Altered responsiveness to chemokines due to targeted disruption of SHIP
Chang H. Kim, Giao Hangoc, Scott Cooper, Cheryl D. Helgason, Sandie Yew, R. Keith Humphries, Gerald Krystal, Hal E. Broxmeyer
Chang H. Kim, Giao Hangoc, Scott Cooper, Cheryl D. Helgason, Sandie Yew, R. Keith Humphries, Gerald Krystal, Hal E. Broxmeyer
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Altered responsiveness to chemokines due to targeted disruption of SHIP

Abstract

SHIP has been implicated in negative signaling in a number of hematopoietic cell types and is postulated to downregulate phosphatidylinositol-3-kinase– (PI-3K–) initiated events in diverse receptor signaling pathways. Because PI-3K is implicated in chemokine signaling, we investigated whether SHIP plays any role in cellular responses to chemokines. We found that a number of immature and mature hematopoietic cells from SHIP-deficient mice manifested enhanced directional migration (chemotaxis) in response to the chemokines stromal cell–derived factor-1 (SDF-1) and B-lymphocyte chemoattractant (BLC). SHIP–/– cells were also more active in calcium influx and actin polymerization in response to SDF-1. However, colony formation by SHIP-deficient hematopoietic progenitor cell (HPCs) was not inhibited by 13 myelosuppressive chemokines that normally inhibit proliferation of HPCs. These altered biologic activities of chemokines on SHIP-deficient cells are not caused by simple modulation of chemokine receptor expression in SHIP-deficient mice, implicating SHIP in the modulation of chemokine-induced signaling and downstream effects.

Authors

Chang H. Kim, Giao Hangoc, Scott Cooper, Cheryl D. Helgason, Sandie Yew, R. Keith Humphries, Gerald Krystal, Hal E. Broxmeyer

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Bone marrow HPC, macrophages and B cells from SHIP-deficient mice have e...
Bone marrow HPC, macrophages and B cells from SHIP-deficient mice have enhanced chemotaxis to SDF-1. (a) Bone marrow cells were examined for their ability to transmigrate from the upper chamber toward SDF-1 at indicated concentrations in the lower chamber. After chemotaxis, myeloid progenitors in input and the lower chamber were assayed by methylcellulose colony assay. HPC (CFU-GM) migration was normalized for the number of input colony-forming HPCs to obtain HPC migration rate (% of input ± SD). Chemotaxis of CD11b/Mac-1+ F4/80+ bone marrow macrophages (b) and bone marrow B220+ B cells (c) in response to SDF-1. Data are expressed as the mean (± SD) of percent cell migration obtained from triplicated points. Results are each 1 representative of 5 independent experiments with consistent results. *Significant differences were observed between the wild-type and SHIP-deficient cells (P < 0.03).