Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

RSK (p90 Ribosomal S6 Kinase)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_382

Synonyms

Historical Background

The p90 ribosomal S6 kinase (RSK) family comprises four mammalian Ser/Thr kinases (RSK1-4) (Romeo et al. 2012). The first RSK family member was identified as a kinase activity in maturating Xenopus laevis oocytes that phosphorylated the 40S ribosomal subunit protein S6 (rpS6) (Erikson and Maller 1985, 1986). Although the p70 ribosomal S6 kinases 1 and 2 (S6K1 and S6K2) were later shown to be the predominant S6 kinases operating in somatic cells (Blenis et al. 1991; Chung et al. 1992), RSK1 and RSK2 were found to phosphorylate rpS6 in response to ERK1/ERK2 pathway activation (Cohen et al. 2005; Roux et al. 2007). Interestingly, whereas S6K1/S6K2 phosphorylate all sites on rpS6 (Ser235, Ser236, Ser240, and Ser244), RSK1 and RSK2 were shown to specifically phosphorylate Ser235 and Ser236 (Roux et al. 2007). It should be noted, however, that the molecular mechanism(s) underlying the diverse effects of rpS6 phosphorylation on cellular and organismal physiology are still poorly understood (Meyuhas 2015).

Structure of the RSK Isoforms

The RSK isoforms are 73–80% identical to each other and are mostly divergent in their amino- and carboxyl-termini sequences. The structure of RSK is complex and comprises two functionally distinct kinase domains, a linker region, and N- and C-terminal tails. While the N-terminal-kinase domain (NTKD) shares homology with kinases of the AGC family (PKA, PKG, PKC), the C-terminal kinase domain (CTKD) is homologous to the calcium/calmodulin-dependent protein kinases (CaMKs). It is thought that during evolution, the genes for two different protein kinases have fused, generating a single polypeptide capable of receiving an upstream activating signal from the Ras/MAPK pathway to its CTKD and transmitting, with high efficiency and fidelity, an activating input to its NTKD. Thus, the CTKD appears to be only involved in autophosphorylation of RSK, resulting in its activation, and the NTKD is responsible for downstream substrate phosphorylation (Bjorbaek et al. 1995). The C-terminal tail contains an ERK1/ERK2 docking motif, known as the D domain, and interaction of RSK with ERK1/ERK2 was shown to depend on a short motif consisting of Leu-Arg-Gln-Arg-Arg (Roux et al. 2003; Smith et al. 1999). Finally, the C-terminal tail of all RSK isoforms contains a type 1 PDZ domain-binding motif, consisting of Thr-Xaa-Leu, where Xaa is any amino acid. This motif was shown to be functional with at least some PDZ domain-containing proteins (Thomas et al. 2005), but more work will be needed to fully determine its role and biological significance.

Activation Mechanisms

The RSK isoforms contain six phosphorylation sites that are responsive to mitogenic stimulation. Mutational analysis revealed that four of these sites (Ser221, Ser352, Ser369, and Thr562 in mouse RSK1) are essential for RSK activation (Dalby et al. 1998). Of these, Ser221 (located in the NTKD activation loop), Ser352 (turn motif), and Ser369 (hydrophobic motif) are located within sequences highly conserved in other AGC kinases (Newton 2003). The current model of RSK activation suggests that ERK and RSK form an inactive complex in quiescent cells that is facilitated by the D domain on RSK (Hsiao et al. 1994; Zhao et al. 1996). After mitogenic stimulation, ERK1/2 phosphorylate Thr562 in the activation loop of the CTKD (Sutherland et al. 1993) and possibly Thr348 and Ser352 in the linker region between the two kinase domains (Dalby et al. 1998). Activation of the CTKD leads to autophosphorylation at Ser369 (Vik and Ryder 1997), which creates a docking site for phosphoinositide-dependent protein kinase 1 (PDK1) (Frodin et al. 2000). In turn, PDK1 phosphorylates Ser221 in the activation loop of the NTKD (Jensen et al. 1999; Richards et al. 1999) and, along with phosphorylated Ser352 and Ser369, promote an intramolecular allosteric mechanism that allows the NTKD to phosphorylate downstream substrates (Frodin et al. 2002). RSK also autophosphorylates at a C-terminal residue that releases ERK1/ERK2 binding, presumably to allow these kinases to find their respective substrates throughout the cell (Roux et al. 2003).

The process of RSK activation is closely linked to ERK1/ERK2 activity, and MEK1/MEK2 inhibitors (U0126, PD98059, PD184352) have been widely used to study RSK function. Four different classes of RSK inhibitors targeting the NTKD (SL-0101, BI-D1870, LJH685) or the CTKD (FMK) have been identified (Aronchik et al. 2014; Cohen et al. 2005; Sapkota et al. 2007; Smith et al. 2005). While BI-D1870, SL-0101, and LJH685 are ATP-competitive inhibitors, FMK (fluoromethylketone) is an irreversible inhibitor that covalently modifies the CTKD of RSK1, RSK2, and RSK4. Like most pharmacological inhibitors of protein kinases, it should be noted that the RSK inhibitors were reported to inhibit additional protein kinases (Aronchik et al. 2014; Bain et al. 2007). Alternate mechanisms of activation for RSK have been described (Kang et al. 2008; Zaru et al. 2007), but these appear to be cell type and context specific. One of these involves tyrosine phosphorylation by Src, which was shown to stabilize the interaction between ERK and RSK and thereby increase the rate at which RSK becomes activated (Kang et al. 2008). Another mechanism involves regulation of the hydrophobic motif of RSK by the related enzymes, MAPK-activated protein kinases 2 and 3 (MK2/3), which can facilitate RSK activation upon stimulation of the stress-responsive p38 MAPK pathway (Zaru et al. 2007).

