Involvement of RIP2 in mast cell activation downstream of the high-affinity IgE receptor FcϵRI (HYP4P.304)

RIP2 is a dual-specificity kinase which is activated following the engagement of the peptidoglycan sensors NOD1 and NOD2. Despite abundant expression of RIP2 in various tissues and cell types, as well as having numerous reported binding partners, its role has primarily been demonstrated as important solely downstream of NOD1/2 signaling. We report that RIP2 potentially has a role downstream of signaling through the high affinity IgE receptor, FcϵRI. We demonstrate that members of the Src family kinases as well as Syk, which are involved in FcϵRI signaling, bind to and promote tyrosine phosphorylation of RIP2. Importantly, we show that loss of RIP2 affects mast cell activation downstream of FcϵRI but not activation mediated through other pathways such as through purinergic receptor engagement. Lastly, use of Gefitnib, a potent RIP2 inhibitor, shows downregulation of FcϵRI-mediated responses. Altogether, these data provide evidence for the involvement of RIP2 in a novel, non-NOD-mediated signaling pathway and suggest that Gefitinib or specific RIP2 inhibitors may be useful for the treatment of disorders in which mast cell FcϵRI signaling play an important role such as in allergy or asthma.