Download Gene Section RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide 6)

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Review
RPS6KA6 (Ribosomal Protein S6 Kinase,
90kDa, Polypeptide 6)
Tuoen Liu, Shousong Cao
Department of Internal Medicine, Division of Oncology, Washington University School of Medicine,
St Louis, Missouri, United States (TL), Department of Medicine, Roswell Park Cancer Institute, Elm
and Carlton Streets, Buffalo, New York 14263, United States (SC)
Published in Atlas Database: October 2013
Online updated version : http://AtlasGeneticsOncology.org/Genes/RPS6KA6ID43481chXq21.html
DOI: 10.4267/2042/53645
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2014 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Review on RPS6KA6, with data on DNA/RNA, on
the protein encoded and where the gene is
implicated.
contains 22 exons that span approximately 75 kb of
genomic DNA and are located on cosmids E1, H22
and G9 in a telomeric to centromeric orientation
(Yntema et al, 1999; Dümmler et al., 2005;
Kantojärvi et al., 2011).
Identity
Protein
Other names: PP90RSK4, RSK4
HGNC (Hugo): RPS6KA6
Location: Xq21.1
Note
Human RPS6KA6 gene codes for the protein
RSK4, a serine- threonine kinase with 745 amino
acids, also a member of the 90 kDa ribosomal S6
kinase (RSK) family which includes other three
members RSK1, RSK2 and RSK3 (Yntema et al.,
1999; Dümmler et al., 2005; Anjum and Blenis,
2008; Serra et al., 2013).
Abstract
DNA/RNA
Description
The human RPS6KA6 gene is located at Xq21, and
The basic structure of the RSK4. The RSK4 protein includes two kinases domains: amino-terminal kinase domain (NTKD) and
carboxyl-terminal kinase domain (CTKD), a linker region and amino- and carboxyl-terminal tails. The NTKD is responsible for
substrate phosphorylation and CTKD regulates sutophosphorylation of the RSK4. The two kinase domains are connected by a
linker region which is about 100 amino acids containing essential regulatory domains including hydrophobic and turn motifs,
involved in the activation of NTKD. An ERK-docking motif, known also as the D domain, is located in the carboxyl-terminal tail
(Dümmler et al., 2005; Anjum and Blenis, 2008; Romeo et al., 2012).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
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Liu T, Cao S
The activation of the RSK4 family protein. All RSK family membranes including RSK4 are involved in MAPK pathways and
can be activated by various molecules including growth factors, neurotransmitters, hormones, phorbol esters. First, activation of
cell surface receptors creates docking site for adaptor molecules like growth factor receptor-bound protein-2 (GRB2). GRB2 links
the receptor to the guanine nucleotide-exchange factor son of sevenless (SOS). SOS catalyses GDP release and GTP binding to
the small G-protein Ras. The GTP-bound Ras then binds to the Raf protein kinases. Upon the activation of Raf, it activates
MAPK kinase (MEK), then downstream extracellular signal-regulated kinase (ERK). All four RSK family members are directly
phosphorylated and activated by ERK1/2. RSKs are also phosphorylated by 3'-phosphoinositide-dependent kinase-1 (PDK1)
which is a serine-threonine kinase. Activated RSKs can then phosphorylate their substrates via serine and threonine sites
(Anjum and Blenis, 2008).
Description
Expression
RSK4 is a serine- threonine kinase and there are six
phosphorylation sites in RSK4: Ser232, Thr368,
Ser372, Ser389, Thr581, and Ser742. Upon
activation of the cell surface receptors, ERK first
bound to the ERK-docking motif in the carboxylterminal and phosphorylates Ser372 in the linker
region and Thr581 in the CTKD. Phosphorylation
of Thr581 activates CTK which autophosphorylates
RSK4 at Ser389 in the linker region.
Phosphorylation of Ser389 recruites and activiates
PDK1 which phosphorylates Ser232 in NTKD.
After dissociation of PDK1 from RSK, the Ser386
phosphorylated motif interacts with NTKD and
activates the NTK in synergy with phosphorSer232. The phosphorylation of Ser372 increases
the activity of NTK. Thr368 is phosphorylated by
ERK and Ser742 can be phosphorylated by
activated NTK, which leads to the association of
RSK and ERK, serving as an inhibitory feedback
mechanism to "shut off" the process (Dümmler et
al., 2005). The CTKD activity of RSK1, RSK2 and
RSK4 can be regulated by the irreversible inhibitor,
pyrrolopyrimidine
FMK
(Z-VAD-FMK,
benzyloxycarbonyl-Val-Ala-DL-Aspfluoromethylketone) (Romeo et al., 2012).
RSK4 expression is low in both mouse and human
embryonic and adult tissues compared with other
three RSK family members. RSK4 mRNA was
detected in the brain, cerebellum, heart, kidney and
skeletal muscle, but not in other tissues such as
lung, liver, pancreas and adipose. Specifically,
RSK4 was found to be ubiquitously expressed at a
low level through mouse development, and it is
more highly expressed in specific phases of
embryogenesis such as egg cylinder, gastrula and
organ genesis (Kohn et al., 2003; Lleonart et al.,
2006; Romeo et al., 2012).
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
Localisation
RSK is predominantly located in cytosol, and
contrary to other RSKs, its expression is relatively
low and does not significantly accumulate in the
nucleus after mitogenic stimulation (Dümmler et
al., 2005; Romeo et al., 2012).
Function
Recent studies showed RSK4 can be either
oncogenic or tumor suppressive depending on many
factors, and Cyclin D1 inhibited RSK4 expression
and serum starvation enhanced the inhibition.
