SHIP, SHIP2, and PTEN activities are regulated in vivo by modulation of their protein levels: SHIP is up-regulated in macrophages and mast cells by lipopolysaccharide.
The phosphatidylinositol-3 kinase (PI3K) pathway plays a central role in regulating numerous biologic processes, including survival, adhesion, migration, metabolic activity, proliferation, differentiation, and end cell activation through the generation of the potent second messenger PI-3,4,5-trisphosphate (PI-3,4,5-P(3)). To ensure that activation of this pathway is appropriately suppressed/terminated, the ubiquitously expressed 54-kDa tumor suppressor PTEN hydrolyzes PI-3,4,5-P(3) to PI-4,5-P(2), whereas the 145-kDa hematopoietic-restricted SH2-containing inositol 5'-phosphatase SHIP (also known as SHIP1), the 104-kDa stem cell-restricted SHIP sSHIP, and the more widely expressed 150-kDa SHIP2 break it down to PI-3,4-P(2). In this review, we focus on the properties of these phospholipid phosphatases and summarize recent data showing that the activities of these negative regulators often are modulated by simply altering their protein levels. We also highlight the critical role that SHIP plays in lipopolysaccharide-induced macrophage activation and in endotoxin tolerance.
Sly
Laura M
LM
The Terry Fox Laboratory, British Columbia Cancer Agency, 601 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada.
Rauh
Michael J
MJ
Kalesnikoff
Janet
J
Büchse
Tom
T
Krystal
Gerald
G
D000818:Animals; D025461:Feedback, Physiological; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D008407:Mast Cells / Q000201:enzymology / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000187:drug effects
D008070:Lipopolysaccharides; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases