Src homology 2 domain-containing inositol 5-phosphatase 1 mediates cell cycle arrest by Fc gamma RIIB

We previously found that low affinity receptors for the Fc portion of IgG, Fc-/RUB, which are widely expressed by hematopoietic cells, can negatively regulate receptor tyrosine kinase-dependent cell proliferation. We investig ated here the mechanisms of this inhibition. We used as experimental models wild-type mast cells, which constitutively express the stem cell factor re ceptor Kit and Fc gamma RIIB, Fc gamma RIIB-deficient mast cells reconstitu ted with wild-type or mutated Fc gamma RIIB, and Src homology 2 domain-cont aining inositol polyphosphate 5-phosphatase 1 (SHIP1)deficient mast cells. We found that, upon coaggregation with Kit, Fc gamma RIIB are tyrosyl-phosp horylated, recruit SHIP1, but not SHIP2, SH2 domain-containing protein tyro sine phosphatase-1 or -2, abrogate Akt phosphorylation, shorten the duratio n of the activation of mitogen-activated protein kinases of the Ras and Rac pathways, abrogate cyclin induction, prevent cells from entering the cell cycle, and block thymidine incorporation. Fc gamma RIIB-mediated inhibition of Mt-dependent cell proliferation was reduced in SHIP1-deficient mast cel ls, whereas inhibition of IgE-induced responses was abrogated. Cell prolife ration was, however, inhibited by coaggregating Mt with Fc gamma RIIB whose intracytoplasmic domain was replaced with the catalytic domain of SHIP1. T hese results demonstrate that Fc gamma RIIB use SHIP1 to inhibit pathways s hared by receptor tyrosine kinases and immunoreceptors to trigger cell prol iferation and cell activation, respectively, but that, in the absence of SH IP1, Fc-/RUB can use other effectors that specifically inhibit cell prolife ration.