Protein Phosphatase 2A Regulates the Stability of Pim Protein Kinases

The pim family of proto-oncogenes encodes three serine-threonine kinases that have been implicated in the development of malignancies in mice and in humans. Expression of the Pim protein kinases is tightly regulated at the transcriptional, post-transcriptional, and translational levels. Dysregulation of pim transcription and pim mRNA stability have been implicated in Pim-mediated transformation. The data presented herein demonstrate that expression of the Pim kinases is additionally regulated at the post-translational level, by the serine-threonine phosphatase protein phosphatase 2A (PP2A). The catalytic subunit of PP2A associates with the Pim kinases in vivo , and the Pim kinases are substrates of PP2A phosphatase activity in vitro . Furthermore, overexpression of PP2A reduces the levels of the Pim proteins, whereas inhibition of PP2A activity by the protein phosphatase inhibitor okadaic acid stabilizes the Pim proteins. Finally, the effects of PP2A on the expression of the Pim proteins can affect Pim function. Taken together, these data suggest that PP2A activity is important for the regulation of the stability and function of the Pim kinases.