Docking of Syk to FcεRI is enhanced by Lyn but limited in duration by SHIP1

Authors

William K. Kanagy, Department of Pathology, University of New Mexico, Albuquerque, NM 87131
Cédric Cleyrat, Department of Pathology, University of New Mexico, Albuquerque, NM 87131, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131,Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131
Mohamadreza Fazel, Department of Physics, University of New Mexico, Albuquerque, NM 87131
Shayna R. Lucero, Department of Pathology, University of New Mexico, Albuquerque, NM 87131
Marcel P. Bruchez, Department of Biological Sciences and Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA 15213
Keith A. Lidke, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, Department of Physics, University of New Mexico, Albuquerque, NM 87131
Bridget S. Wilson, Department of Pathology, University of New Mexico, Albuquerque, NM 87131, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131
Diane S. Lidke, Department of Pathology, University of New Mexico, Albuquerque, NM 87131, Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131

Document Type

Article

Publication Date

9-1-2022

Abstract

The high-affinity immunoglobulin E (IgE) receptor, FcεRI, is the primary immune receptor found on mast cells and basophils. Signal initiation is classically attributed to phosphorylation of FcεRI β- and γ-subunits by the Src family kinase (SFK) Lyn, followed by the recruitment and activation of the tyrosine kinase Syk. FcεRI signaling is tuned by the balance between Syk-driven positive signaling and the engagement of inhibitory molecules, including SHIP1. Here, we investigate the mechanistic contributions of Lyn, Syk, and SHIP1 to the formation of the FcεRI signalosome. Using Lyn-deficient RBL-2H3 mast cells, we found that another SFK can weakly monophosphorylate the γ-subunit, yet Syk still binds the incompletely phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs). Once recruited, Syk further enhances γ-phosphorylation to propagate signaling. In contrast, the loss of SHIP1 recruitment indicates that Lyn is required for phosphorylation of the β-subunit. We demonstrate two noncanonical Syk binding modes,

Recommended Citation

Kanagy WK, Cleyrat C, Fazel M, Lucero SR, Bruchez MP, Lidke KA, Wilson BS, Lidke DS. Docking of Syk to FcεRI is enhanced by Lyn but limited in duration by SHIP1. Mol Biol Cell. 2022 Sep 1;33(10):ar89. doi: 10.1091/mbc.E21-12-0603. Epub 2022 Jul 6. PMID: 35793126; PMCID: PMC9582627.