Altered responsiveness to chemokines due to targeted disruption of SHIP

SHIP has been implicated in negative signaling in a number of hematopoietic cell types and is postulated to downregulate phosphatidylinositol-3-kinase -(PI-3 K-) initiated events in diverse receptor signaling pathways. Because PI-SK is implicated in chemokine signaling, we investigated whether SHIP p lays any role in cellular responses to chemokines. We found that a number o f immature and mature hematopoietic cells from SHIP-deficient mice manifest ed enhanced directional migration (chemotaxis) in response to the chemokine s stromal cell-derived factor-1 (SDF-1) and B-lymphocyte chemoattractant (B LC). SHIP-/- cells were also more active in calcium influx and actin polyme rization in response to SDF-1. However, colony formation by SHIP-deficient hematopoietic progenitor cell (HPCs) was not inhibited by 13 myelosuppressi ve chemokines that normally inhibit proliferation of HPCs. These altered bi ologic activities of chemokines on SHIP-deficient cells are not caused by s imple modulation of chemokine receptor expression in SHIP-deficient mice, i mplicating SHIP in the modulation of chemokine-induced signaling and downst ream effects.