FEBS Letters
Volume 583, Issue 4 , Pages 615-620, 18 February 2009

14-3-3 Binding to Pim-phosphorylated Ser166 and Ser186 of human Mdm2 – Potential interplay with the PKB/Akt pathway and p14ARF

Edited by Angel Nebreda

  • Nicola T. Wood

      Affiliations

    • MRC Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK
    • ,
  • David W. Meek

      Affiliations

    • Biomedical Research Centre, Ninewells Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK
    • ,
  • Carol MacKintosh

      Affiliations

    • MRC Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK
    • Corresponding Author InformationCorresponding author. Fax: +44 1382 223778.

Received 24 September 2008; received in revised form 24 December 2008; accepted 11 January 2009. published online 21 January 2009.

Abstract 

Here we show that 14-3-3 proteins bind to Pim kinase-phosphorylated Ser166 and Ser186 on the human E3 ubiquitin ligase mouse double minute 2 (Mdm2), but not protein kinase B (PKB)/Akt-phosphorylated Ser166 and Ser188. Pim-mediated phosphorylation of Ser186 blocks phosphorylation of Ser188 by PKB, indicating potential interplay between the Pim and PKB signaling pathways in regulating Mdm2. In cells, expression of Pim kinases promoted phosphorylation of Ser166 and Ser186, interaction of Mdm2 with endogenous 14-3-3s and p14ARF, and also increased the amount of Mdm2 protein by a mechanism that does not require Pim kinase activities. The implications of these findings for regulation of the p53 pathway, oncogenesis and drug discovery are discussed.

Structured summary

MINT-6823587:

PIM3 (uniprotkb:Q86V86) phosphorylates (MI:0217) MDM2 (uniprotkb:Q00987) by protein kinase assay (MI:0424)

MINT-6823623:

MDM2 (uniprotkb:Q00987) physically interacts (MI:0218) with p14ARF (uniprotkb:Q8N7268N726) by coimmunoprecipitation (MI:0019)

MINT-6823537:

PKB (uniprotkb:P31749) phosphorylates (MI:0217) MDM2 (uniprotkb:Q00987) by protein kinase assay (MI:0424)

MINT-6823574:

PIM2 (uniprotkb:QP1W9) phosphorylates (MI:0217) MDM2 (uniprotkb:Q00987) by protein kinase assay (MI:0424)

MINT-6823555:

PIM1 (uniprotkb:P11309)P phosphorylates (MI:0217) MDM2 (uniprotkb:Q00987) by protein kinase assay (MI:0424)

Abbreviations: Mdm2, mouse double minute 2, NES, nuclear export sequence, NLS, nuclear localization sequence, PKB, protein kinase B (also known as Akt), PP2A, protein phosphatase 2A.

Keywords: 14-3-3, Cancer, Mdm2, Phosphorylation, Pim kinase

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PII: S0014-5793(09)00030-1

doi:10.1016/j.febslet.2009.01.003

FEBS Letters
Volume 583, Issue 4 , Pages 615-620, 18 February 2009

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