Mitogen- and stress-activated protein kinase (MSK1/2) regulated gene expression in normal and disease states

Abstract

The mitogen- and stress-activated protein kinases (MSK) are epigenetic modifiers that regulate gene expression in normal and disease cell states. MSK1 and 2 are involved in a chain of signal transduction events bringing signals from the external environment of a cell to specific sites in the genome. MSK1/2 phosphorylate histone H3 at multiple sites, resulting in chromatin remodeling at regulatory elements of target genes and the induction of gene expression. Several transcription factors (RELA of NF-κB, CREB) are also phosphorylated by MSK1/2 and contribute to induction of gene expression. In response to signal transduction pathways, MSK1/2 can stimulate genes involved in cell proliferation, inflammation, innate immunity, neuronal function, and neoplastic transformation. Abrogation of the MSK-involved signaling pathway is among the mechanisms by which pathogenic bacteria subdue the host’s innate immunity. Depending on the signal transduction pathways in play and the MSK-targeted genes, MSK may promote or hinder metastasis. Thus, depending on the type of cancer and genes involved, MSK overexpression may be a good or poor prognostic factor. In this review, we focus on mechanisms by which MSK1/2 regulate gene expression, and recent studies on their roles in normal and diseased cells.

MSK1 absence hinders BDNF-dependent striatal neurodevelopment and leads to schizophrenia symptoms

“…MeCP2 is expressed by both glutamatergic and GABAergic neurons, and its activity is critical for proper brain development and striatal function (48). MSK1 substrates include several transcription factors such as CREB, Histone H3 and the DNA binding proteins of the high mobility group (HMG) (53, 54). We hypothesized that MSK1 could also mediates BDNF-dependent MeCP2 phosphorylation in striatal neurons.…”

Interruption of p38MAPK-MSK1-CREB-MITF-M pathway to prevent hyperpigmentation in the skin

“…BI2B had inhibited not only the activation of CREB through phosphorylation (Figure 5 A; Figure 6 A) but also the activation of p38 MAPK in α-MSH-activated melanocyte cultures (Figure 7 B). We then considered MSK1 as a candidate of linker between p38 MAPK and CREB, since MSK1 can be activated by p38 MAPK -catalyzed phosphorylation 35 , 36 , and kinase activity of MSK1 phosphorylates CREB 13 , 37 . B16F0 cells increased the phosphorylation of MSK1 at the T581 residue after stimulation with α-MSH, which was inhibited by treatment with BI2B (Figure 7 C).…”

“…Pyridinylimidazole derivatives SB202190 and SB203580 were employed as ATP-competitive inhibitors of p38 MAPK -catalyzed kinase activity 38 . Structurally unrelated chemicals SB-747651A and RMM-46 were employed as MSK1 inhibitors, in which SB-747651A targets to the kinase activity of N -terminal kinase domain on protein substrates including CREB, and RMM-46 to C -terminal kinase domain-catalyzed autophosphorylation (activation) of N -terminal kinase domain 37 .…”

Mechanisms of Microglia Proliferation in a Rat Model of Facial Nerve Anatomy

“…In addition, mitogen- and stress-activated kinase-1 (MSK1) was recognized to be phosphorylated in M-CSF-stimulated microglia in vitro [ 109 ]. Since MSK1 is phosphorylated by p38 [ 118 , 119 ] and the activated MSK1 (p-MSK1) in turn activates CREB [ 120 ], the p38–MSK1–CREB signaling cascade is assumed to serve in microglial proliferation. ATF2 was also phosphorylated in M-CSF-stimulated microglia in vitro, and a link between p38 and ATF2 was reported in microglia in an LPS-induced neuroinflammation model [ 114 ], suggesting the existence of a p38–ATF2 pathway in M-CSF-dependent microglial proliferation.…”