Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

S6K (S6 Kinase)

  • Isadora Carolina Betim Pavan
  • Fernando Riback Silva
  • Ana Paula Morelli
  • Fernando Moreira Simabuco
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101816

Synonyms

Historical Background

The ribosomal S6 protein kinases (S6Ks) represent a superfamily of proteins which were originally discovered to phosphorylate ribosomal protein S6. Proteins known as p90 ribosomal S6 kinases (RSKs) have been first identified as able to phosphorylate ribosomal protein S6 (Jones et al. 1988). A short time later, S6K1 protein was discovered gaining a major role in S6 phosphorylation in somatic cells, while RSKs gained less significance in this process (Banerjee et al. 1990). It is important to note that RSKs and S6Ks belong to different subfamilies of serine/threonine kinases but received similar names because S6 protein is a common substrate for both. After 10 years since S6K1 has been cloned, an S6K1 homologous protein was discovered, which was named S6K2 (Saitoh et al. 1998).

Since it was confirmed a direct correlation between S6K1 and mTOR, when it was shown that S6K1 is phosphorylated at T389 by mTOR through kinase assays in vitro (Burnett et al. 1998a), many studies have been performed to discover the functions of the mTOR/S6K1 signaling axis. For instance, it has been determined that this axis mainly acts on the control of protein biosynthesis and cell growth and proliferation (Magnuson et al. 2011).

As observed, many studies have been focused on understanding the S6K1 functions, given that p70-S6K1 is the canonical isoform of S6Ks. Due to the high degree of similarity between S6K1 and S6K2, it was believed that both isoforms had overlapping functions and for a long time S6K2 was neglected. However, it has been shown that S6K2 may present a different regulation and may be involved in different cellular processes (Pardo et al. 2006; Pavan et al. 2016).

The S6K Family

The S6K proteins together with 4E-BP1 are the major effectors of the mTORC1 (mammalian target of rapamycin complex 1) pathway, which is activated in response to growth factors, insulin, glucose, and amino acids (Fig. 1). Once activated, S6Ks stimulate protein synthesis, cell growth, and survival (Tavares et al. 2015; Fig. 1). S6K proteins belong to the AGC kinase superfamily, which also includes other serine/threonine kinases, such as PKA, Akt (PKB), PKCs, PKG, PDK-1, SGK, and p90-RSK (Mora et al. 2004). S6Ks, RSK (p90) and MSK, belong to the ribosomal protein S6 kinases family (broadly named RSKs).
S6K (S6 Kinase), Fig. 1

The mTOR/S6K signaling pathway. Amino acids, glucose, insulin, and growth factors activate mTORC1, which then activates S6K1 and S6K2. Downstream effectors of S6Ks are shown according to their involvement in several biological processes. Full arrows indicate activation. Blunt arrows indicate inhibition

Two genes of S6Ks are known, named S6K1 (RPS6KB1) and S6K2 (RPS6KB2), encoding two different proteins called p70-S6K1 and p54-S6K2, respectively (Banerjee et al. 1990; Saitoh et al. 1998). p70-S6K1 is the most studied isoform and contains 502 amino acids, whereas p54-S6K2 contains 482 amino acids (Tavares et al. 2015; Fig. 2). p70-S6K1 and p54-S6K2 present larger isoforms generated by alternative use of the AUG translation initiation codons, named p85-S6K1 and p56-S6K2, respectively. Both p85-S6K1 and p56-S6K2 contain an addition of 23 or 13 amino acids, respectively, and a nuclear localization signal (NLS) at the N-terminal compared to their shorter isoforms (Banerjee et al. 1990). Moreover, S6K2 also presents another NLS at its C-terminal (Saitoh et al. 1998).
S6K (S6 Kinase), Fig. 2

Architecture domain organization of S6Ks isoforms and their posttranslational modifications (PTMs). S6K1 and S6K2 proteins are produced from two different genes, RPS6KB1 and RPS6KB2, respectively. Alternative translational start codon is used to produce shorter isoforms of S6K1 (p70-S6K1) and S6K2 (p54-S6K2). The long isoforms, p85-S6K1 and p56-S6K2, exhibit a difference of 23 and 13 amino acids, respectively, compared to their shorter isoforms. N N-terminal domain, KD kinase domain, C C-terminal domain, NLS nuclear localization signal, Pro proline-rich domain, PDZ PDZ domain, P phosphorylated residues, Ub ubiquitinated residues, Ac acetylated residues. p31-S6K1 isoform is produced by an alternative splicing from RPS6KB1 gene

S6K1 and S6K2 share high identity in their kinase domains (84%), with less similarities in their N-terminal (43%) and C-terminal (59%) (Magnuson et al. 2011; Saitoh et al. 1998). S6Ks exhibit some conserved sites of serine and threonine in their kinase domains, linker domain, and C-terminal, which are essential for their activation by phosphorylation (Fig. 2; Weng et al. 1998). Interestingly, there are some differences between S6K1 and S6K2 in their architectures, specifically at the N- and C-terminal, indicating that S6Ks may be related to different cellular compartments or have different molecular targets. For example, a PDZ-binding domain at C-terminal in S6K1 is important for its interaction with Neurabin and, consequently, recruitment to the actin cytoskeleton (Burnett et al. 1998b). On the other hand, S6K2 contains a proline-rich domain in its C-terminal, consisting of five consecutive prolines, which may support the interaction with SH3 (Src homology 3) and/or WW domain-containing proteins (Macias et al. 2002).

Although S6K1 and S6K2 present known structural differences, scarce information is attributed to the S6K2 isoforms. A recent proteomic analysis based on p70-S6K1 and p54-S6K2 interactomes has shown that S6Ks have different interacting partners, strongly suggesting that some proteins may be new targets for the different S6K isoforms (Pavan et al. 2016). Interactions will be described in a later section, showing different functions of S6K proteins and their involvement in several cellular processes.

A shorter S6K1 isoform termed p31-S6K1 is required for cellular transformation and is generated by alternative splicing, which is regulated by the splicing factor SF2/ASF. Functions of p31-S6K1 are still unclear, but it is known that its kinase domain is severely truncated and it is overexpressed in breast cancer (Fig. 2; Karni et al. 2007).

S6Ks Regulation

S6Ks Phosphorylation and Activation

The most accepted model of S6Ks activation consists on its phosphorylation on four major residues at the C-terminal domain, S411, S418, S421, and S424, inducing its structure to a relaxed conformation (Ferrari et al. 1992; Fig. 3). This first event allows the exposure of an internal region which can be phosphorylated by mTOR on T389 and T388 for S6K1 and S6K2, respectively, leading to its partial activation (Weng et al. 1998). The maximum activation of S6Ks is only achieved when PDK1 phosphorylates T229 and T228 at the T-loop region, for S6K1 and S6K2, respectively (Magnuson et al. 2011; Pullen et al. 1998). It is important to note that the phosphorylation of T388/T389 acts as a docking site for PDK1. The casein kinase 2 (CK2) protein is also able to phosphorylate S6K1 on S17 at its N-terminal domain, enabling S6K1 translocation from nucleus to the cytoplasm (Panasyuk et al. 2006). S6K1, but not S6K2, interacts with PP2A leading to its dephosphorylation and inactivation (Peterson et al. 1999).
S6K (S6 Kinase), Fig. 3

Conventional model of S6Ks activation. (a) The interaction between the N- and C-terminal domains is autoinhibitory. (b) Phosphorylation of multiple residues at the C-terminal allows a more relaxed conformation of the S6K’s structure. (c) mTORC1 phosphorylates S6K1 and S6K2 on T389 and T388, respectively, resulting in their partial activation. (d) At last, the T-loop site phosphorylation by PDK1 on T229 and T228 for S6K1 and S6K2, respectively, leads to their full activation (Adapted from Magnuson et al. 2011)

Other Posttranslational Modification

S6K1 and S6K2 are also acetylated by p300 acetyltransferase on the K516 residue at the C-terminal domain, inhibiting phosphorylation and activation by mTORC1 on the T389/T388 residue (Fenton et al. 2010). Besides, a study has shown that both S6K1 and S6K2 are ubiquitinated (Wang et al. 2008). The ubiquitin ligase protein ROC1 specifically interacts with S6K1, leading to its degradation (Panasyuk et al. 2008).

Subcellular Localization

A study has shown that S6K1 and S6K2 have different subcellular localizations, since it has been evidenced that GFP-tagged p70-S6K1 is spread throughout the cell, while p54-S6K2 presents an intense localization in the nucleus and nucleolus (Pavan et al. 2016). Thus, these findings agree with the presence of a nuclear localization signal at the C-terminal domain of p54-S6K2, which is not present in p70-S6K1. Although p85-S6K1 presents a nuclear localization signal at its N-terminal domain, a study has shown that it is mainly cytoplasmic (Rosner and Hengstschläger 2011).

S6K Targets and Their Related Biological Processes

Several targets of S6Ks have been described and will be presented bellow along with their biological processes involved. Their relationships with S6Ks are summarized in Fig. 1.

Molecular Chaperone

Chaperonin containing TCP-1 (CCTβ) is a large multi-subunit complex that mediates protein folding in eukaryotic cells, participating in the folding of newly synthesized polypeptides, like actin, tubulin, and regulators of cell cycle. A study has identified CCTβ as a downstream target for p90-S6K (RSK) and p70-S6K1. p90- and p70-S6K phosphorylate the CCTβ subunit on S260, indicating that its phosphorylation is an important contributor to cell division (Abe et al. 2009).

Apoptosis

Apoptosis is a molecular process of programmed cell death, critical for development, tissue homeostasis, and protection against pathogens. The Bcl-2 family regulates cell death and is regulated by cytokines or other death-survival signals at different levels. Studies have demonstrated the involvement of S6K1 in cell survival by blocking apoptosis through phosphorylation of Bcl-2-associated death promoter (BAD) (Harada et al. 2001). Besides, S6K1 binds and phosphorylates murine double minute 2 (Mdm2) (Lai et al. 2010), preventing its translocation to the nucleus, where Mdm2 leads to the ubiquitination of the nuclear tumor suppressor protein p53. As a consequence, the increase of p53 protein levels leads to cell cycle arrest and/or apoptosis. Furthermore, S6K1 can phosphorylate and inhibit GSK3, generating a signal for cell surviving (Park et al. 2002).

mRNA Splicing

Phosphorylation of the ribosomal S6 protein, target of S6K1 and S6K2, is tightly correlated with enhanced translation initiation of a subset of mRNAs that encodes components of the protein synthesis machinery (Park et al. 2002). It has been demonstrated that Cdc42, an important protein in cell growth, can stimulate mRNA splicing via S6K1 and CBC, the nuclear cap-binding complex. S6K1, together with PI3 kinase, can phosphorylate the 80-kDa subunit of the CBC, CBP80, at residues that are growth factor dependent and rapamycin sensitive (Wilson et al. 2000). The role of S6Ks in the splicing process was also investigated for the nuclear protein SKAR (S6K1 Aly/REF-like target), identified as another target of S6K1 and a linker between pre-mRNA splicing and the mTOR pathway (Richardson et al. 2004).

Inflammation

Transforming growth factor-activated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, being essential for the production of tumor necrosis factor-α TNF-α. TAK1 also plays a key regulatory role in several cytokine-mediated signal transduction cascades, including Interleukin-1 (IL-1) and the downstream signaling of Toll-like receptors (TLRs). It has been shown that S6K1 negatively regulates TLR-mediated signals by inhibiting TAK1 activity (Kim et al. 2014). S6K1 overexpression causes a marked reduction in NF-κB and AP-1 activities. Conversely, cells with S6K1 knockout or knockdown display enhanced production of inflammatory cytokines.

Metabolism

S6K1 has emerged as a critical signaling component in the development of insulin resistance through phosphorylation and inhibition of insulin receptor substrate 1 (IRS-1), acting as a negative feedback loop. A study has shown that S6K1 can directly phosphorylate IRS-1 on S1101 in vitro at its C-terminal domain, inhibiting its downstream activity. The phosphorylation of IRS-1 S1101 is increased in the liver of obese db/db and wild type on a high-fat diet, but not in S6K1 knockout mice maintained on the same diet, indicating that nutrient and hormonal-dependent activation of S6K1 causes insulin resistance (Tremblay et al. 2007).

As a constituent of insulin pathway, the heterotrimeric AMP-activated protein kinase (AMPK) is a known energy sensor that plays a key role in regulating energy metabolism. In response to the reduction of intracellular ATP levels, AMPK inhibits protein, carbohydrate, and lipid biosynthesis, as well as cell growth and proliferation. A study has shown that S6K1 is an inhibitory AMPK kinase, forming a complex with the α2AMPK catalytic subunit and phosphorylating it on S491 (Dagon et al. 2012). This phosphorylation is critical for leptin action on food intake and body weight. S6K1 is also able to phosphorylate and activate PFK-2 (6-phosphofructo-2-kinase), which regulates glycolysis by catalyzing formation of fructose-2,6-bisphosphate, an allosteric activator of PFK-1 of the glycolytic pathway (Deprez 1997).

In the energy metabolism, the production of ketone bodies as an alternative energy source is critical to maintain energy homeostasis during fasting, and its regulation is accomplished by transcriptional networks, such as the peroxisome proliferator-activated receptor (PPAR) family. A study demonstrated that S6K2 can suppress PPARα activity, a ligant-activated transcription factor, impairing the recruitment of nuclear receptor corepressor 1 (NCoR1) to the cell’s nucleus. The S6K2 knockout mice exhibit increased activity of PPARα and consequently increased production of ketone bodies. Nonetheless, the ob/ob mice present increased S6K2 phosphorylation activity and NCoR1 primarily located to the nucleus, leading to decreased production of ketone bodies (Kim et al. 2012).

The anabolic effects of the mTOR/S6K1 pathway are also related to the production of nucleotides, which are necessary for ribosome biogenesis and cell growth. Indeed, S6K1 is able to phosphorylate carbamoyl-phosphate synthase, aspartate carbamoyltransferase, and dihydroorotase (CAD) on S1859, an enzyme that participates in the early stages of pyrimidine synthesis pathway (Ben-Sahra et al. 2013).

Signal Transduction

Akt, a protein that regulates many processes including metabolism, proliferation, cell survival, growth, and angiogenesis, is upstream to the mTOR/S6K pathway (Fig. 1; Magnuson et al. 2011). It has been reported that S6K2 presents a positive feedback regulation on Akt (Sridharan and Basu 2011). Another protein, B-Raf, involved in the transduction of mitogenic signals from the cell membrane to the nucleus, forms a complex with S6K2 and protein kinase C epsilon (PKCɛ), mediating the activation of S6K2, but not S6K1, by FGF-2 (Pardo et al. 2006). Finally, it has been shown that activation of Erk is able to activate mTOR by inhibiting the TSC1/2 complex (Ma et al. 2005).

Cell Proliferation

One of the involvements of S6Ks in cell proliferation can be highlighted by the interaction of S6K2 with hnRNPF, a protein involved in the splicing process. It has been reported that S6K2, mTOR, and hnRNPF form a complex that is predominantly nuclear and regulates cell proliferation (Goh et al. 2010).

Protein Synthesis

It is largely reported that S6Ks participate in protein synthesis by their interaction with the ribosomal protein S6, considered the main target of S6Ks (Tavares et al. 2015). S6Ks also interact with programmed cell death protein 4 (PDCD4), a protein that inhibits translation initiation and plays a role in apoptosis. The interaction seems to inhibit PDCD4 leading to its ubiquitination and thus increased translation (Carayol et al. 2008). Besides, it has been described that both S6Ks phosphorylate eukaryotic translation initiation factor 4B (eIF4B), a protein required for the binding of the 40S ribosome subunit to the mRNA 5′ cap. eIF4B phosphorylation by S6Ks increases its interaction with eukaryotic translation initiation factor 3 (eIF3), promoting protein synthesis (Jastrzebski et al. 2007; Raught et al. 2004).

S6K1 also binds and inhibits fragile X mental retardation protein (FMRP), a protein that participates in the development of synapses between neurons and associates to several mRNAs, repressing their translation (Narayanan et al. 2008). Finally, S6K1 inhibits eukaryotic elongation factor 2 kinase (eEF2K), a threonine kinase that diminishes protein synthesis (Wang et al. 2001).

Transcription

S6K1 involvement in transcription is based on its interaction with transcription factors. The relationships between S6K1 and cAMP-responsive element modulator (CREM), a transcriptional regulator that binds to the cAMP response element (CRE), and S6K1 and ERα (estrogen receptor α), a nuclear hormone receptor involved in the regulation of eukaryotic gene expression, have been described (Degroot et al. 1994; Yamnik et al. 2009). S6K1 also interacts with the signaling adaptor STING, forming a complex that is necessary for the activation of the transcription factor IRF3, a protein involved in immunity (Wang et al. 2016).

S6K2 also has interacting partners involved in transcription. Yin Yang 1 (YY1), a multifunctional transcription factor that exhibits positive and negative control on a large number of genes, binds to S6K2 forming a complex that is mediated by the mTOR pathway (Ismail et al. 2013). Besides, S6K2 interacts with the transcription factor RAR-related orphan receptor gamma (RORγ), which is important for Th17 cells differentiation (McGuire et al. 2014). Finally, S6K2 is able to phosphorylate histone H3 on T45, modulating transcription (Ismail et al. 2014).

Cytoskeleton

It has been reported that S6K1 interacts directly with F-actin (Ip et al. 2011), participating in the cytoskeleton organization. S6K1 also activates Rac1 (Ras-related C3 botulinum toxin substrate 1) and Cdc42 (CDC42 small effector protein 1), two GTPases from the Rho family involved in the regulation of cytoskeleton reorganization, playing a role in the migration of ovarian cancer cells (Ip et al. 2011).

S6Ks in Diseases

Studies have demonstrated the participation of the mTOR/S6K1 axis in the aging process and age-associated disorders. The mTOR pathway inhibition by rapamycin has been demonstrated to increase the life span of mice (Roizen 2010). Additionally, increased S6K1 activity has been associated with endothelial cells senescence due to increased superoxide production by mitochondria, uncoupling endothelial nitric oxide synthase (eNOS), and reducing nitric oxide (NO) levels (Rajapakse et al. 2011). NO is known to impair the aging process of those cells.

In the central nervous system, multiple lines of evidence point to a potential role of S6Ks in synaptic plasticity and consequently learning and memory. A study indicates the involvement of both S6Ks in those processes, showing deficiencies in synaptic plasticity of S6K1 or S6K2 knockout mice (Antion et al. 2008). In addition, another study has demonstrated an important role of S6K1 in the phosphorylation of FMRP, a protein involved in the fragile X mental retardation syndrome (Narayanan et al. 2008).

The relation between S6Ks, mTOR, and cancer has been widely investigated (Tavares et al. 2015). A study has shown that the overexpression of both S6Ks increases viability, migration, and chemotherapy resistance of prostate cancer cells (Amaral et al. 2016). It has been also demonstrated that 4E-BP1 and S6K2 play an important role in breast cancer development (Karlsson et al. 2013). Besides, as already mentioned, it is known that the short isoform p31-S6K1 is overexpressed in breast cancer cells (Karni et al. 2007). In 2010, PF-4708671, an specific cell-permeable inhibitor of S6K1, but not of S6K2, has been reported, suggesting that it may contribute to the treatment of cancer and others human diseases associated with S6Ks (Pearce et al. 2010).

Summary

Over the past 30 years, several studies have contributed to a better understanding of the mTOR/S6Ks signaling pathway. However, many questions remain unclear, such as how do post translational modifications regulate S6Ks activity? Despite the high similarity between S6K isoforms, S6K1 still remains the most studied isoform, while literature has limited information about S6K2. Understanding how these isoforms act in different biological processes and what are their protein targets may clarify the specific involvement of S6K1 or S6K2 in human diseases, such as cancer, diabetes, obesity, and neurological disorders. Nonetheless, the development of specific inhibitors, as PF-4708671 for S6K1 and a still unknown inhibitor for S6K2, may guide us to a better understanding of this protein family and open the field for therapeutic applications targeting S6Ks.

