4.4 Article

Differential mast cell outcomes are sensitive to FceRI-Syk binding kinetics

期刊

MOLECULAR BIOLOGY OF THE CELL
卷 28, 期 23, 页码 3397-3414

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AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E17-06-0350

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资金

  1. National Institutes of Health (NIH) [R01GM100114]
  2. New Mexico Spatiotemporal Modeling Center [NIH P50GM085273]
  3. NIH [P30CA118100]

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Cross-linking of immunoglobulin E-bound FceRI triggers multiple cellular responses, including degranulation and cytokine production. Signaling is dependent on recruitment of Syk via docking of its dual SH2 domains to phosphorylated tyrosines within the FceRI immunoreceptor tyrosine-based activation motifs. Using single-molecule imaging in live cells, we directly visualized and quantified the binding of individual mNeonGreen-tagged Syk molecules as they associated with the plasma membrane after Fc epsilon RI activation. We found that Syk colocalizes transiently to Fc epsilon RI and that Syk-Fc epsilon RI binding dynamics are independent of receptor aggregate size. Substitution of glutamic acid for tyrosine between the Syk SH2 domains (Syk-Y130E) led to an increased Syk-Fc epsilon RI off-rate, loss of site-specific Syk autophosphorylation, and impaired downstream signaling. Genome edited cells expressing only SykY130E were deficient in antigen-stimulated calcium release, degranulation, and production of some cytokines (TNF-alpha, IL-3) but not others (MCP-1, IL-4). We propose that kinetic discrimination along the Fc epsilon RI signaling pathway occurs at the level of Syk-Fc epsilon RI interactions, with key outcomes dependent upon sufficiently long-lived Syk binding events.

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