Reference SummaryLi Q, Proc Natl Acad Sci U S A 2020 Aug 25;117(34):20538-20548
Title |
Mechanism of PRL2 phosphatase-mediated PTEN degradation and tumorigenesis. |
Authors |
Li Q; Bai Y; Lyle LT; Yu G; Amarasinghe O; Nguele Meke F; Carlock C; Zhang ZY |
Journal |
Proc Natl Acad Sci U S A |
Volume |
117 |
Issue |
34 |
Year |
2020 |
Pages |
20538-20548 |
Abstract |
Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) levels are frequently found reduced in human cancers, but how PTEN is down-regulated is not fully understood. In addition, although a compelling connection exists between PRL (phosphatase of regenerating liver) 2 and cancer, how this phosphatase induces oncogenesis has been an enigma. Here, we discovered that PRL2 ablation inhibits PTEN heterozygosity-induced tumorigenesis. PRL2 deficiency elevates PTEN and attenuates AKT signaling, leading to decreased proliferation and increased apoptosis in tumors. We also found that high PRL2 expression is correlated with low PTEN level with reduced overall patient survival. Mechanistically, we identified PTEN as a putative PRL2 substrate and demonstrated that PRL2 down-regulates PTEN by dephosphorylating PTEN at Y336, thereby augmenting NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Given the strong cancer susceptibility to subtle reductions in PTEN, the ability of PRL2 to down-regulate PTEN provides a biochemical basis for its oncogenic propensity. The results also suggest that pharmacological targeting of PRL2 could provide a novel therapeutic strategy to restore PTEN, thereby obliterating PTEN deficiency-induced malignancies. |
Links |
J:295972 – MGI References 32788364 – National Library of Medicine/PubMed |
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| [not specified]-Ptentm2.2Ppp/+ | Adrenal gland tumor | Adrenal gland |
20 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Adrenal gland tumor | Adrenal gland |
12.3 |
||
| [not specified]-Ptentm2.2Ppp/+ | Adrenal gland tumor - high grade | Adrenal gland |
20 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Adrenal gland tumor - high grade | Adrenal gland |
10.5 |
||
| [not specified]-Ptentm2.2Ppp/+ | Adrenal gland tumor - low grade | Adrenal gland |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Adrenal gland tumor - low grade | Adrenal gland |
1.8 |
||
| [not specified]-Ptentm2.2Ppp/+ | Intestine - Large Intestine tumor | Intestine - Large Intestine |
5.6 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Intestine - Large Intestine tumor | Intestine - Large Intestine |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Intestine - Large Intestine tumor - high grade | Intestine - Large Intestine |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Intestine - Large Intestine tumor - low grade | Intestine - Large Intestine |
5.6 |
||
| [not specified]-Ptentm2.2Ppp/+ | Intestine - Small Intestine tumor | Intestine - Small Intestine |
3.3 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Intestine - Small Intestine tumor | Intestine - Small Intestine |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Intestine - Small Intestine tumor - high grade | Intestine - Small Intestine |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Intestine - Small Intestine tumor - low grade | Intestine - Small Intestine |
3.3 |
||
| [not specified]-Ptentm2.2Ppp/+ | Leukocyte lymphoma | Leukocyte |
62.2 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Leukocyte lymphoma | Leukocyte |
17.5 |
||
| [not specified]-Ptentm2.2Ppp/+ | Leukocyte lymphoma - high-grade | Leukocyte |
51.1 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Leukocyte lymphoma - high-grade | Leukocyte |
12.3 |
||
| [not specified]-Ptentm2.2Ppp/+ | Leukocyte lymphoma - low-grade | Leukocyte |
11.1 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Leukocyte lymphoma - low-grade | Leukocyte |
3.5 |
||
| [not specified]-Ptentm2.2Ppp/+ | Liver tumor | Liver |
7.8 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Liver tumor | Liver |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Liver tumor - high grade | Liver |
1.1 |
||
| [not specified]-Ptentm2.2Ppp/+ | Liver tumor - low grade | Liver |
6.7 |
||
| [not specified]-Ptentm2.2Ppp/+ | Lung tumor | Lung |
17.8 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Lung tumor | Lung |
10.5 |
||
| [not specified]-Ptentm2.2Ppp/+ | Lung tumor - high grade | Lung |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Lung tumor - high grade | Lung |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Lung tumor - low grade | Lung |
17.8 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Lung tumor - low grade | Lung |
10.5 |
||
| [not specified]-Ptentm2.2Ppp/+ | Mammary gland tumor | Mammary gland |
35.8 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Mammary gland tumor | Mammary gland |
8.1 |
||
| [not specified]-Ptentm2.2Ppp/+ | Mammary gland tumor - high grade | Mammary gland |
26.4 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Mammary gland tumor - high grade | Mammary gland |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Mammary gland tumor - low grade | Mammary gland |
9.4 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Mammary gland tumor - low grade | Mammary gland |
8.1 |
||
| [not specified]-Ptentm2.2Ppp/+ | Prostate gland tumor | Prostate gland |
18.9 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Prostate gland tumor | Prostate gland |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Prostate gland tumor - high grade | Prostate gland |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Prostate gland tumor - low grade | Prostate gland |
18.9 |
||
| [not specified]-Ptentm2.2Ppp/+ | Testis tumor | Testis |
2.7 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Testis tumor | Testis |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Testis tumor - high grade | Testis |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Testis tumor - low grade | Testis |
2.7 |
||
| [not specified]-Ptentm2.2Ppp/+ | Uterus tumor | Uterus |
9.4 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Uterus tumor | Uterus |
2.7 |
||
| [not specified]-Ptentm2.2Ppp/+ | Uterus tumor - high grade | Uterus |
1.9 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Uterus tumor - high grade | Uterus |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | Uterus tumor - low grade | Uterus |
7.5 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | Uterus tumor - low grade | Uterus |
2.7 |
||
| [not specified] | (Unspecified organ) tumor | (Unspecified organ) |
0 |
||
| [not specified]-Ptp4a2Gt(AQ0673)Wtsi | (Unspecified organ) tumor | (Unspecified organ) |
0 |
||
| [not specified]-Ptentm2.2Ppp/+ | (Unspecified organ) tumor | (Unspecified organ) |
78.9 |
||
| [not specified]-Ptentm2.2Ppp/+ Ptp4a2Gt(AQ0673)Wtsi | (Unspecified organ) tumor | (Unspecified organ) |
19.3 |