From the ITIM(s) of lymphocyte to the platelet integrins: SHIP, a protein crossing multiple roads?

The SH2 domain-containing inositol 5-phosphatase, SHIP, known to dephosphorylate inositol (1,3,4,5)-tetrakisphosphate and phosphatidylinositol (3,4,5)-trisphosphate has been shown to be expressed in a variety of hemopoietic cells. Stimulation of antigen receptors on lymphocytes can result in either positive or negative signaling, resulting in activation or inhibitory responses. The ITIM is a conserved intracytoplasmic motif widely used for negative signaling. Negative signaling in B cells is initiated by co-crosslinking of the antigen receptor and the Fc gamma RIIB receptor, resulting in cessation of B-cell signaling events and, in turn, inhibition of B-cell proliferation. In negative signaling of B cells, SHIP has been shown to be recruited to Fc gamma RIIB resulting in an inhibition of calcium influx. SHIP also associates with Shc, thereby linking Fc gamma RIIB to the Ras pathway. SHIP has been shown to be present in human platelets and may be involved in platelet activation evoked by thrombin. Thrombin stimulation induces a tyrosine phosphorylation of SHIP, this effect being both aggregation- and integrin engagement-dependent. Phosphorylated SHIP has also been shown to be relocated to the actin cytoskeleton upon activation again in an integrin engagement-dependent manner. The striking correlation between phosphatidylinositol 3,4-bisphosphate production, the tyrosine phosphorylation of SHIP and its relocation upon thrombin stimulation suggest a role for SHIP in the aggregation-dependent accumulation of this important phosphoinositide.