SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival.
SHIP is an inositol 5' phosphatase that hydrolyzes the PI3'K product PI(3,4,5)P3. 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 PI3'K-dependent PI(3,4,5)P3 accumulation and PKB activation. These data indicate that SHIP is a negative regulator of growth factor-mediated PKB activation and myeloid cell survival.
Liu
Q
Q
Amgen Institute, Toronto, Ontario, Canada M5G 2C1.
Sasaki
T
T
Kozieradzki
I
I
Wakeham
A
A
Itie
A
A
Dumont
D J
DJ
Penninger
J M
JM
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D017209:Apoptosis; D015139:Blotting, Southern; D015153:Blotting, Western; D001853:Bone Marrow / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation; D004789:Enzyme Activation; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013012:Sorbitol / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism; D013997:Time Factors
D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D013012:Sorbitol; D000841:Anisomycin; D003513:Cycloheximide; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases