SHIP is an inositol 5 phosphatase that hydrolyzes the PI3K 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 PI3K-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.

SummaryShip is an Src homology 2 domain containing inositol polyphosphate 5-phosphatase which has been implicated as an important signaling molecule in hematopoietic cells. In B cells, Ship becomes associated with Fc ␥ receptor IIB (Fc ␥ RIIB), a low affinity receptor for the Fc portion of immunoglobulin (Ig)G, and is rapidly tyrosine phosphorylated upon B cell antigen receptor (BCR)-Fc ␥ RIIB coligation. The function of Ship in lymphocytes was investigated in Ship Ϫ / Ϫ recombination-activating gene (Rag) Ϫ / Ϫ chimeric mice generated from gene-targeted Ship Ϫ / Ϫ embryonic stem cells. Ship Ϫ / Ϫ Rag Ϫ / Ϫ chimeras showed reduced numbers of B cells and an overall increase in basal serum Ig. Ship Ϫ / Ϫ splenic B cells displayed prolonged Ca 2 ϩ influx, increased proliferation in vitro, and enhanced mitogen-activated protein kinase (MAPK) activation in response to BCR-Fc ␥ RIIB coligation. These results demonstrate that Ship plays an essential role in Fc ␥ RIIB-mediated inhibition of BCR signaling, and that Ship is a crucial negative regulator of Ca 2 ϩ flux and MAPK activation.

We have studied the mechanism of delta 1‐crystallin gene activation, which occurs early in lens cell differentiation, and have previously shown that an essential element of the delta 1‐crystallin enhancer is bound by a group of nuclear factors, delta EF2, among which delta EF2a is highly enriched in lens cells. In this report we show that the cDNA of delta EF2a codes for the chicken SOX‐2 protein (cSOX‐2), which is structurally related to the sex‐determining factor SRY. Sox‐2 is expressed at high levels in the early developing lens in both chicken and mouse embryos. Overexpression of delta EF2a/cSOX‐2 increased delta 1‐crystallin enhancer activity to a plateau in lens cells, but not in fibroblasts, consistent with the previously drawn conclusion that delta EF2a activates transcription only in concert with another factor present in the lens. This result supports the model that SOX proteins act as architectural components in the activating complex formed on an enhancer, as indicated for another HMG domain protein, lymphoid enhancer binding factor 1 (LEF‐1). We also show that SOX protein binding is essential for lens‐specific promoter activity of the mouse gamma F‐crystallin gene. This work is the first to show delta‐ and gamma‐crystallin genes as examples of direct regulatory targets of SOX proteins and provides evidence that diversified crystallin genes are regulated, at least partly, by a common mechanism.