Partially distinct molecular mechanisms mediate inhibitory Fc gamma RIIB signaling in resting and activated B cells'

Fc gamma RIIB functions as an inhibitory receptor to dampen B cell Ag recep tor signals and immune responses. Accumulating evidence indicates that ex v ivo B cells require the inositol 5-phosphatase, Src homology domain 2-conta ining inositol 5-phosphatase (SHIP), for Fc gamma RIIB-mediated inhibitory signaling. However, we report here that LPS-activated primary B cells do no t require SHIP and thus differ from resting B cells. SHIP-deficient B cell blasts display efficient Fc gamma RIIB-dependent inhibition of calcium mobi lization as well as Akt and extracellular signal-related protein kinase pho sphorylation. Surprisingly, Fc gamma RIIB-dependent degradation of phosphat idylinositol 3,4,5-trisphosphate and conversion into phosphatidylinositol 3 ,4-bisphosphate occur in SHIP-deficient B cell blasts, demonstrating the fu nction of an additional inositol 5-phosphatase. Further analysis reveals th at while resting cells express only SHIP, B cell blasts also express the re cently described inositol 5-phosphatase, SHIP-2. Finally, data suggest that both SHIP-2 and SHIP can mediate downstream biologic consequences of Fc ga mma RIIB signaling, including inhibition of the proliferative response.