Molecular Targeting of ERKs/RSK2 Signaling Axis in Cancer Prevention

Abstract

RSK2 is a downstream signaling protein of ERK1 and ERK2 and plays a key role in physiological homeostasis. For this reason, RSK2 is a highly conserved protein among the p90RSK family members. In its location in the signaling pathway, RSK2 is a kinase just upstream of transcription and epigenetic factors, and a few kinases involved in cell cycle regulation and protein synthesis. Moreover, activation of RSK2 by growth factors is directly involved in cell proliferation, anchorage-independent cell transformation and cancer development. Direct evidences regarding the etiological roles of RSK2 in cancer development in humans have been published by our research group illustrating that elevated total- and phospho-RSK2 protein levels mediated by ERK1 and ERK2 are higher in skin cancer tissues compared to normal skin tissues. Notably, it has been shown that RSK2 ectopic expression in JB6 Cl41 cells induces cell proliferation and anchorage- independent cell transformation. Importantly, knockdown of RSK2 suppresses Ras-mediated foci formation and anchorage-independent colony growth of cancer cells. Kaempferol is a one of the natural compounds showing selectivity in inhibiting RSK2 activity in epidermal growth factor-induced G1/S cell cycle transition and cell transformation. Thus, ERKs/RSK2 signaling axis is an important target signaling molecule in chemoprevention.

Kaempferol-immobilized titanium dioxide promotes formation of new bone: effects of loading methods on bone marrow stromal cell differentiation in vivo and in vitro

“…Kaempferol also inhibited cell proliferation of cancer cells. 43 The measurement of cell proliferation assay in this study also contradicted previous studies. These results indicated that the differences depended on the loading method of kaempferol.…”

Optogenetic actuator/ERK biosensor circuits identify MAPK network nodes that shape ERK dynamics

“…ERK2 and CRAF isoforms are implicated in the well-established ERK-RAF NFB, known to regulate ERK dynamics (Santos et al 2007; Ryu et al 2015; Blum et al 2019), and to enable consistent ERK dynamics under MEK or ERK perturbations (Fritsche-Guenther et al 2011; Sturm et al 2010). RSK2 encodes the p90 ribosomal S6 kinase 2 protein, an ERK substrate regulating survival and proliferation (Cargnello and Roux 2011; Yoo et al 2015). RSK2 is also known to be involved in an ERK-induced NFB targeting SOS (Douville and Downward 1997; Saha et al 2012; Lake et al 2016), whose significance in the regulation of ERK dynamics has been less well studied.…”

Quantitative Proteomics Analysis of Sporadic Medullary Thyroid Cancer Reveals FN1 as a Potential Novel Candidate Prognostic Biomarker

“…Notably, Cho et al discovered that RPS6KA3, which is activated by its upstream kinases, ERK1 and ERK2, plays a central role in human skin cancer development [35]. It was also reported that RPS6KA3 is activated by different growth factors that are closely related to cell proliferation, anchorage-independent cell transformation, and cancer development [36]. In the present study, although RPS6KAS was not associated with clinicopathologic characteristics of sporadic MTC, it was significantly upregulated in MTC tumorous tissues and could be used to distinguish sporadic MTC tumorous tissues from the paired normal thyroid tissues; the AUC of RPS6KAS was similar to that of the clinical biomarker CALCA and CEACAM5.…”