Negative regulation of Pim-1 protein kinase levels by the B56beta subunit of PP2A

Oncogene. 2007 Aug 2;26(35):5145-53. doi: 10.1038/sj.onc.1210323. Epub 2007 Feb 12.

Abstract

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 the PP2A regulatory B subunit, B56beta, but not B56alpha, gamma, delta, epsilon or B55alpha. Using short hairpin RNA targeted at B56beta, we demonstrate that decreasing the level of B56beta 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 B56beta. Dephosphorylation of Pim-1 then allows for ubiquitinylation and protein degradation of Pim-1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Down-Regulation
  • Humans
  • Mice
  • Mice, Knockout
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / metabolism
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Proto-Oncogene Proteins c-pim-1 / metabolism*
  • RNA, Small Interfering / pharmacology
  • Ubiquitin / metabolism

Substances

  • NIMA-Interacting Peptidylprolyl Isomerase
  • Protein Subunits
  • RNA, Small Interfering
  • Ubiquitin
  • Proto-Oncogene Proteins c-pim-1
  • Phosphoprotein Phosphatases
  • PIN1 protein, human
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse