THE PHOSPHATIDYLINOSITOL POLYPHOSPHATE 5-PHOSPHATASE SHIP AND THE PROTEIN-TYROSINE-PHOSPHATASE SHP-2 FORM A COMPLEX IN HEMATOPOIETIC-CELLS WHICH CAN BE REGULATED BY BCR ABL AND GROWTH-FACTORS/

We report here that interleukin-3 (IL-3) and erythropoietin (EPO) indu ce formation of a complex composed of two SH2-containing phosphatases, the tyrosine phosphatase SHP-2 and the SH2 containing inositol 5-phos phatase (SHIP), Both SHP-2 and SHIP are known to be involved in growth factor signal transduction, but their potential interaction in the sa me pathway is novel, SHIP has previously been shown to associate with SHC, and potentially to be involved in regulating apoptosis, In contra st, in some model systems, SHP-2 has been demonstrated to positively r egulate cell growth, Both phosphatases in the complex were tyrosine ph osphorylated, and the amount of SHIP coprecipitating with SHP-2 was in versely related to the amount of SHIP coprecipitating with SHC, In hem atopoietic cells transformed by the BCR/ABL oncogene, this phosphatase complex was found to be constitutively present with both components h eavily tyrosine phosphorylated, Also, other proteins were detected in the complex, including BCR/ABL itself and c-CBL, However, transformati on by BCR/ABL was associated with a reduced SHIP protein expression, w hich could further affect the accumulation of various inositol polypho sphates in these leukemic cells, These data suggest that the function of SHIP and SHP-2 in normal cells are linked and that BCR/ABL alters t he function of this signaling complex.