Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction

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Abstract

Extracellular signals activate mitogen-activated protein kinase (MAPK) cascades to execute complex cellular programs, like proliferation, differentiation and apoptosis. In mammalian cells, three MAPK families have been characterized: extracellular signal-regulated kinase (ERK), which is activated by growth factors, peptide hormones and neurotransmitters, and Jun kinase (JNK) and p38 MAPK, which are activated by cellular stress stimulus as well as growth factors. This review describes the family of 90 kDa ribosomal S6 kinases (RSK; also known as p90rsk or MAPK-activated protein kinase-1, MAPKAP-K1), which were among the first substrates of ERK to be discovered and which has proven to be a ubiquitous and versatile mediator of ERK signal transduction. RSK is composed of two functional kinase domains that are activated in a sequential manner by a series of phosphorylations. Recently, a family of RSK-related kinases that are activated by ERK as well as p38 MAPK were discovered and named mitogen- and stress-activated protein kinases (MSK). A number of cellular functions of RSK have been proposed. (1) Regulation of gene expression via association and phosphorylation of transcriptional regulators including c-Fos, estrogen receptor, NFκB/IκBα, cAMP-response element-binding protein (CREB) and CREB-binding protein; (2) RSK is implicated in cell cycle regulation in Xenopus laevis oocytes by inactivation of the Myt1 protein kinase leading to activation of the cyclin-dependent kinase p34cdc2; (3) RSK may regulate protein synthesis by phosphorylation of polyribosomal proteins and glycogen synthase kinase-3; and (4) RSK phosphorylates the Ras GTP/GDP-exchange factor, Sos leading to feedback inhibition of the Ras-ERK pathway.

Introduction

Protein phosphorylation at serine and threonine residues is a major regulatory mechanism utilized by second messenger systems that are coupled to cell surface receptors or induced by cellular perturbations such as stress stimuli and oncogenic transformation. Extracellular signals are transduced by protein kinase cascades leading to a variety of cellular responses including proliferation, differentiation, apoptosis, contraction, secretion and motility. Mitogen-activated protein kinases (MAPK) are ubiquitous kinases involved in signal transduction in eukaryotic organisms (Kyriakis and Avruch, 1996, Robinson and Cobb, 1997, Cohen, 1997, Lewis et al., 1998). This family of kinases is characterized by their activation by MAPK kinases through dual phosphorylation of threonine and tyrosine residues in the activation loop and by their substrate specificity which is proline-directed phosphorylation of serine or threonine. Members of the MAPK family include extracellular signal-regulated kinases (ERK1 and 2), which are activated in response to a large array of extracellular signaling molecules, notably growth factors, via the Ras protooncogene. Jun kinases (JNK) and p38 MAPKs constitute two other families, collectively known as stress-activated protein kinases (SAPK), since they are induced by UV radiation, heat shock, oxidative and osmotic stress or tumor-necrosis factor-α (TNF-α).

Among the substrates of ERK are the family of p90 kDa ribosomal S6 kinases (RSK; also known as p90rsk or mitogen-activated protein kinase-activated protein kinase-1, MAPKAP-K1) (Jones et al., 1988, Sturgill et al., 1988, Alcorta et al., 1989, Zhao et al., 1995). RSK is unique among serine-threonine kinases in that it contains two functional kinase domains: an N-terminal kinase that phosphorylates the substrates of RSK and a C-terminal kinase involved in the activation mechanism of RSK. The RSK isoforms are activated by virtually all extracellular signaling molecules that stimulate the Ras-ERK pathway, i.e. growth factors and cytokines as well as many peptide hormones and neurotransmitters. The substrates of RSK include transcription factors like cAMP response element-binding protein (CREB), the estrogen receptor-α (ERα), IκBα/NFκB and c-Fos (Xing et al., 1996, Ghoda et al., 1997, Schouten et al., 1997, Joel et al., 1998) (Fig. 1). Furthermore, RSK associates with the transcriptional coactivator proteins CREB-binding protein (CBP) and p300 (Nakajima et al., 1996). RSK binds to polyribosomes and phosphorylates several proteins in the ribosomal complex (Angenstein et al., 1998). Finally, RSK has been shown to phosphorylate glycogen synthase kinase-3 (GSK3), the neural cell adhesion molecule, L1 CAM, the Ras GTP/GDP-exchange factor, Sos and the p34cdc2-inhibitory kinase Myt1 (Sutherland et al., 1993b, Wong et al., 1996, Douville and Downward, 1997, Palmer et al., 1998). The diversity of these substrates suggests that RSK is involved in regulation of a wide range of cellular functions. The RSK family of kinases includes three isoforms: RSK1, RSK2 and RSK3 that are encoded by distinct genes and show 75–80% amino acid identity (Jones et al., 1988, Alcorta et al., 1989, Moller et al., 1994, Zhao et al., 1995). While broadly distributed, the three members of the RSK family show variable tissue expression suggesting that they may be involved in different functions in the organism.

