INTERLEUKIN-3 INDUCES THE ASSOCIATION OF THE INOSITOL 5-PHOSPHATASE SHIP WITH SHP2

We recently purified and cloned a 145-kDa protein that becomes tyrosin e phosphorylated and associated with She in response to multiple cytok ines. Based on its predicated amino acid sequence and its enzymatic ac tivity, we have called this protein SHIP, for Src homology a-containin g inositol phosphatase. To gain further insight into the intracellular pathways that this putative signal transduction intermediate might re gulate we have investigated whether SHIP binds to intracellular protei ns other than She. The results presented herein demonstrate that follo wing interleukin-3 stimulation, SHIP binds to the tyrosine phosphatase , SHP2 (also called Syp, PTP1D, SHPTP2, and PTP2C) and that Shc is not present in these SHIP-SHP2 complexes. Time course studies reveal that SHIP's association with SHP2 is transient and is maximal at 10 min of stimulation with interleukin-3. me further show that the association of SHIP with SHP2 occurs through the direct interaction of the SH2 dom ain of SHIP with a pYXN(I/V) sequence within SHP2.