Protein Kinases and Their Inhibitors in Pluripotent Stem Cell Fate Regulation

Abstract

Protein kinases modulate the reversible postmodifications of substrate proteins to their phosphorylated forms as an essential process in regulating intracellular signaling transduction cascades. Moreover, phosphorylation has recently been shown to tightly control the regulatory network of kinases responsible for the induction and maintenance of pluripotency, defined as the particular ability to differentiate pluripotent stem cells (PSCs) into every cell type in the adult body. In particular, emerging evidence indicates that the balance between the self-renewal and differentiation of PSCs is regulated by the small molecules that modulate kinase signaling pathways. Furthermore, new reprogramming technologies have been developed using kinase modulators, which have provided novel insight of the mechanisms underlying the kinase regulatory networks involved in the generation of induced pluripotent stem cells (iPSCs). In this review, we highlight the recent progress made in defining the roles of protein kinase signaling pathways and their small molecule modulators in regulating the pluripotent states, self-renewal, reprogramming process, and lineage differentiation of PSCs.

FGF Signaling Pathway: A Key Regulator of Stem Cell Pluripotency

“…In the canonical Wnt pathway, GSK3 phosphorylates β-catenin and causes its degradation. The inhibition of GSK3 leads to the stabilization of β-catenin and its nuclear translocation (Lee et al, 2019). Shuttling of β-catenin to the nucleus results in self-renewal via revoking the repressor activity of TCF3 (Martello et al, 2012), which has been shown to control ESCs self-renewal by repression of key naïve TFs ESRRB, NANOG, KLF4, and TBX3 (Yi et al, 2008;Martello et al, 2012).…”

Androgen Deprivation Induces Reprogramming of Prostate Cancer Cells to Stem-Like Cells

“…Thus, understanding the molecular mechanisms of these cellular rewiring processes involved in the acquisition of drug resistance might help to better design new therapeutic strategies. In recent years, research has been focused on phosphorylation as a tight regulator of the network of kinases responsible for the induction and maintenance of pluripotency [10]. Several protein kinases have been shown to regulate the pluripotency including the MAPK/Erk signal transduction cascade and the phosphoinositide 3-kinase (PI3K)/AKT serine threonine kinase signaling pathway.…”

A Rho Kinase (ROCK) Inhibitor, Y-27632, Inhibits the Dissociation-Induced Cell Death of Salivary Gland Stem Cells

“…Five kinase inhibitors (PD184352, PD0325901, SU5402, CHIR99021, and Y-27632) were used for the treatment of SGSCs in vitro. These kinase inhibitors were previously reported to support the maintenance of pluripotent stem cells [ 19 , 20 , 21 , 22 , 23 , 24 ]. We treated P0 SGSCs with each of the five small molecules for five days to investigate their effects on the formation of spheroids and viability ( Figure 2 a,b).…”

“…In this study, five kinase inhibitors were selected and treated for the maintenance of salivary gland stem cells (SGSCs) in vitro. The kinase inhibitors (PD184352, PD0325901, SU5402, CHIR99021, and Y-27632) used in this study were previously reported to support the maintenance of pluripotent stem cells [ 19 , 20 , 21 , 22 , 23 , 24 ]. Treatment with Y-27632 showed the most significant effects on the morphology and viability of passage 0 (P0) SGSCs.…”