SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival

SHIP is an inositol 5 ' phosphatase that hydrolyzes the PI3 ' K product PI(3,4,5)P-3. We show that SHIP-deficient mice exhibit dramatic chronic hyperplasia of myeloid cells resulting in splenomegaly, lymphadenopathy, and myeloid infiltration of vital organs. Neutrophils and bone marrow-derived mast cells from SHIP-/- mice are less susceptible to programmed cell death induced by various apoptotic stimuli or by growth factor withdrawal. Engagement of IL3-R and GM-CSF-R in these cells leads to increased and prolonged PI3 ' K-dependent PI(3,4,5)P-3 accumulation and PKB activation. These data indicate that SHIP is a negative regulator of growth factor-mediated PKB activation and myeloid cell survival.