Positive and negative regulation of FcεRI signaling by SHP‐1

Abstract

SHP‐1 is a cytoplasmic tyrosine phosphatase and, in mast cells, has been shown to negatively regulate the initial signaling triggered by high affinity receptors for IgE (FcεRI). To clarify the molecular mechanisms of SHP‐1 in mast cells, we generated bone marrow‐derived mast cells (BMMCs) from SHP‐1‐deficient motheaten (me) and control (wt) mice and examined downstream signaling events and final outputs following FcεRI crosslinking. FcεRI‐induced tyrosine phosphorylation of SLP‐76 and LAT was increased in me‐derived BMMCs. The activity of Syk that is responsible for the phosphorylation of SLP‐76 and LAT was comparable in both BMMCs, implying that SLP‐76 and LAT might be substrates of SHP‐1 in mast cells. Lack of SHP‐1 expression resulted in enhanced activation of mitogen activated protein kinases, Erk, JNK, and p38, and transcription of cytokine genes such as TNFα and IL‐6, in good accordance with the previous implication of SHP‐1 as a negative regulator. In contrast, FcεRI‐induced calcium mobilization was severely impaired in me‐derived BMMCs. Whereas wt‐BMMCs showed sprolonged increase in calcium flux upon high intensity stimulation, BMMCs derived from me mice demonstrated decreased and transient responses. In addition, me‐BMMCs exhibited diminished calcium flux at low intensity stimulation. Thapsigargin induced similar level of calcium flux in both BMMCs, indicating that BMMCs lacking SHP‐1 expression are still capable of mobilizing calcium. These studies revealed that SHP‐1 not only regulates FcεRI‐signaling negatively but can act as a positive regulator in mast cells. The experiments to clarify possible molecular mechanisms for the positive regulation of calcium signaling by SHP‐1 are currently under study.