THE MYELOID LEUKEMIA-ASSOCIATED PROTEIN SET IS A POTENT INHIBITOR OF PROTEIN PHOSPHATASE 2A

Two potent heat-stable protein phosphatase 2A (PP2A) inhibitor protein s designated I-1(PP2A) and I-2(PP2A) have been purified to apparent ho mogeneity from extracts of bovine kidney (Li, M., Guo, H., and Damuni, Z. (1995) Biochemistry 34, 1988-1996). N-terminal and internal amino acid sequencing indicated that I-2(PP2A) was a truncated form of SET, a largely nuclear protein that is fused to nucleoporin Nup214 in acute non-lymphocytic myeloid leukemia. Experiments using purified preparat ions of recombinant human SET confirmed that this protein inhibited PP 2A. Half-maximal inhibition of the phosphatase occurred at about 2 nM SET. By contrast, SET (up to 20 nM) did not affect the activities of p urified preparations of protein phosphatases 1, 2B, and 2C. The result s indicate that SET is a potent and specific inhibitor of PP2A and sug gest that impaired regulation of PP2A may contribute to acute myeloid leukemogenesis.