PTPN11 (SHP2) Is Indispensable for Growth Factors and Cytokine Signal Transduction During Bovine Oocyte Maturation and Blastocyst Development

Abstract

This study was aimed to investigate the role of SHP2 (Src-homology-2-containing phosphotyrosine phosphatase) in intricate signaling networks invoked by bovine oocyte to achieve maturation and blastocyst development. PTPN11 (Protein Tyrosine Phosphatase, non-receptor type 11) encoding protein SHP2, a positive transducer of RTKs (Receptor Tyrosine Kinases) and cytokine receptors, can play a significant role in bovine oocyte maturation and embryo development, but this phenomenon has not yet been explored. Here, we used different growth factors, cytokines, selective activator, and a specific inhibitor of SHP2 to ascertain its role in bovine oocyte developmental stages in vitro. We found that SHP2 became activated by growth factors and cytokines treatment and was highly involved in the activation of oocyte maturation and embryo development pathways. Activation of SHP2 triggered MAPK (mitogen-activated protein kinases) and PI3K/AKT (Phosphoinositide 3-kinase/Protein kinase B) signaling cascades, which is not only important for GVBD (germinal vesical breakdown) induction but also for maternal mRNA translation. Inhibition of phosphatase activity of SHP2 with PHPS1 (Phenylhydrazonopyrazolone sulfonate 1) reduced oocytes maturation as well as bovine blastocyst ICM (inner cell mass) volume. Supplementation of LIF (Leukemia Inhibitory Factor) to embryos showed an unconventional direct relation between p-SHP2 and p-STAT3 (Signal transducer and activator of transcription 3) for blastocyst ICM development. Other than growth factors and cytokines, cisplatin was used to activate SHP2. Cisplatin activated SHP2 modulate growth factors effect and combine treatment significantly enhanced quality and rate of developed blastocysts.

Growth Factors, and Cytokines; Understanding the Role of Tyrosine Phosphatase SHP2 in Gametogenesis and Early Embryo Development

“…SHP2 showed nuclear localization in several reproductive tissues, like our previous study on in vitro oocyte maturation and one study regarding sperm maturation, which stated that SHP2 showed nuclear expression in germ cell-supporting cells (cumulus cells and sertoli cells); however, the function of nuclear-localized SHP2 still requires exploration in those tissues [17,28]. Ran et al found that nuclear-localized SHP2 in the uterus was essential for the estrogen receptor-α (ER-α) nuclear transcription of progesterone (pgr) gene in mice, and for the tissue (uterus)-specific SHP2 knockout to completely inhibit embryo implantation [32].…”

“…SHP2 plays a significant role in oocyte meiotic maturation by inhibiting mitochondrial degradation via enhancing mTOR dependent mitochondrial biogenesis and inhibiting mitophagy [52]. The inhibition of SHP2 with Phenyl hydrazono pyrazolone sulfonate 1 (PHPS1), which is an active site-directed inhibitor, also significantly reduced meiotic maturation [17]. One study stated that mitochondria localized SHP2 dephosphorylated and inhibited adenine nucleotide translocase 1 (ANT1), which is essential for the nucleotide-binding domain and leucine-rich repeat containing (NLRP3) localization in mitochondria, and this resulted in reactive oxygen species (ROS) induced apoptosis [53].…”

“…A plethora of literature is available on the well-known role of growth factors and cytokines for oocyte meiotic resumption and maturation, but very few studies have explored the mechanisms of action of these factors. SHP2 shows expression in the ovaries of several species; however, up till now, no study completely explored the conventional or unconventional functions of SHP2, by deleting SHP2 from the ovaries or ovary specific tissues [17,98]. One study identified SHP2 expression in granulosa cells and found that its function was essential for FSH signaling [99].…”

“…The site-directed inhibitor (PHPS1) of SHP2 significantly reduced oocyte maturation, which demonstrates that active SHP2 is involved in oocyte meiotic maturation. MAP kinases and PI3K/AKT signaling plays a vital role in oocyte maturation, and research has found that active SHP2 inhibition significantly reduced the signaling [17]. One study also identified the SHP2 functional role in oocyte mitochondria and concluded that SHP2 blocked mitochondrial degradation via inhibiting mitophagy [52].…”

Lupeol, a Plant-Derived Triterpenoid, Protects Mice Brains against Aβ-Induced Oxidative Stress and Neurodegeneration

“…Western blotting was performed as described previously, with some modification [ 30 , 31 ]. The protein concentrations were quantified by using a Bio-Rad Protein Assay Kit (Bio-Rad Laboratories, CA, USA).…”