High-affinity immunoglobulin E receptor–Spleen tyrosine kinase–Phospholipase C gamma–Protein kinase C mu–Extracellular signal-regulated kinase signaling axis (FcεRI–Syk–PLCγ–PKCμ–ERK axis)

The High-affinity immunoglobulin E receptor (FcεRI)–Spleen tyrosine kinase (Syk)–Phospholipase C gamma (PLCγ)–Protein kinase C mu (PKCμ)–Extracellular signal-regulated kinase (ERK) signaling axis is a central pathway in mast cells that orchestrates the allergic inflammatory response. Activation is initiated when multivalent allergens cross-link IgE antibodies bound to FcεRI, leading to the phosphorylation of receptor ITAMs and the recruitment of Syk (Siraganian et al., 2010, PMID: 20176265). Syk then activates a complex network involving PLCγ and PKCμ (also known as PKD1), which triggers calcium mobilization and the ERK/MAPK cascade (Kalesnikoff & Galli, 2008, PMID: 18178474). This signaling sequence results in the rapid degranulation of mast cells, releasing mediators such as histamine and proteases, and the subsequent production of pro-inflammatory cytokines and lipid mediators (Gilfillan & Rivera, 2009, PMID: 19461655). Dysregulation of this axis is a hallmark of Type I hypersensitivity reactions, including allergic asthma, rhinitis, and systemic anaphylaxis (Olivera & Rivera, 2005, PMID: 15803150). Therapeutic targeting of this axis involves blocking the initial IgE-receptor interaction with antibodies like Omalizumab or inhibiting key kinases such as Syk with small molecules like Fostamatinib to prevent mast cell activation (Metcalfe et al., 2009, PMID: 19302547).

Other names

FcεRI signaling pathwayIgE-mediated mast cell activation pathwaySyk-dependent mast cell signalingFcεRI-Syk-PLCγ-PKCμ-ERK signaling axis in mast cells

Inhibition of IgE-FcεRI interaction, inhibition of Spleen Tyrosine Kinase (Syk) activity, and modulation of downstream MAPK signaling to prevent mast cell degranulation.