title: 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.affiliation: Departments of Microbiology/Immunology and Medicine and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Kim
authors.forename: G
authors.initials: G
authors.lastname: Hangoc
authors.forename: S
authors.initials: S
authors.lastname: Cooper
authors.forename: C D
authors.initials: CD
authors.lastname: Helgason
authors.forename: S
authors.initials: S
authors.lastname: Yew
authors.forename: R K
authors.initials: RK
authors.lastname: Humphries
authors.forename: G
authors.initials: G
authors.lastname: Krystal
authors.forename: H E
authors.initials: HE
authors.lastname: Broxmeyer
mesh_terms: 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
chemical_list: 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