FROM THE ITIM(S) OF LYMPHOCYTE TO THE PLA TELET INTEGRINS - SHIP, A PROTEIN CROSSING MULTIPLE ROADS

The SH2 domain-containing inositol 5-phosphatase, SHIP, known to depho sphorylate inositol (1,3,4,5)-tetrakisphosphate and phosphatidylinosit ol (3,4,5)-trisphosphate has been shown to be expressed in a variety o f hemopoietic cells. Stimulation of antigen receptors on lymphocytes c an result in either positive or negative signaling, resulting in activ ation or inhibitory responses. The ITIM is a conserved intracytoplasmi c motif widely used for negative signaling. Negative signaling in B ce lls is initiated by co-crosslinking of the antigen receptor and the Fc gamma RIIB receptor, resulting in cessation of B-cell signaling event s and, in turn, inhibition of B-cell proliferation. In negative signal ing of B cells, SHIP has been shown to be recruited to Fc gamma RIIB r esulting 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 tyrosin e phosphorylation of SHIP, this effect being both aggregation- and int egrin engagement-dependent. Phosphorylated SHIP has also been shown to be relocated to the actin cytoskeleton upon activation again in an in tegrin engagement-dependent manner. The striking correlation between p hosphatidylinositol 3,4-bisphosphate production, the tyrosine phosphor ylation of SHIP and its relocation upon thrombin stimulation suggest a role for SHIP in the aggregation-dependent accumulation of this impor tant phosphoinositide.