FcαRI Dynamics Are Regulated by GSK-3 and PKCζ During Cytokine Mediated Inside-Out Signaling

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

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)3191
JournalFrontiers in Immunology
Volume9
DOIs
Publication statusPublished - 2018

Cite this

ten Broeke, T., Honing, H., Brandsma, A. M., Jacobino, S., Bakema, J. E., Kanters, D., ... Leusen, J. H. W. (2018). FcαRI Dynamics Are Regulated by GSK-3 and PKCζ During Cytokine Mediated Inside-Out Signaling. Frontiers in Immunology, 9, 3191. https://doi.org/10.3389/fimmu.2018.03191