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-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.
Kim
C H
CH
Departments of Microbiology/Immunology and Medicine and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Hangoc
G
G
Cooper
S
S
Helgason
C D
CD
Yew
S
S
Humphries
R K
RK
Krystal
G
G
Broxmeyer
H E
HE
D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D018925:Chemokines / Q000494:pharmacology*; D019743:Chemokines, CXC / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D019707:Receptors, Chemokine / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000199:Actins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019707:Receptors, Chemokine; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D002118:Calcium