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 Kraft

Research output: Contribution to journalArticle

18 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Proto-Oncogene Proteins c-pim-1
Phosphorylation
Protein Kinases
Cell growth
Cell Cycle
Proteins
Cells
Degradation
Cyclin-Dependent Kinases
Ubiquitination
Ligases
Growth
Ubiquitin
S Phase
Oncogenes
Proteolysis
Cell Survival
Carrier Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Cen, B., Mahajan, S., Zemskova, M., Beharry, Z., Lin, Y. W., Cramer, S. D., ... Kraft, A. (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

Regulation of Skp2 levels by the Pim-1 protein kinase. / Cen, Bo; Mahajan, Sandeep; Zemskova, Marina; Beharry, Zanna; Lin, Ying Wei; Cramer, Scott D.; Lilly, Michael B.; Kraft, Andrew.

In: Journal of Biological Chemistry, Vol. 285, No. 38, 17.09.2010, p. 29128-29137.

Research output: Contribution to journalArticle

Cen, B, Mahajan, S, Zemskova, M, Beharry, Z, Lin, YW, Cramer, SD, Lilly, MB & Kraft, A 2010, 'Regulation of Skp2 levels by the Pim-1 protein kinase', Journal of Biological Chemistry, vol. 285, no. 38, pp. 29128-29137. https://doi.org/10.1074/jbc.M110.137240
Cen B, Mahajan S, Zemskova M, Beharry Z, Lin YW, Cramer SD et al. Regulation of Skp2 levels by the Pim-1 protein kinase. Journal of Biological Chemistry. 2010 Sep 17;285(38):29128-29137. https://doi.org/10.1074/jbc.M110.137240
Cen, Bo ; Mahajan, Sandeep ; Zemskova, Marina ; Beharry, Zanna ; Lin, Ying Wei ; Cramer, Scott D. ; Lilly, Michael B. ; Kraft, Andrew. / Regulation of Skp2 levels by the Pim-1 protein kinase. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 38. pp. 29128-29137.
@article{001ec375529f433bb575444926209b71,
title = "Regulation of Skp2 levels by the Pim-1 protein kinase",
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.",
author = "Bo Cen and Sandeep Mahajan and Marina Zemskova and Zanna Beharry and Lin, {Ying Wei} and Cramer, {Scott D.} and Lilly, {Michael B.} and Andrew Kraft",
year = "2010",
month = "9",
day = "17",
doi = "10.1074/jbc.M110.137240",
language = "English (US)",
volume = "285",
pages = "29128--29137",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "38",

}

TY - JOUR

T1 - Regulation of Skp2 levels by the Pim-1 protein kinase

AU - Cen, Bo

AU - Mahajan, Sandeep

AU - Zemskova, Marina

AU - Beharry, Zanna

AU - Lin, Ying Wei

AU - Cramer, Scott D.

AU - Lilly, Michael B.

AU - Kraft, Andrew

PY - 2010/9/17

Y1 - 2010/9/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77956547992&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956547992&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110.137240

DO - 10.1074/jbc.M110.137240

M3 - Article

C2 - 20663873

AN - SCOPUS:77956547992

VL - 285

SP - 29128

EP - 29137

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 38

ER -