Cooperation of adapter molecules in proximal signaling cascades during allergic inflammation.

Activation of mast cells through their high-affinity immunoglobulin E receptor (FcepsilonRI) plays an important role in allergic disorders. Other mast cell-activating stimuli, such as Toll-like receptor (TLR) ligands, synergize with FcepsilonRI to enhance allergic inflammation. Thus, there is much interest in understanding how signaling occurs downstream of these receptors. One key event for FcepsilonRI-mediated mast cell activation is the inducible formation of multimolecular proximal signaling complexes. These complexes are nucleated by adapter proteins, scaffolds that localize various signaling molecules through their multiple molecule-binding domains. Here we review recent findings in proximal signaling cascades with an emphasis on how adapter molecules cooperate with each other to generate an optimal signal in mast cells, and we discuss how signals crosstalk between FcepsilonRI and TLRs in enhancing mast cell activation. Deciphering the molecular mechanisms leading to mast cell activation will hopefully bring new ideas for the development of novel therapeutics to control allergic diseases.