Tyrosine phosphatase SHP-1 in allergic and anaphylactic inflammation

Abstract

Protein tyrosine phosphatase SHP-1 is an essential regulatory molecule in many different signaling pathways. The biological importance of SHP-1 is underscored by the motheaten mutant mouse strains with immunological disorders involving multiple organs and by the close association of aberrant SHP-1 expression with several human diseases. Recent studies provided some compelling evidence that supports a role of SHP-1 in regulating mast cell development and function and also in regulating type 2 allergic inflammatory responses in both innate and adaptive immune responses. In this article, we summarize the recent advancement of our understanding of this interesting phosphatase in the important area of allergic inflammation.

Fig. 1

Schematic illustration of potential mechanisms by which SHP-1 regulates mast cell development and function. SHP-1 can bind to FcεRI and down-regulates its signaling after cross-linking induced by antigen and IgE, thus to control mast cell degranulation. In the process, SHP-1 may bind the adapter molecule LAT2. SHP-1 is also recruited to c-Kit when its ligand SCF is recognized. Through this interaction, SHP-1 is able to regulate mast cell differentiation, maturation, and survival, since c-Kit is essential for mast cells. The c-Kit signaling is largely through the PI3 kinase pathway. SHP-1 may be a target for intracellular oxidants, but SHP-1 may also be able to control oxidant-induced Th2 cytokine production by mast cells. This process is potentially regulated by the NF-κB signaling pathway. Finally, SHP-1 is a negative regulator of endotoxin (LPS)-induced mast cell production of IL-13. However, this regulation is independent of oxidant stress and NF-κB but possibly involves the MAP kinase signaling pathway. The up-regulation of anti-apoptotic gene Bcl-2 in the absence of SHP-1 regulation is able to increase the survival of mast cells, probably by a mechanism that keeps the cells in the G0/G1 phase of the cell cycle that slows down cell proliferation