Journal
ONCOGENE
Volume 26, Issue 35, Pages 5145-5153Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210323
Keywords
Pim-1; PP2A; B56 beta; protein kinase; Pin1
Funding
- NCI NIH HHS [K01 CA086957, R01 CA100855] Funding Source: Medline
- NIGMS NIH HHS [5 T32 GM08617] Funding Source: Medline
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The Pim protein kinases are serine threonine protein kinases that regulate important cellular signaling pathway molecules, and enhance the ability of c-Myc to induce lymphomas. We demonstrate that a cascade of events controls the cellular levels of Pim. We find that overexpression of the protein phosphatase ( PP) 2A catalytic subunit decreases the activity and protein levels of Pim-1. This effect is reversed by the application of okadaic acid, an inhibitor of PP2A, and is blocked by SV40 small T antigen that is known to disrupt B subunit binding to PP2A A and C subunits. Pim-1 can coimmunoprecipitate with th e PP2A regulatory B subunit, B56 beta, but not B56 alpha, c, delta, e or B55 alpha. Using short hairpin RNA targeted at B56b, we demonstrate that decreasing the level of B56b increases the half-life of Pim-1 from 0.7 to 2.8 h, and decreases the ubiquitinylation level of Pim-1. We also find that Pin1, a prolyl-isomerase, is capable of binding Pim-1 and leads to a decrease in the protein level of Pim-1. On the basis of these observations, we hypothesize that phosphorylated Pim-1 binds Pin1 allowing the interaction of PP2A through B56b. Dephosphorylation of Pim-1 then allows for ubiquitinylation and protein degradation of Pim-1.
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