SHP2 Nuclear/Cytoplasmic Trafficking in Granulosa Cells Is Essential for Oocyte Meiotic Resumption and Maturation

Src-homology-2-containing phosphotyrosine phosphatase (SHP2), a classic cytoplasmic protein and a major regulator of receptor tyrosine kinases and G protein-coupled receptors, plays a significant role in preimplantation embryo development. In this study, we deciphered the role of SHP2 in the somatic compartment of oocytes during meiotic maturation. SHP2 showed nuclear/cytoplasmic localization in bovine cumulus and human granulosa (COV434) cells. Follicle-stimulating hormone (FSH) treatment significantly enhanced cytoplasmic SHP2 localization, in contrast to the E(2) treatment, which augmented nuclear localization. Enhanced cytoplasmic SHP2 was found to negatively regulate the expression of the ERα-transcribed NPPC and NPR2 mRNAs, which are vital for oocyte meiotic arrest. The co-immunoprecipitation results revealed the presence of the SHP2/ERα complex in the germinal vesicle-stage cumulus–oocyte complexes, and this complex significantly decreased with the progression of meiotic maturation. The complex formation between ERα and SHP2 was also confirmed by using a series of computational modeling methods. To verify the correlation between SHP2 and NPPC/NPR2, SHP2 was knocked down via RNA interference, and NPPC and NPR2 mRNAs were analyzed in the control, E(2), and FSH-stimulated COV434 cells. Furthermore, phenyl hydrazonopyrazolone sulfonate 1, a site-directed inhibitor of active SHP2, showed no significant effect on the ERα-transcribed NPPC and NPR2 mRNAs. Taken together, these findings support a novel nuclear/cytoplasmic role of SHP2 in oocyte meiotic resumption and maturation.