Chapter 11 - Regulation of Mast Cell Degranulation by SHIP

Abstract

This chapter discusses the biological properties of the recently cloned SH2-containing inositol 5’-phosphatase (SHIP) and its role in IgE-induced cell signaling and degranulation. SHIP recruitment via its SH2 domain to the tyrosine-phosphorylated immunoreceptor tyrosine-based inhibition motif (ITIM) of the inhibitory co-receptor FcvRⅡB has been shown to inhibit FcɛRI- and BCR-induced degranulation and proliferation, respectively. More recently, SHIP has been shown, even in the absence of FcvRIIB co-clustering, to suppress IgE-mediated mast cell degranulation and prevent steel factor (SF)-mediated mast cell degranulation. It can also inhibit B cell chemotaxis. Shc needs to bind with SHIP in order to become tyrosine phosphorylated after FcɛRI activation by IgE. Both IgE- and SF-mediated degranulation are strictly dependent on the influx of extracellular calcium. Thapsigargin was used to study the role of SHIP in mast cell degranulation downstream of the calcium influx. A model for IgE-induced degranulation of mast cells in which binding of IgE alone to the FcɛRI on normal primary mast cells activates a constitutively associated Src family member (predominantly Lyn), most likely via CD45, to tyrosine phosphorylate the β and γ-immunoreceptor tyrosine-based activation motifs (ITAM) is also proposed. Ship plays a vital role in both setting the threshold for and limiting degranulation by hydrolysing PI-3,4,5-P3 and thus restricting the entry of extracellular calcium and activation of certain PKC isoforms. It has also been suggested that the development of drugs that can specifically increase SHIP activity in mast cells might dramatically reduce allergic responses.