RSK2-induced stress tolerance enhances cell survival signals mediated by inhibition of GSK3β activity

Abstract

Our previous studies demonstrated that RSK2 plays a key role in cell proliferation and transformation induced by tumor promoters such as epidermal growth factor (EGF) in mouse and human skin cells. However, no direct evidence has been found regarding the relationship of RSK2 and cell survival. In this study, we found that RSK2 interacted and phosphorylated GSK3β at Ser9. Notably, GSK3β phosphorylation at Ser9 was suppressed in RSK2(-/-) MEFs compared with RSK2(+/+) MEFs by stimulation of EGF and calcium ionophore A23187, a cellular calcium stressor. In proliferation, we found that RSK2 deficiency suppressed cell proliferation compared with RSK2(+/+) MEFs. In contrast, GSK3β(-/-) MEFs induced the cell proliferation compared with GSK3β(+/+) MEFs. Importantly, RSK2(-/-) MEFs were induced severe cellular morphology change by A23187 and enhanced G1/G0 and sub-G1 accumulation of the cell cycle phase compared with RSK2(+/+) MEFs. The sub-G1 induction in RSK2(-/-) MEFs by A23187 was correlated with increase of cytochrome c release, caspase-3 cleavage and apoptotic DNA fragmentation compared with RSK2(+/+) MEFs. Notably, return back of RSK2 into RSK2(-/-) MEFs restored A23187-induced morphological change, and decreased apoptosis, apoptotic DNA fragmentation and caspase-3 induction compared with RSK2(-/-)/mock MEFs. Taken together, our results demonstrated that RSK2 plays an important role in stress-tolerance and cell survival, resulting in cell proliferation and cancer development.

Magnolin inhibits cell migration and invasion by targeting the ERKs/RSK2 signaling pathway

“…RSK2 is a member of the RSK family and is phosphorylated at the C-terminal kinase and linker domains by ERK1/2 [ 8 ] and at the N-terminal kinase domain by phosphoinositide-dependent kinase 1 (PDK1) [ 9 ]. Activated RSK2 transduces its activation signal to various downstream target proteins including transcription and epigenetic factors [ 10 – 12 ], kinases [ 13 ], and scaffolding proteins such as nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α (IκBα) [ 14 ], and regulates diverse cellular activities involved in cell proliferation, transformation and motility [ 15 ]. For instance, our previous results have demonstrated that the enhanced cAMP-dependent transcription factor 1 (ATF1) activity, caused by the epidermal growth factor (EGF)-mediated Ras/ERKs/RSK2 signaling pathway, induces cell proliferation and transformation [ 16 ].…”

“…For instance, our previous results have demonstrated that the enhanced cAMP-dependent transcription factor 1 (ATF1) activity, caused by the epidermal growth factor (EGF)-mediated Ras/ERKs/RSK2 signaling pathway, induces cell proliferation and transformation [ 16 ]. The increased NF-κB transactivation activity, resulting from the RSK2-IκBα signaling pathway, modulates cell survival induced by the FAS-mediated death signaling pathway [ 13 ]. A recent report demonstrates that RSK2 promotes the invasion and metastasis of head and neck squamous cell carcinoma cells in humans [ 17 ].…”

“…The mitogen-activated protein kinase (MAPK) family is comprised of three subfamilies including ERKs, p38 kinases and c-Jun N-terminal kinases (JNKs), which play a key role in the regulation of cellular responsiveness by the diverse extracellular stimuli such as growth factors, peptide hormones, and environmental stressors such as ultraviolet light [ 13 , 21 , 22 ]. The ERKs/RSK2 signaling axis plays a pivotal role in cell proliferation, differentiation, survival, and transformation [ 8 , 10 , 13 , 15 , 21 ], in addition to cell migration through the induction of matrix metalloproteinases (MMPs), which are the enzymes that degrade the extracellular matrix, such as collagen and gelatin, to facilitate the metastasis of cancer cells [ 6 ]. Recently, our research group found that magnolin, a major component of Magnolia flos (Shin-Yi) that has been traditionally used as an oriental medicine to treat headaches, nasal congestion and inflammatory reactions [ 23 ], inhibits the Ras/ERKs/RSK2 signaling axis by targeting the active pocket of ERK1 and ERK2 with IC 50 values of 87 nM and 16.5 nM, respectively [ 5 ].…”

Inhibition of glycogen synthase kinase 3 beta (GSK3β) suppresses the progression of esophageal squamous cell carcinoma by modifying STAT3 activity

“…Since the accumulation of β‐catenin has been demonstrated to promote the development of multiple cancers, GSK3β was thought to act as a tumor suppressor by controlling the level of β‐catenin. Several studies have reported the anti‐tumorigenesis role of GSK3β using gain‐ and loss‐of‐function approaches in different tumors such as breast and skin tumors . Moreover, GSK3β overexpression has been reported to affect the viability of cancer cells by enhancing the degradation of pro‐tumorigenesis factors such as Cdc25A and c‐Myc .…”

“…| 2313 by controlling the level of β-catenin. Several studies have reported the anti-tumorigenesis role of GSK3β using gain-and loss-of-function approaches in different tumors such as breast and skin tumors 50,51.…”