Recently, a novel family of RSK-related kinases that include mitogen- and stress-activated protein kinase (MSK) and RSK-B were discovered (Deak et al., 1998, Pierrat et al., 1998, New et al., 1999). These kinases (here referred to as MSK) contain two protein kinase domains in a single polypeptide typical of the RSK family and share ∼90% amino acid sequence identity, but are only 40% identical to RSK. MSK are substrates of ERK, but are also phosphorylated by p38 MAPK and are therefore induced by cellular stress stimuli and TNF-α (Fig. 1). MSK may regulate transcription mediated by CREB, ATF-1 and AP-1.

In the present review, we describe the biochemistry of RSK and MSK, the molecular mechanism involved in regulation of kinase activity and the roles of RSK and MSK in cellular regulation.

Section snippets

Discovery of RSK

RSK was discovered in Xenopus laevis oocytes by Erikson and Maller in 1985 as an intracellular kinase activity that phosphorylated the 40 S ribosomal subunit protein S6 (Erikson and Maller, 1985, Erikson, 1991, Blenis, 1993). The phosphorylation of S6 protein is believed to promote the translation of selected mRNAs important for cell growth (Jefferies et al., 1997). Two ribosomal S6 protein kinases (S6KI and S6KII) with molecular size of 90 kDa were identified by fractionation of cell extracts,

Structure-function relationship of RSK

The three RSK isoforms show the same overall structure with two kinase domains, a linker region and short N-terminal and C-terminal tails (Fig. 2). Moreover, the six known phosphorylation sites are conserved in all isoforms. Both kinase domains show all the structural characteristics of a prototype kinase. The N-terminal kinase belongs to the AGC group of kinases, which include protein kinase A (PKA) and protein kinase C (PKC). Within this group the N-terminal kinase is most closely related to

Role of RSK in signal transduction

Growth factor and cytokine receptors linked to intracellular tyrosine kinases activate three major signaling pathways in the regulation of cell proliferation and differentiation (Superti-Furga and Courtneidge, 1995, Hubbard et al., 1998). These include phosphoinositol 3-kinase (PI3-K) and protein kinase B (PKB) leading to cell survival, p70S6K that stimulates growth-associated protein synthesis and the Ras-ERK pathway involved in cell division or differentiation. Activation of the Ras-ERK

RSK in transcriptional regulation

The activation and nuclear translocation of RSK is concomitant with immediate-early gene expression indicating that RSK may phosphorylate and activate transcription factors (Chen et al., 1992, Chen et al., 1993). Indeed, a number of transcription factors have been identified as substrates of RSK.

The transcription factor CREB is an important regulator of immediate early gene transcription and has been implicated in thymocyte proliferation and apoptosis (Barton et al., 1996) and memory formation (

Other cellular actions of RSK

RSK is likely to regulate cell cycle progression through substrates like CREB, CBP/p300, ERα, IκBα/NFκB, c-Fos, GSK3 and Sos, which have all been implicated in growth control in various cell types. Nevertheless, no data are available that directly link RSK and these proteins with cell cycle regulation. However, a c-Fos mutant with substitutions of serines by glutamates in sites that are phosphorylated by ERK and RSK (to mimic serine phosphorylations) promoted the transformation of rat 208

Activation mechanism of RSK

Despite the fact that RSK was among the first substrates of ERK to be identified (Sturgill et al., 1988) its mechanism of activation is only recently starting to emerge. Unraveling the function of the two kinase domains and multi-site phosphorylations has posed serious obstacles. Purified RSK that had been deactivated by treatment with phosphatase in vitro, could only be partially activated by incubation with active ERK (Sturgill et al., 1988, Chung et al., 1991, Zhao et al., 1996). This

Mutations in RSK2 associated with Coffin–Lowry syndrome

Analysis of the rsk2 gene in Coffin–Lowry patients revealed intragenic deletions, nonsense and splice-site mutations that resulted in absent or truncated, non-functional proteins (Trivier et al., 1996, Merienne et al., 1998, Jacquot et al., 1998). Furthermore, missense mutations resulted in amino acid substitutions that would lead to functional impairment of RSK2. These mutations included G75V, V82F and G431D which are located nearby or within the glycine-rich ATP-binding sites in the

MSK, new relatives of RSK

Recently, three groups have identified two protein kinases that constitute a new sub-family of RSK-related protein kinases (Deak et al., 1998, Pierrat et al., 1998, New et al., 1999). Searching the NCBI EST database for kinases homologous to the N-terminal kinase of RSK1, a full-length and a partial sequence encoding two novel kinases were found that were 75% identical to each other and about 40% identical to RSK1 (Deak et al., 1998). These kinases were activated by growth factors and cellular

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