protein Kinase C, Original Research, glycogen synthase kinase-3, Kinase, Chemistry, Cell Membrane, Protein phosphatase 2, Cell biology, Immunoglobulin A, Protein Kinase C zeta, 030104 developmental biology, Cytokine, Cytokines, Signal transduction, lcsh:RC581-607, IgA, 030215 immunology, Protein Binding, Signal Transduction |
| الوصف: | IgA binding to FcαRI (CD89) is rapidly enhanced by cytokine induced inside-out signaling. Dephosphorylation of serine 263 in the intracellular tail of FcαRI by PP2A and PI3K activation are instrumental in this process. To further investigate these signaling pathways, we targeted downstream kinases of PI3K. Our experiments revealed that PI3K activates PKCζ, which subsequently inhibits GSK-3, a constitutively active kinase in resting cells and found here to be associated with FcαRI. We propose that GSK-3 maintains FcαRI in an inactive state at homeostatic conditions. Upon cytokine stimulation, GSK-3 is inactivated through a PI3K-PKCζ pathway, preventing the maintenance of phosphorylated inactive FcαRI. The concomitantly activated PP2A is then able to dephosphorylate and activate FcαRI. Moreover, FRAP and FLIP studies showed that FcαRI activation coincides with an increased mobile fraction of the receptor. This can enhance FcαRI valency and contribute to stronger avidity for IgA immune complexes. This tightly regulated inside-out signaling pathway allows leukocytes to respond rapidly and efficiently to their environment and could be exploited to enhance the efficacy of future IgA therapeutics. |
| وصف الملف: | image/pdf |
| اللغة: | English |
| تدمد: | 1664-3224 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::42ee8419afff7f74b1830ea8ddb8fcb0 https://dspace.library.uu.nl/handle/1874/377319 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....42ee8419afff7f74b1830ea8ddb8fcb0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 16643224 |
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