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, B56β, but not B56α, γ, δ, ε or B55α. Using short hairpin RNA targeted at B56β, we demonstrate that decreasing the level of B56β 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 B56β. Dephosphorylation of Pim-1 then allows for ubiquitinylation and protein degradation of Pim-1.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5145-5153 |
| Number of pages | 9 |
| Journal | Oncogene |
| Volume | 26 |
| Issue number | 35 |
| DOIs | |
| State | Published - Aug 2 2007 |
| Externally published | Yes |
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Keywords
- B56β
- Pim-1
- Pin1
- PP2A
- Protein kinase
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research
- Genetics
Cite this
Negative regulation of Pim-1 protein kinase levels by the B56β subunit of PP2A. / Ma, J.; Arnold, H. K.; Lilly, M. B.; Sears, R. C.; Kraft, Andrew.
In: Oncogene, Vol. 26, No. 35, 02.08.2007, p. 5145-5153.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Negative regulation of Pim-1 protein kinase levels by the B56β subunit of PP2A
AU - Ma, J.
AU - Arnold, H. K.
AU - Lilly, M. B.
AU - Sears, R. C.
AU - Kraft, Andrew
PY - 2007/8/2
Y1 - 2007/8/2
N2 - 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, B56β, but not B56α, γ, δ, ε or B55α. Using short hairpin RNA targeted at B56β, we demonstrate that decreasing the level of B56β 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 B56β. Dephosphorylation of Pim-1 then allows for ubiquitinylation and protein degradation of Pim-1.
AB - 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, B56β, but not B56α, γ, δ, ε or B55α. Using short hairpin RNA targeted at B56β, we demonstrate that decreasing the level of B56β 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 B56β. Dephosphorylation of Pim-1 then allows for ubiquitinylation and protein degradation of Pim-1.
KW - B56β
KW - Pim-1
KW - Pin1
KW - PP2A
KW - Protein kinase
UR - http://www.scopus.com/inward/record.url?scp=34547642807&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547642807&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1210323
DO - 10.1038/sj.onc.1210323
M3 - Article
C2 - 17297438
AN - SCOPUS:34547642807
VL - 26
SP - 5145
EP - 5153
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 35
ER -