title: Phosphatase of regenerating liver 2 (PRL2) deficiency impairs Kit signaling and spermatogenesis.
abstract: 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 Kit-mediated 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.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, and.
authors.forename: Yuanshu
authors.initials: Y
authors.lastname: Dong
authors.forename: Lujuan
authors.initials: L
authors.lastname: Zhang
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Bai
authors.forename: Hong-Ming
authors.initials: HM
authors.lastname: Zhou
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Campbell
authors.forename: Hanying
authors.initials: H
authors.lastname: Chen
authors.forename: Weidong
authors.initials: W
authors.lastname: Yong
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D005260:Female; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013091:Spermatogenesis / Q000502:physiology; D013737:Testis / Q000166:cytology / Q000378:metabolism
chemical_list: D017874:Immediate-Early Proteins; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; D017027:Protein Tyrosine Phosphatases; C111533:Ptp4a2 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Protein Phosphatase; Pten; Signal Transduction; Spermatogenesis; Testis