References

  1. Abe Y, Yoon SO, Kubota K, Mendoza MC, Gygi SP, Blenis J. p90 ribosomal S6 kinase and p70 ribosomal S6 kinase link phosphorylation of the eukaryotic chaperonin containing TCP-1 to growth factor, insulin, and nutrient signaling. J Biol Chem. 2009;284(22):14939–48.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Amaral CL, Freitas LB, Tamura RE, Tavares MR, Pavan ICB, Bajgelman MC, et al. S6Ks isoforms contribute to viability, migration, docetaxel resistance and tumor formation of prostate cancer cells. BMC Cancer. BMC Cancer. 2016;16(1):602.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Antion MD, Merhav M, Hoeffer CA, Reis G, Kozma SC, Thomas G, et al. Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity. Learn Mem. 2008;15(1):29–38.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Banerjee P, Ahmad MF, Grove JR, Kozlosky C, Price DJ, Avruch J. Molecular structure of a major insulin/mitogen-activated 70-kDa S6 protein kinase. Proc Natl Acad Sci U S A. 1990;87(21):8550–4.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Ben-Sahra I, Howell JJ, Asara JM, Manning BD. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science. 2013;339(6125):1323–8.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci U S A. 1998a;95(4):1432–7.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Burnett PE, Blackshaw S, Lai MM, Qureshi IA, Burnett AF, Sabatini DM, et al. Neurabin is a synaptic protein linking p70 S6 kinase and the neuronal cytoskeleton. Proc Natl Acad Sci U S A. 1998b;95(14):8351–6.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Carayol N, Katsoulidis E, Sassano A, Altman JK, Druker BJ, Platanias LC. Suppression of programmed cell death 4 (PDCD4) protein expression by BCR-ABL-regulated engagement of the mTOR/p70 S6 kinase pathway. J Biol Chem. 2008;283(13):8601–10.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Dagon Y, Hur E, Zheng B, Wellenstein K, Cantley LC, Kahn BB. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin’s effect on food intake. Cell Metab. Elsevier Inc.2012;16(1):104–12.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Degroot RP, Ballou LM, Sassonecorsi P. Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to mitogen- induced gene expression 1036. Cell. 1994;79:81–91.CrossRefGoogle Scholar
  11. Deprez J. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J Biol Chem. 1997;272(28):17269–75.PubMedCrossRefGoogle Scholar
  12. Fenton TR, Gwalter J, Ericsson J, Gout IT. Histone acetyltransferases interact with and acetylate p70 ribosomal S6 kinases in vitro and in vivo. Int J Biochem Cell Biol. 2010;42(2):359–66.PubMedCrossRefGoogle Scholar
  13. Ferrari S, Bannwarth W, Morley SJ, Totty NF, Thomas G. Activation of p70s6k is associated with phosphorylation of four clustered sites displaying Ser/Thr-Pro motifs. Proc Natl Acad Sci U S A. 1992;89(15):7282–6.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Goh ETH, Pardo OE, Michael N, Niewiarowski A, Totty N, Volkova D, et al. Involvement of heterogeneous ribonucleoprotein F in the regulation of cell proliferation via the mammalian target of rapamycin/S6 kinase 2 pathway. J Biol Chem. 2010;285(22):17065–76.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ. p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci U S A. 2001;98(17):9666–70.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Ip CKM, Cheung ANY, Ngan HYS, Wong AST. p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells. Oncogene. 2011;30(21):2420–32.PubMedCrossRefGoogle Scholar
  17. Ismail HMS, Myronova O, Tsuchiya Y, Niewiarowski A, Tsaneva I, Gout I. Identification of the general transcription factor Yin Yang 1 as a novel and specific binding partner for S6 Kinase 2. Cell Signal. 2013;25(5):1054–63.PubMedCrossRefGoogle Scholar
