PRMT8 Controls the Pluripotency and Mesodermal Fate of Human Embryonic Stem Cells By Enhancing the PI3K/AKT/SOX2 Axis

Abstract

Basic fibroblast growth factor (bFGF) supplementation is critical to maintain the pluripotency of human pluripotent stem cells (hPSCs) through activation of PI3K/AKT, rather than MEK/ERK pathway. Thus, elaborate molecular mechanisms that preserve PI3K/AKT signaling upon bFGF stimulation may exist in hPSCs. Protein arginine methyltransferase 8 (PRMT8) was expressed and then its level gradually decreased during spontaneous differentiation of human embryonic stem cells (hESCs). PRMT8 loss- or gain-of-function studies demonstrated that PRMT8 contributed to longer maintenance of hESC pluripotency, even under bFGF-deprived conditions. Direct interaction of membrane-localized PRMT8 with p85, a regulatory subunit of PI3K, was associated with accumulation of phosphoinositol 3-phosphate and consequently high AKT activity. Furthermore, the SOX2 induction, which was controlled by the PRMT8/PI3K/AKT axis, was linked to mesodermal lineage differentiation. Thus, we propose that PRMT8 in hESCs plays an important role not only in maintaining pluripotency but also in controlling mesodermal differentiation through bFGF signaling toward the PI3K/AKT/SOX2 axis. Stem Cells 2017;35:2037-2049.

Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis

“…MiR-200 was found to have both direct and indirect mechanisms of targeting CXCL1 to inhibit cancer angiogenesis [26]. In an experimental animal model, after co-injection of CXCL1 with human adipose-derived mesenchymal stem cells (hADSCs), hADSCs promoted residual BC proliferation and metastasis via the PI3K/AKT/SOX2 axis [27]. CXCL2 shares 90% amino acid homology with CXCL1.…”

FGF Signaling Pathway: A Key Regulator of Stem Cell Pluripotency

“…This interaction results in the enhancement of AKT activity instead of the MEK/ERK pathway. PRMT8/PI3K/AKT axis maintains pluripotency of hESC as well as mesodermal differentiation via the regulation of Sox2 (Jeong et al, 2017). In a recent study, Haghighi et al (2018) showed that among the downstream mediators of FGF2 signaling pathways, the MAPK pathway plays a pivotal role in maintaining the pluripotency of hiPSCs.…”

SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond

“…These various interdependencies between PI3K/AKT and SOX2, detected across a spectrum of different malignant and healthy (stem) cell types, have led to the notion of an independent PI3K/AKT/SOX2 signaling branch that diverges from the canonical PI3K/AKT/mTORC1 axis (see refs. [100,101] and Fig. 2 for schematic illustration).…”