I2PP2A/SET

Figure: SDS-PAGE pattern of purified preparations of I1PP2Aand I2PP2A/SET. The gels were stained with Coomassie Blue. The position of marker proteins is indicated.

Background: I2PP2A/SET is a potent inhibitor of Protein Phosphatase 2A (PP2A), a major mammalian protein serine/threonine phosphatase that regulates diverse cellular processes. Purified preparations of I2PP2A/SET inhibit all forms of the phosphatase tested to date in a substrate selective manner. For example, the preparations inhibit PP2A potently (ki ~ 0.1 – 0.5 nM) with Myelin Basic Protein (MBP) and Histone H1 but not with Casein as substrate.  I2PP2A/SET was found to occur as a fusion protein with the nucleoporin CAN (NUP214) in a patient with acute undifferentiated leukemia. Elevated expression of I2PP2A/SET occurs in a number of other human cancers.  Transient expression of I2PP2A/SET in HEK-293 cells caused an increase in the DNA binding and AP1 activity of the proto-oncogene c-Jun. The sphingolipid second messenger cermaide binds to I2PP2A/SET and prevents it from inhibiting PP2A in intact cells. This contributes, at least partly, to the mechanism by which Ceramide promotes apoptosis. I2PP2A/SET is a multifunctional protein. In addition to PP2A inhibition, it prevents the inhibition of E-CDK-2 by p21Cip1, it associates with B cyclin, it regulates histone binding to DNA, transcriptional activity and chromatin condensation. I2PP2A/SET undergoes phosphorylation at Ser9 and Ser24 in intact cells. The functional significance of these phosphorylations is uncertain. Some studies indicate that Ser9 phosphorylation may causes cytoplasmic detention of I2PP2A in Alzheimer disease.

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