Abstract
The PRL (phosphatase of regenerating liver) phosphatases are implicated in the control of cell proliferation and invasion. Aberrant PRL expression is associated with progression and metastasis of multiple cancers. However, the specific in vivo function of the PRLs remains elusive. Here we show that deletion of PRL2, the most ubiquitously expressed PRL family member, leads to impaired placental development and retarded growth at both embryonic and adult stages. Ablation of PRL2 inactivates Akt and blocks glycogen cell proliferation, resulting in reduced spongiotrophoblast and decidual layers in the placenta. These structural defects cause placental hypotrophy and insufficiency, leading to fetal growth retardation. We demonstrate that the tumor suppressor PTEN is elevated in PRL2-deficient placenta. Biochemical analyses indicate that PRL2 promotes Akt activation by down-regulating PTEN through the proteasome pathway. This study provides the first evidence that PRL2 is required for extra-embryonic development and associates the oncogenic properties of PRL2 with its ability to negatively regulate PTEN, thereby activating the PI3K-Akt pathway.
Highlights
The physiological functions of the PRL phosphatases are poorly understood
This study provides the first evidence that PRL2 is required for extra-embryonic development and associates the oncogenic properties of PRL2 with its ability to negatively regulate PTEN, thereby activating the PI3K-Akt pathway
We show that loss of PRL2 leads to an increase in PTEN, which in turn inactivates Akt, leading to reduced cell proliferation in PRL2Ϫ/Ϫ placenta
Summary
The physiological functions of the PRL phosphatases are poorly understood. Results: PRL2 deficiency causes placental insufficiency, decreased spongiotrophoblast proliferation, and growth retardation. Ablation of PRL2 inactivates Akt and blocks glycogen cell proliferation, resulting in reduced spongiotrophoblast and decidual layers in the placenta. These structural defects cause placental hypotrophy and insufficiency, leading to fetal growth retardation. This study provides the first evidence that PRL2 is required for extra-embryonic development and associates the oncogenic properties of PRL2 with its ability to negatively regulate PTEN, thereby activating the PI3K-Akt pathway. We show that loss of PRL2 leads to an increase in PTEN, which in turn inactivates Akt, leading to reduced cell proliferation in PRL2Ϫ/Ϫ placenta Together, these results provide the first evidence that PRL2 is required for extra-embryonic development by promoting cell proliferation via the PI3K-Akt signaling pathway
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