Role of phosphatase of regenerating liver 1 (PRL1) in spermatogenesis.
The PRL phosphatases are oncogenic when overexpressed but their in vivo biological function is less well understood. Previous gene deletion study revealed a role for PRL2 in spermatogenesis. We report here the first knockout mice lacking PRL1, the most related homolog of PRL2. We found that loss of PRL1 does not affect spermatogenesis and reproductive ability of male mice, likely due to functional compensation by the relatively higher expression of PRL2 in the testes. However, PRL1-/-/PRL2+/-male mice show testicular atrophy phenotype similar to PRL2-/-mice. More strikingly, deletion of one PRL1 allele in PRL2-/-male mice causes complete infertility. Mechanistically, the total level of PRL1 and PRL2 is negatively correlated with the PTEN protein level in the testis and PRL1+/-/PRL2-/-mice have the highest level of PTEN, leading to attenuated Akt activation and increased germ cell apoptosis, effectively halting spermatozoa production. These results provide the first evidence that in addition to PRL2, PRL1 is also required for spermatogenesis by downregulating PTEN and promoting Akt signaling. The ability of the PRLs to suppress PTEN expression underscores the biochemical basis for their oncogenic potential.
Departments of Medicinal Chemistry and Molecular Pharmacology and of Chemistry, Purdue Center for Cancer Research, and Purdue Center for Drug Discovery, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
Yunpeng
Y
Bai
Department of Biochemistry and Molecular Biology, Indianapolis, IN 46202, USA.
Hong-Ming
HM
Zhou
Department of Biochemistry and Molecular Biology, Indianapolis, IN 46202, USA.
Lujuan
L
Zhang
Department of Biochemistry and Molecular Biology, Indianapolis, IN 46202, USA.
Yuanshu
Y
Dong
Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore.
Qi
Q
Zeng
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Weinian
W
Shou
Departments of Medicinal Chemistry and Molecular Pharmacology and of Chemistry, Purdue Center for Cancer Research, and Purdue Center for Drug Discovery, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.|Department of Biochemistry and Molecular Biology, Indianapolis, IN 46202, USA.
Zhong-Yin
ZY
Zhang
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