Phosphatase of regenerating Liver 2 (PRL2) deficiency impairs kit Signaling and Spermatogenesis

Yuanshu Dong, Lujuan Zhang, Yunpeng Bai, Hong Ming Zhou, Amanda M. Campbell, Hanying Chen, Weidong Yong, Wenjun Zhang, Qi Zeng, Weinian Shou, Zhong Yin Zhang

Research output: Contribution to journalArticle

20 Scopus citations


Background: The PRLs are oncogenic when overexpressed but their physiological function is not well defined. Results: PRL2-deficient mice exhibit testis hypotrophy, decreased sperm production, and impaired reproductive potential. Conclusion: PRL2 promotes Kit signaling and germ cell survival by down-regulating PTEN. Significance: The study reveals the biological importance of PRL2 in spermatogenesis and identifies PRL2 as a novel target for cancer and male contraception. The Phosphatase of Regenerating Liver (PRL) proteins promote cell signaling and are oncogenic when overexpressed. However, our understanding of PRL function came primarily from studies with cultured cell lines aberrantly or ectopically expressing PRLs. To define the physiological roles of the PRLs, we generated PRL2 knock-out mice to study the effects of PRL deletion in a genetically controlled, organismal model. PRL2- deficient male mice exhibit testicular hypotrophy and impaired spermatogenesis, leading to decreased reproductive capacity. Mechanistically, PRL2 deficiency results in elevated PTEN level in the testis, which attenuates the Kit-PI3K-Akt pathway, resulting in increased germ cell apoptosis. Conversely, increased PRL2 expression in GC-1 cells reduces PTEN level and promotes Akt activation. Our analyses of PRL2-deficient animals suggest that PRL2 is required for spermatogenesis during testis development. The study also reveals that PRL2 promotes Kitmediated PI3K/Akt signaling by reducing the level of PTEN that normally antagonizes the pathway. Given the strong cancer susceptibility to subtle variations in PTEN level, the ability of PRL2 to repress PTEN expression qualifies it as an oncogene and a novel target for developing anti-cancer agents.

Original languageEnglish (US)
Pages (from-to)3799-3810
Number of pages12
JournalJournal of Biological Chemistry
Issue number6
StatePublished - Feb 7 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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