Positive and Negative Regulation of High Affinity IgE Receptor Signaling by Src Homology Region 2 Domain-Containing Phosphatase 1

Abstract

Src homology region 2 domain-containing phosphatase 1 (SHP-1), a cytoplasmic protein tyrosine phosphatase, plays an important role for the regulation of signaling from various hematopoietic cell receptors. Although SHP-1 is shown to be a negative signal modulator in mast cells, its precise molecular mechanisms are not well defined. To elucidate how SHP-1 regulates mast cell signaling, we established bone marrow-derived mast cells from SHP-1-deficient motheaten and wild-type mice and analyzed downstream signals induced by cross-linking of high affinity IgE receptor, FcεRI. Upon FcεRI ligation, motheaten-derived bone marrow-derived mast cells showed enhanced tyrosine phosphorylation of Src homology region 2 domain-containing leukocyte protein of 76 kDa (SLP-76) and linker for activation of T cells, activation of mitogen-activated protein kinases and gene transcription and production of cytokine. Because the activity of Syk, responsible for the phosphorylation of SLP-76 and linker for activation of T cells, is comparable irrespective of SHP-1, both molecules might be substrates of SHP-1 in mast cells. Interestingly, the absence of SHP-1 expression disrupted the association between SLP-76 and phospholipase Cγ, which resulted in the decreased phospholipase Cγ phosphorylation, calcium mobilization, and degranulation. Collectively, these results suggest that SHP-1 regulates FcεRI-induced downstream signaling events both negatively and positively by functioning as a protein tyrosine phosphatase and as an adaptor protein contributing to the formation of signaling complex, respectively.

SH2 Domain-Containing Phosphatase-2 Protein-Tyrosine Phosphatase Promotes FcεRI-Induced Activation of Fyn and Erk Pathways Leading to TNFα Release from Bone Marrow-Derived Mast Cells

“…In mast cells, recent studies of SHP1 and SHP2 functions in the FcRI pathway (Ref. 57) and this study), provide evidence for distinct roles of these related phosphatases. A previous study of motheaten mice that are deficient in SHP1 had implicated SHP1 in repressing allergic inflammation (9).…”

Mouse host unlicensed NK cells promote donor allogeneic bone marrow engraftment

“…A different SHP1 function upon activation was also described for NK and mast cells. 23,24 These results indicate profound functional differences in the ability of host-NK subsets to affect donor alloBMC engraftment based on licensing, suggesting their potential use in clinical BMT.…”

IgE and Mast Cells

“…Interestingly, this Fcε-Fcγ construct diminished phosphorylation of Syk as well as Erk, which could readily explain reductions in cytokine synthesis (Mertsching et al, 2008). Shp-1 is thought to dephosphorylate several early molecules in FcεRI signal transduction pathway, including Syk, LAT, SLP76, and the β/γ chains of FcεRI itself (Nakata et al, 2008;Xie, Zhang, & Siraganian, 2000). SHIP and Shp-1 can also associate with FcεRI and regulate its function independently of FcγRIIb (Huber, Kalesnikoff, Reth, & Krystal, 2002;Nakata et al, 2008); it may be that coligation of FcγRIIb simply prolongs and amplifies these existing inhibitory signals Fig.…”