Different modes of mast cell activation. Mast cell identity is maintained by the coordinated actions of several TFs such as MITF, GATA-2, STAT-5, and ATF-3. Mast cells can be activated by different GPCRs such as MRGPRX2 and high-affinity IgE receptor FcεR1. However, there are notable differences between MRGPRX2- and FcεR1-mediated mast cell activation. Although ligand binding to MRGPRX2 leads to intracellular calcium increase and degranulation, there is very limited cytokine response. However, high-affinity antigen-mediated FcεR1 cross-linking involves higher intracellular calcium levels, degranulation, and inflammatory cytokine and chemokine response involving various TFs such as NF-κB, NFAT, AP-1, EGR1, and EGR2. Despite similar levels of FcεR1 receptor phosphorylation, low-affinity antigen-mediated FcεR1 cross-linking involves a smaller increase in intracellular calcium levels and degranulation, and the inflammatory response is more chemokine based compared with high-affinity antigen-mediated activation. This is due to the involvement of cytoplasmic Fgr kinase and the membrane-bound LAT2 adaptor. Finally, although cytoskeleton rearrangements such as microtubule polymerization and actin depolymerization are a common feature of all forms of degranulation, the components of SNARE machinery are less well known in MRGPRX2-mediated degranulation.