The role of SHIP in cytokine-induced signaling

The phosphatidylinositol (PI)-3 kinase (PI3K) pathway plays a central role in regulating many biological processes via the generation of the key second messenger PI-3,4,5-trisphosphate (PI-3,4,5-P-3). This membrane-associated phospholipid, which is rapidly, albeit transiently, synthesized from PI-4,5-P-2 by PI3K in response to a diverse array of extracellular stimuli, attracts pleckstrin homology (PH) domain-containing proteins to membranes to mediate its many effects, To ensure that the activation of this pathway is appropriately suppressed/terminated, the ubiquitously expressed tumor suppressor PTEN hydrolyzes PI-3,4,5-P-3 back to PI-4,5-P-2 while the 145-kDa hemopoietic-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 hydrolyze PI-3,4,5-P-3 to PI-3,4-P-2. In this review we will concentrate on the properties of the three SHIPs, with special emphasis being placed on the role that SHIP plays in cytokine-induced signaling.