Glycogen synthase kinase 3beta activation is a prerequisite signal for cytokine production and chemotaxis in human mast cells.

In addition to regulating mast cell homeostasis, the activation of KIT following ligation by stem cell factor promotes a diversity of mast cell responses, including cytokine production and chemotaxis. Although we have previously defined a role for the mammalian target of rapamycin complex 1 in these responses, it is clear that other signals are also required for maximal KIT-dependent cytokine production and chemotaxis. In this study, we provide evidence to support a role for glycogen synthase kinase 3beta (GSK3beta) in such regulation in human mast cells (HuMCs). GSK3beta was observed to be constitutively activated in HuMCs. This activity was inhibited by knockdown of GSK3beta protein following transduction of these cells with GSK3beta-targeted shRNA. This resulted in a marked attenuation in the ability of KIT to promote chemotaxis and, in synergy with FcepsilonRI-mediated signaling, cytokine production. GSK3beta regulated KIT-dependent mast cell responses independently of mammalian target of rapamycin. However, evidence from the knockdown studies suggested that GSK3beta was required for activation of the MAPKs, p38, and JNK and downstream phosphorylation of the transcription factors, Jun and activating transcription factor 2, in addition to activation of the transcription factor NF-kappaB. These studies provide evidence for a novel prerequisite priming mechanism for KIT-dependent responses regulated by GSK3beta in HuMCs.