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Protein phosphatase 2A regulates the stability of Pim protein kinases
Julie A Losman1, X Peter Chen, Bao Q Vuong
1Integrated Program in Molecular, Cellular, and Biophysical Studies, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Abstract:
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.
Insights
Protein phosphatase 2A (PP2A) regulates Pim kinase stability and function. PP2A associates with Pim kinases, affecting their levels and stability, which is crucial for Pim-mediated cellular processes.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- The Pim family of proto-oncogenes encodes serine-threonine kinases implicated in human and mouse malignancies.
- Pim kinase expression is regulated at transcriptional, post-transcriptional, and translational levels, with dysregulation linked to transformation.
- Previous studies highlighted transcriptional and mRNA stability roles in Pim-mediated transformation.
Purpose of the Study:
- To investigate the post-translational regulation of Pim kinase expression.
- To determine the role of protein phosphatase 2A (PP2A) in modulating Pim kinase levels and function.
Main Methods:
- Investigated the association between PP2A catalytic subunit and Pim kinases in vivo.
- Assessed Pim kinases as substrates for PP2A phosphatase activity in vitro.
- Utilized overexpression of PP2A and inhibition of PP2A activity (using okadaic acid) to study effects on Pim protein levels.
Main Results:
- The catalytic subunit of PP2A physically associates with Pim kinases.
- Pim kinases are direct substrates of PP2A phosphatase activity.
- PP2A overexpression decreased Pim protein levels, while PP2A inhibition stabilized them, indicating PP2A's role in Pim protein turnover.
Conclusions:
- Pim kinase expression is additionally regulated at the post-translational level by PP2A.
- PP2A activity is critical for controlling the stability and function of Pim kinases.
- These findings reveal a novel regulatory mechanism impacting oncogenic kinase activity.