  18. Ismail HMS, Hurd PJ, Khalil MIM, Kouzarides T, Bannister A, Gout I. S6 kinase 2 is bound to chromatin-nuclear matrix cellular fractions and is able to phosphorylate Histone H3 at Threonine 45 in vitro and in vivo. J Cell Biochem. 2014;115(6):1048–62.PubMedCrossRefGoogle Scholar
  19. Jastrzebski K, Hannan KM, Tchoubrieva EB, Hannan RD, Pearson RB. Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors. 2007;25(4):209–26.PubMedCrossRefGoogle Scholar
  20. Jones SW, Erikson E, Blenis J, Maller JL, Erikson RL. A Xenopus ribosomal protein S6 kinase has two apparent kinase domains that are each similar to distinct protein kinases. Proc Natl Acad Sci U S A. 1988;85(10):3377–81.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Karlsson E, Perez-Tenorio G, Amin R, Bostner J, Skoog L, Fornander T, et al. The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials. Breast Cancer Res. 2013;15(5):R96.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR. The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol. 2007;14(3):185–93.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Kim K, Pyo S, Um SH. S6 kinase 2 deficiency enhances ketone body production and increases peroxisome proliferator-activated receptor alpha activity in the liver. Hepatology. 2012;55(6):1727–37.PubMedCrossRefGoogle Scholar
  24. Kim SY, Baik K-H, Baek K-H, Chah K-H, Kim KA, Moon G, et al. S6K1 negatively regulates TAK1 activity in the toll-like receptor signaling pathway. Mol Cell Biol. 2014;34(3):510–21.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Lai KP, Leong WF, Chau JFL, Jia D, Zeng L, Liu H, et al. S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response. EMBO J Nat Publ Group. 2010;29(17):2994–3006.Google Scholar
  26. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. 2005;121(2):179–93.PubMedCrossRefGoogle Scholar
  27. Macias MJ, Wiesner S, Sudol M. WW and SH3 domains, two different scaffolds to recognize proline-rich ligands. FEBS Lett. 2002;513(1):30–7.PubMedCrossRefGoogle Scholar
  28. Magnuson B, Ekim B, Fingar DC. Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks. Biochem J. 2011;441(1):1–21.CrossRefGoogle Scholar
  29. McGuire DJ, Rowse AL, Li H, Peng BJ, Sestero CM, Cashman KS, et al. CD5 enhances Th17-cell differentiation by regulating IFN-γ response and RORγt localization. Eur J Immunol. 2014;44(4):1137–42.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Mora A, Komander D, van Aalten DMF, Alessi DR. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Dev Biol. 2004;15(2):161–70.PubMedCrossRefGoogle Scholar
  31. Narayanan U, Nalavadi V, Nakamoto M, Thomas G, Ceman S, Bassell GJ, et al. S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade. J Biol Chem. 2008;283(27):18478–82.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Panasyuk G, Nemazanyy I, Zhyvoloup A, Bretner M, Litchfield DW, Filonenko V, et al. Nuclear export of S6K1 II is regulated by protein kinase CK2 phosphorylation at Ser-17. J Biol Chem. 2006;281(42):31188–201.PubMedCrossRefGoogle Scholar
  33. Panasyuk G, Nemazanyy I, Filonenko V, Gout I. Ribosomal protein S6 kinase 1 interacts with and is ubiquitinated by ubiquitin ligase ROC1. Biochem Biophys Res Commun. 2008;369(2):339–43.PubMedCrossRefGoogle Scholar
  34. Pardo OE, Wellbrock C, Khanzada UK, Aubert M, Arozarena I, Davidson S, et al. FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2. EMBO J. 2006;25(13):3078–88.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Park I-H, Bachmann R, Shirazi H, Chen J. Regulation of ribosomal S6 kinase 2 by mammalian target of rapamycin. J Biol Chem. 2002;277(35):31423–9.PubMedCrossRefGoogle Scholar
  36. Pavan ICB, Yokoo S, Granato DC, Meneguello L, Carnielli CM, Tavares MR, et al. Different interactomes for p70-S6K1 and p54-S6K2 revealed by proteomic analysis. Proteomics. 2016;16(20):2650–66.PubMedCrossRefGoogle Scholar
