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  Laura M Sly, Michael J Rauh, Janet Kalesnikoff, Tom Büchse, Gerald Krystal  Experimental Hematology  Volume 31, Issue 12, Pages 1170-1181 (December 2003) DOI: 10.1016/j.exphem.2003.09.011

Figure 1 Structures of SHIP, sSHIP, SHIP2, and PTEN. The numbers to the right of the proteins refer to the total number of amino acids. The gray boxes indicate the phosphatase domains. Experimental Hematology 2003 31, 1170-1181DOI: (10.1016/j.exphem.2003.09.011)

Figure 2 Model of IL-3–induced translocation of SHIP to the plasma membrane (based in part on previous studies [50,51]). 1) IL-3 stimulates the Jak2-mediated tyrosine phosphorylation of the βIL-3 subunit of the IL-3R at Y577. 2) This attracts Shc via its PTB domain. 3) Shc then is tyrosine phosphorylated by Lyn or Jak2, primarily at Y239 and 317, and 4) this attracts SHIP via its SH2 domain, which then 5) hydrolyzes the PI3K-generated PI-3,4,5-P3 to PI-3, 4-P2, and this curtails PI-3,4,5-P3-mediated activation of multiple pathways. For more details on PI-3,4,5-P3-mediated events, see [2]. Experimental Hematology 2003 31, 1170-1181DOI: (10.1016/j.exphem.2003.09.011)

Figure 3 Model of LPS-induced macrophage activation. See text for details. The gray boxes in TLR4, MyD88, TIRAP, and TICAM-1 indicate the TIR domains. The hatched boxes in MyD88 and the IRAKs indicate the death domains. Asterisk (∗) indicates a PI3K-dependent process. Experimental Hematology 2003 31, 1170-1181DOI: (10.1016/j.exphem.2003.09.011)

Figure 4 Role of SHIP in LPS-induced endotoxin tolerance. A first dose of LPS activates the PI3K pathway, which stimulates a number of pathways, including the MyD88/TIRAP/IRAK/TRAF6/NFκB pathway and the TICAM/IRF3/IFN-β/JAK/Stat1 pathway to trigger the production of pro-inflammatory cytokines and NO (see Fig. 2). Activation of the IFN-β pathway also leads to up-regulation of the negative regulator SOCS1. LPS also up-regulates the transcription of TGF-β, which, in turn, activates the transcription of the negative regulator SHIP. Transcription of a third negative regulator, IRAK-M, also is increased in an IFN-α–/IFN-β– and TGF-β–independent manner (left panel). A second dose of LPS does not activate the downstream production of pro-inflammatory mediators such as NO and TNF-α because of the increased levels of these three negative regulators (right panel). Experimental Hematology 2003 31, 1170-1181DOI: (10.1016/j.exphem.2003.09.011)