RSK1 and RSK2 serine/threonine kinases regulate different transcription programs in cancer

Abstract

The 90 kDa ribosomal S6 kinases (RSKs) are serine threonine kinases comprising four isoforms. The isoforms can have overlapping functions in regulation of migration, invasion, proliferation, survival, and transcription in various cancer types. However, isoform specific differences in RSK1 versus RSK2 functions in gene regulation are not yet defined. Here, we delineate ribosomal S6 kinases isoform-specific transcriptional gene regulation by comparing transcription programs in RSK1 and RSK2 knockout cells using microarray analysis. Microarray analysis revealed significantly different mRNA expression patterns between RSK1 knockout and RSK2 knockout cell lines. Importantly some of these functions have not been previously recognized. Our analysis revealed RSK1 has specific roles in cell adhesion, cell cycle regulation and DNA replication and repair pathways, while RSK2 has specific roles in the immune response and interferon signaling pathways. We further validated that the identified gene sets significantly correlated with mRNA datasets from cancer patients. We examined the functional significance of the identified transcriptional programs using cell assays. In alignment with the microarray analysis, we found that RSK1 modulates the mRNA and protein expression of Fibronectin1, affecting cell adhesion and CDK2, affecting S-phase arrest in the cell cycle, and impairing DNA replication and repair. Under similar conditions, RSK2 showed increased ISG15 transcriptional expression, affecting the immune response pathway and cytokine expression. Collectively, our findings revealed the occurrence of RSK1 and RSK2 specific transcriptional regulation, defining separate functions of these closely related isoforms.

Identification of RSK substrates using an analog-sensitive kinase approach

“…Ramos showed that even in the same cell-type, two RSKs regulate different transcription programs. By using microarray analysis in glioblastoma-derived cells were RSK1 or RSK2 were knocked-down, this group showed that these two kinases do not induce the same gene transcription patterns ( 20 ). In brief, RSKs and their link to cancer clearly depends on the RSK isoform and the type of cancer.…”

“…In line with these data, a recent study showed that all four RSK isoforms were phosphorylating very similar peptides in a peptide array type of screening ( 12 ). Other works however support nonredundant activities of the distinct RSK isoforms in cells, likely linked to differences in the range of substrates phosphorylated by the different kinase isoforms ( 20 ).…”

Therapeutic targeting of p90 ribosomal S6 kinase

“…Both of these inhibitors have shown efficacy in xenograft models. In cancer RSK1 and RSK2 regulate differing transcriptional programs in glioblastoma multiforme ( Yang et al, 2022 ). Additionally, in lung cancer RSK1 appears to function as a tumor suppressor whereas RSK2 promoted metastasis ( Lara et al, 2011 ).…”

Biochemical interaction of twenty steroid derivatives with ribosomal protein kinase 4 S6 (RSK-4) surface using a theoretical model

“…This clinical phatology involves several risks factors such age (Zabransky et al, 2022), smoking (Phua et al, 2022), alcohol consumption (Mayen et al, 2022), obesity (Bao et al, 2022), diabetes (Lazarus and Bays, 2022), physical inactivity (Minihan et al, 2022), radiation exposure (Einstein et al, 2007), and genetic factors (Garcia-Pelaez et al, 2022;Jiang et al, 2023). In this way, several genetic expressions have been involved in the development of cancers; for example, the expression of ribosomal S6 p90 kinase family [RSK 1-4; which belongs to the group of highly conserved Ser/Thr kinases] (Yang et al, 2023;Casalvieri et al, 2017). In addition, a study showed that RSK-1 could be associated to tumor growth and metastasis, using a triple-negative breast cancer model (Czaplinska et al, 2018).…”