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Review
. 2023 Dec 19:11:1297292.
doi: 10.3389/fcell.2023.1297292. eCollection 2023.

Therapeutic targeting of p90 ribosomal S6 kinase

Eric B Wright  1 , Deborah A Lannigan  1   2
Affiliations
Review

Therapeutic targeting of p90 ribosomal S6 kinase

Eric B Wright et al. Front Cell Dev Biol. .

Abstract

The Serine/Threonine protein kinase family, p90 ribosomal S6 kinases (RSK) are downstream effectors of extracellular signal regulated kinase 1/2 (ERK1/2) and are activated in response to tyrosine kinase receptor or G-protein coupled receptor signaling. RSK contains two distinct kinase domains, an N-terminal kinase (NTKD) and a C-terminal kinase (CTKD). The sole function of the CTKD is to aid in the activation of the NTKD, which is responsible for substrate phosphorylation. RSK regulates various homeostatic processes including those involved in transcription, translation and ribosome biogenesis, proliferation and survival, cytoskeleton, nutrient sensing, excitation and inflammation. RSK also acts as a major negative regulator of ERK1/2 signaling. RSK is associated with numerous cancers and has been primarily studied in the context of transformation and metastasis. The development of specific RSK inhibitors as cancer therapeutics has lagged behind that of other members of the mitogen-activated protein kinase signaling pathway. Importantly, a pan-RSK inhibitor, PMD-026, is currently in phase I/1b clinical trials for metastatic breast cancer. However, there are four members of the RSK family, which have overlapping and distinct functions that can vary in a tissue specific manner. Thus, a problem for transitioning a RSK inhibitor to the clinic may be the necessity to develop isoform specific inhibitors, which will be challenging as the NTKDs are very similar to each other. CTKD inhibitors have limited use as therapeutics as they are not able to inhibit the activity of the NTKD but could be used in the development of proteolysis-targeting chimeras.

Keywords: RSK; p90 ribosomal S6 kinase; p90RSK; phosphorylation; small molecule inhibitor; substrate.

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Conflict of interest statement

DL holds patents on the RSK analogues based on SL0101. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
RSK structure family sequence alignment. Numbering is relative to human RSK1. A schematic of RSK shows the NTKD and CTKD with phosphorylation sites required to activate the RSK NTKD, which then phosphorylates RSK substrates (A). ERK1/2 docks on the C terminus and phosphorylates several sites within the CTKD and linker region. CTKD phosphorylation of Ser380 within the linker region creates a docking site for PDK1, which then phosphorylates Ser221 in the NTKD, resulting in full activation of RSK. The 4 isoforms of the human RSK family are highly homologous, as shown in the consensus sequence (B). Key functional regions of the kinases are highlighted or annotated.
FIGURE 2
FIGURE 2
RSK substrates and their molecular functions. RSK kinase activity can activate or inhibit targets directly by the effect of phosphorylation, by regulating subcellular localization, or by introducing or inhibiting binding sites for other proteins. Substrates identified only by phosphoproteomic screens without subsequent description of the effects of RSK phosphorylation are listed as unknown. RSK substrate functions can be broadly classified into transcription, translation and ribosomal biogenesis, cell cycle regulation and proliferation, survival, nutrient sensing, excitation-contraction coupling, and inflammation. Nutrient sensing includes response to intracellular and extracellular metabolites and metals and ions. Phosphorylation sites are shown for each protein relative to amino acid numbering in the human protein, except for where the phospho site is unknown or the corresponding site is a non-phosphorylatable residue in human. A comprehensive list of RSK phosphorylation sites, motifs, and the validation methods used are detailed in Supplementary Table S1.
FIGURE 3
FIGURE 3
RSK isoform overexpression in cancer. Immunohistochemistry staining of tumors for each RSK isoform are assigned as high, medium, low relative to normal tissue. For each tumor and RSK isoform, the percent high or medium are shown. These data were obtained from the Human Protein Atlas.
FIGURE 4
FIGURE 4
Negative feedback in the MAPK pathway by RSK. Ligand binding to a receptor tyrosine kinase (RTK) initiates docking of GRB2 and SOS, which then activates Ras to its GTP-bound form. Sequential phosphorylations lead to RSK activation. RSK phosphorylates sites on FGFR1, SOS1 to inhibit their function in the MAPK cascade. RSK multi-phosphorylation of GAB2 creates a docking site for 14-3-3 proteins, which block SHP2 complexing with Gab2. RSK inhibits the Ras guanine exchange factor NF1 through an unknown mechanism. RSK phosphorylates capicua to relieve transcriptional suppression of DUSP6.
FIGURE 5
FIGURE 5
RSK inhibitor structures. Select inhibitors are shown from each series described in the text. (A) RSK-specific NTKD inhibitors (black), (B) RSK-specific CTKD inhibitors (blue), (C) non-specific NTKD inhibitors (orange), (D) non-specific CTKD inhibitors (red), (E) other non-specific inhibitors (green). A list of inhibitory efficacy of the various compounds in vitro kinase and cell-based assays is provided in Supplementary Tables S2, S3.
FIGURE 6
FIGURE 6
Kinase-inhibitor crystal structures. (A) The active kinase in complex with the ATP surrogate AMP-PNP (Protein Data Bank ID 3G51) adopts a DGF motif-in, α C helix-in conformation. In Type II inhibitors, such as (B) SL0101 (PDB ID 3UBD), (C) BI-D1870 (5D9K), and (D) LJH685 (PDB ID 4NUS), the DFG motif flips out to face away from the ATP binding pocket. (E) The unliganded CTKD (PDB ID 2QR8) adopts an inactive conformation. (F) The covalent inhibitors CN-NHiPr (PDB ID 4D9U) and (G) dimethyl fumarate (PDB ID 5O1S) are Type I inhibitors that adopt a DFG-in, C-in conformation and covalently bond to a reactive cysteine, C436.
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