Biological Functions

RSK appears to be a multifunctional ERK1/ERK2 effector because it participates in various cellular processes (Cargnello and Roux 2011; Romeo et al. 2012). A recent proteomics study determined that RSK phosphorylates a large number of substrates in cells involved in a wide range of biological functions (Galan et al. 2014). Although a number of RSK functions can be deduced from the nature of its substrates, data from many groups point towards roles for the RSKs in nuclear signaling, cell cycle progression and cell proliferation, cell growth and protein synthesis, and cell migration and cell survival. RSK was found to regulate several transcription factors, including SRF, c-Fos, and Nur77. On the basis of its substrates, RSK seems to have important functions in cellular growth control and proliferation. RSK may stimulate cell cycle progression through the regulation of immediate early gene products, such as c-Fos, which promotes the expression of cyclin D1 during the G0/G1 transition to S phase. RSK may also promote proliferation by regulating cell growth-related protein synthesis. Indeed, RSK was found to regulate the tumor suppressor TSC2 and Raptor (Carriere et al. 2008; Roux et al. 2004) and thereby promote mTOR signaling in normal and cancer cells (Romeo et al. 2013). RSK has also been shown to regulate cell survival. RSK phosphorylates and inhibits the proapoptotic proteins Bad and DAPK, thereby promoting survival in response to mitogenic stimulation (Anjum et al. 2005; Shimamura et al. 2000). Many additional RSK substrates have been identified through the years, but at this point, very little is known regarding isoform specificity. Whereas more substrates have been identified for RSK2 than any other RSK isoforms, most studies have not determined isoform selectivity. Therefore, many known substrates of RSK2 may be shared by different RSK family members and more effort will be necessary to assess potential overlapping functions.

Physiological Functions

An important clue into the physiological roles of the RSK isoforms came from the finding that inactivating mutations in the Rps6ka3 gene (which encodes RSK2) were the cause of Coffin-Lowry syndrome (CLS)(Trivier et al. 1996). CLS is an X-linked mental retardation syndrome characterized in male patients by psychomotor retardation and facial, hand, and skeletal malformations (Pereira et al. 2010). Rps6ka3 mutations are extremely heterogeneous and lead to loss of phosphotransferase activity in the RSK2 kinase, most often because of premature termination of translation. It was shown that individuals with CLS consistently presented markedly reduced total brain volume, with cerebellum and hippocampal volumes being particularly impacted in CLS patients. The physiological role of RSK2 was also studied in the mouse through the generation of a deletion model. These mice were shown to have deficiencies in learning and cognitive functions, as well as having poor coordination compared to wild-type littermates (Dufresne et al. 2001; Poirier et al. 2007). The exact cause for these phenotypes remains unknown, but a recent study demonstrated that shRNA-mediated RSK2 depletion perturbs the differentiation of neural precursors into neurons and maintains them as proliferating radial precursor cells (Cargnello and Roux 2011; Romeo et al. 2012). Evidently, more experimentation using RSK2-deficient animals will be required to fully understand the developmental role of RSK2 in the nervous system.

Mice deficient in RSK2 expression also develop a progressive skeletal disease, called osteopenia, due to cell-autonomous defects in osteoblast activity (David et al. 2005). Both c-Fos and ATF4 transcription factors were shown to be critical RSK2 substrates involved in these effects in osteoblasts (Cargnello and Roux 2011; Romeo et al. 2012). In addition, RSK2 knockout mice are approximately 15% smaller than their wild-type littermates, with a specific loss of white adipose tissue that is accompanied by reduced serum levels of the adipocyte-derived peptide, leptin. RSK1/RSK2/RSK3 triple knockout mice are viable, but no other information regarding their phenotype has yet been reported (Cargnello and Roux 2011; Romeo et al. 2012). The Rps6ka6 gene (that codes for RSK4) is located on chromosome X and was suggested to be involved in nonspecific X-linked mental retardation, but definitive evidence remains to be provided. Interestingly, deletion of Drosophila RSK was found to result in defects in learning and conditioning (Putz et al. 2004). More recent work has shown that Drosophila RSK regulates synaptic function and axonal transport in motoneurons (Beck et al. 2015). RSK3 was shown to be important for pathological remodeling of the heart, as it appears to serve a unique role in cardiac myocyte in response to stress (Martinez et al. 2015). RSK4 is perhaps the least understood of RSK isoforms but was shown to inhibit cancer cell proliferation and perhaps promote cellular senescence (Arechavaleta-Velasco et al. 2016; Lopez-Vicente et al. 2011). Consistent with this, RSK4 appears to be downregulated in several types of cancer (Cai et al. 2014; Li et al. 2014; Rafiee et al. 2016).

Summary

Many studies have now clearly established RSK as an important effector of the Ras/MAPK pathway, and it is becoming increasingly clear RSK signaling is deregulated in several human diseases (Romeo and Roux 2011; Sulzmaier and Ramos 2013). Recent studies have expanded the repertoire of biological functions linked to the RSK family of protein kinases, ranging from the regulation of transcription, translation, and protein stability to the control of cell survival, cell motility, cell growth, and proliferation (Galan et al. 2014). It has become clear that other AGC family members such as Akt and S6K have similar functions and often share similar protein targets. These findings emphasize the importance of a tight and intricate regulation of cellular processes that are important for cell growth and cell survival. Combined, these studies have helped to identify additional targets for therapeutic intervention in diseases that are associated with inappropriate signaling downstream of Ras and Raf and reveal novel targets for biomarker development for disease detection.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute for Research in Immunology and Cancer (IRIC), Department of Pathology and Cell Biology, Faculty of MedicineUniversité de MontréalMontrealCanada