Regulation of Skp2 levels by the Pim-1 protein kinase

Bo Cen, Sandeep Mahajan, Marina Zemskova, Zanna Beharry, Ying Wei Lin, Scott D. Cramer, Michael B. Lilly, Andrew S. Kraft

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

The Pim-1 protein kinase plays an important role in regulating both cell growth and survival and enhancing transformation by multiple oncogenes. The ability of Pim-1 to regulate cell growth is mediated, in part, by the capacity of this protein kinase to control the levels of the p27, a protein that is a critical regulator of cyclin-dependent kinases that mediate cell cycle progression. To understand how Pim-1 is capable of regulating p27 protein levels, we focused our attention on the SCFSkp2 ubiquitin ligase complex that controls the rate of degradation of this protein.Wefound that expression of Pim-1 increases the level of Skp2 through direct binding and phosphorylation of multiple sites on this protein. Along with known Skp2 phosphorylation sites including Ser64 and Ser72, we have identified Thr417 as a unique Pim-1 phosphorylation target. Phosphorylation of Thr417 controls the stability of Skp2 and its ability to degrade p27. Additionally, we found that Pim-1 regulates the anaphasepromoting complex or cyclosome (APC/C complex) that mediates the ubiquitination of Skp2. Pim-1 phosphorylates Cdh1 and impairs binding of this protein to another APC/C complex member, CDC27. These modifications inhibit Skp2 from degradation. Marked increases in Skp2 caused by these mechanisms lower cellular p27 levels. Consistent with these observations, we show that Pim-1 is able to cooperate with Skp2 to signal S phase entry. Our data reveal a novel Pim-1 kinase-dependent signaling pathway that plays a crucial role in cell cycle regulation.

Original languageEnglish (US)
Pages (from-to)29128-29137
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number38
DOIs
StatePublished - Sep 17 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Cen, B., Mahajan, S., Zemskova, M., Beharry, Z., Lin, Y. W., Cramer, S. D., Lilly, M. B., & Kraft, A. S. (2010). Regulation of Skp2 levels by the Pim-1 protein kinase. Journal of Biological Chemistry, 285(38), 29128-29137. https://doi.org/10.1074/jbc.M110.137240