  37. Pearce LR, Alton GR, Richter DT, Kath JC, Lingardo L, Chapman J, et al. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J. 2010;431(2):245–55.PubMedCrossRefGoogle Scholar
  38. Peterson RT, Desai BN, Hardwick JS, Schreiber SL. Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein. Proc Natl Acad Sci U S A. 1999;96(8):4438–42.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, et al. Phosphorylation and activation of p70s6k by PDK1. Science. 1998;279(5351):707–10.PubMedCrossRefGoogle Scholar
  40. Rajapakse AG, Yepuri G, Carvas JM, Stein S, Matter CM, Scerri I, et al. Hyperactive S6K1 mediates oxidative stress and endothelial dysfunction in aging: inhibition by resveratrol. PLoS One. 2011;6(4):e19237.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Raught B, Peiretti F, Gingras A-C, Livingstone M, Shahbazian D, Mayeur GL, et al. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 2004;23(8):1761–9.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Richardson CJ, Bröenstrup M, Fingar DC, Jülich K, Ballif BA, Gygi S, et al. SKAR is a specific target of S6 kinase 1 in cell growth control. Curr Biol. 2004;14(17):1540–9.PubMedCrossRefGoogle Scholar
  43. Roizen MF. Rapamycin fed late in life extends lifespan in genetically heterogenous mice. Yearb Anesthesiol Pain Manag Nat Publ Group. 2010;2010(7253):15–6.Google Scholar
  44. Rosner M, Hengstschläger M. Nucleocytoplasmic localization of p70 S6K1, but not of its isoforms p85 and p31, is regulated by TSC2/mTOR. Oncogene. 2011;30(44):4509–22.PubMedCrossRefGoogle Scholar
  45. Saitoh M, ten Dijke P, Miyazono K, Ichijo H. Cloning and characterization of p70(S6 K beta) defines a novel family of p70 S6 kinases. Biochem Biophys Res Commun. 1998;253(2):470–6.PubMedCrossRefGoogle Scholar
  46. Sridharan S, Basu A. S6 kinase 2 promotes breast cancer cell survival via Akt. Cancer Res. 2011;71(7):2590–9.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Tavares MR, Pavan ICB, Amaral CL, Meneguello L, Luchessi AD, Simabuco FM. The S6K protein family in health and disease. Life Sci. 2015;131:1–10.PubMedCrossRefGoogle Scholar
  48. Tremblay F, Brûlé S, Hee Um S, Li Y, Masuda K, Roden M, et al. Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance. Proc Natl Acad Sci USA. 2007;104(35):14056–61.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG. Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase. EMBO J. 2001;20(16):4370–9.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Wang M-L, Panasyuk G, Gwalter J, Nemazanyy I, Fenton T, Filonenko V, et al. Regulation of ribosomal protein S6 kinases by ubiquitination. Biochem Biophys Res Commun. 2008;369(2):382–7.PubMedCrossRefGoogle Scholar
  51. Wang F, Alain T, Szretter KJ, Stephenson K, Pol JG, Atherton MJ, et al. S6 K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3. Nat Immunol. 2016;17(5):514–22.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Weng QP, Kozlowski M, Belham C, Zhang A, Comb MJ, Avruch J. Regulation of the p70 S6 kinase by phosphorylation in vivo. Analysis using site-specific anti-phosphopeptide antibodies. J Biol Chem. 1998;273(26):16621–9.PubMedCrossRefGoogle Scholar
  53. Wilson KF, WJ W, Cerione R. Cdc42 stimulates RNA splicing via the S6 kinase and a novel S6 kinase target, the nuclear cap-binding complex. J Biol Chem. 2000;275(48):37307–10.PubMedCrossRefGoogle Scholar
  54. Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK. S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem. 2009;284(10):6361–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Isadora Carolina Betim Pavan
    • 1
  • Fernando Riback Silva
    • 1
  • Ana Paula Morelli
    • 1
  • Fernando Moreira Simabuco
    • 1
  1. 1.Laboratory of Metabolic Disorders, School of Applied SciencesUniversity of CampinasLimeiraBrazil