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RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide
6)
Liu T, Cao S
RSK4 can induce cellular senescence which is
mediated by p21.
Also, inhibition of RSK4 causes bypass of cellular
senescence induced by stress or oncogene,
suggesting RSK4 inhibition may be an important
factor in facilitating cell transformation. (LópezVicente et al., 2011).
shRNA against RPS6KA6 bypassed p53-dependent
G1 cell cycle arrest and suppressed mRNA
expression of cyclin-dependent kinase inhibitor
p21cip1, suggesting RSK4 is needed for growth
arrest induced by p53 (Berns et al., 2004).
In addition, RSK4 is identified to be an inhibitor of
fibroblast growth factor (FGF)-Ras-ERK signal
transduction. RSK4 plays an inhibitory role during
embryogenesis by suppressing receptor tyrosine
kinase signaling (López-Vicente et al., 2009).
pathway inhibitors may overcome the resistance
mediated by RSK4 in breast cancer (Serra et al.,
2013).
Colon, kidney cancer and melanoma
Note
RSK4 is down-regulated in colon carcinomas, renal
cell
carcinomas
and
colon
adenomas.
Overexpression of RSK4 induced cell arrest and
senescence features in normal fibroblasts and
malignant colon carcinoma cell lines.
In addition, RSK4 is up-regulated in both
replicative and stress-induced senescence and
RSK4 inhibition induces senescence resistance in
colon carcinoma cells, suggesting RSK4 may be a
tumor suppressor gene by regulating senescence
induction and inviting cell proliferation in colon
carcinogenesis and renal cell carcinomas (Myers et
al., 2004).
RSK4 expression causes Sunitinib resistance in
kidney carcinoma and melanoma cells, thus, RSK4
may be a potential resistance marker in Sunitinib
therapy and a potential target for new drug
development to overcome Sunitinib resistance
(Llenaont et al., 2006; Bender and Ullrich, 2012).
Homology
The RSK family members share 73-80% amino
acids similarity to each other and are mostly
different in their amino- and carboxyl-terminal
sequences (Romeo et al., 2012).
Difference from other RSK members whose
activation needs the stimulation by growth factors,
RSK4 can be constitutively activated under serumstarved condition without growth factor.
The constitutive activation is due to constitutive
phosphorylation of Ser232, Ser372 and Ser389
(Dümmler et al., 2005).
PDK1 is required for mitogenic stimulation of
RSK1-3, however, RSK4 does not appear to require
PDK1 to maintain its high basal activity (Romeo et
al., 2012).
Unlike other three family members, RSK4
expression can disrupt mouse mesoderm formation
induced by the FGF-Ras-ERK signaling pathway
(Myers et al., 2004).
Endometrial cancer
Note
RSK4 is frequently hypermethylated in endometrial
cancer and RSK4 methylation is significantly
associated with tumor grade, with higher grade
tumors having lower levels of methylation.
Thus, RSK4 appears to be epigenetically silenced in
endometrial
cancer
as
evidenced
by
hypermethylation (Dewdney et al., 2011).
X-linked mental retardation
Note
RPS6KA6 gene is commonly deleted in complex
X-linked mental retardation patients (Yntema et al.,
1999).
Implicated in
Breast cancer
Autism spectrum disorder
Note
RSK4 is highly expressed and has anti-invasive and
anti-metastatic activities in breast cancer.
Exogenous expression of RSK4 resulted in
decreased breast cancer cell proliferation and
increased accumulation of cells in G0-G1 phase of
the cell cycle, also with enhanced expression
several tumor suppressor genes: retinoblastoma
protein, retinoblastoma-associated 46 kDa protein
(RbAp46), and p21 protein (Thakur et al., 2007;
Thakur et al., 2008). In addition, RSK4 expression
enhances breast cancer cell survival upon
PI3K/mTOR inhibitors treatment through inhibition
of apoptosis and up-regulation of protein
translation. Adding MEK- or RSK-specific
inhibitors can overcome the RSK4 mediated
resistance, thus, combination of RSK and PI3K
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
Note
RPS6KA6 plays a role in brain development and
could be associated with mental retardation.
RSP6KA6 is located in the chromosomal region,
which is commonly deleted in males with mental
retardation.
Its mutation may be associated with autism
spectrum disorders (Kantojärvi et al., 2011).
AIDS
Note
SNP rs5968255, located at human Xq21.1 in a
conserved sequence element near the RPS6KA6
and CYLC1 genes, was identified as a significant
genetic determinant of AIDS progression in HIV
infected women.
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RPS6KA6 (Ribosomal Protein S6 Kinase, 90kDa, Polypeptide
6)
Liu T, Cao S
activities of ribosomal protein S6 kinase 4 in breast cancer
cells. Clin Cancer Res. 2008 Jul 15;14(14):4427-36
However, whether RPS6KA6 gene is functionally
involved in the observed phenotype is not clear
(Siddiqui et al., 2009).
López-Vicente L, Armengol G, Pons B, Coch L, Argelaguet
E, Lleonart M, Hernández-Losa J, de Torres I, Ramon y
Cajal S. Regulation of replicative and stress-induced
senescence by RSK4, which is down-regulated in human
tumors. Clin Cancer Res. 2009 Jul 15;15(14):4546-53
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This article should be referenced as such:
Liu T, Cao S. RPS6KA6 (Ribosomal Protein S6 Kinase,
90kDa, Polypeptide 6). Atlas Genet Cytogenet Oncol
Haematol. 2014; 18(5):330-333.
Thakur A, Sun Y, Bollig A, Wu J, Biliran H, Banerjee S,
Sarkar FH, Liao DJ. Anti-invasive and antimetastatic
Atlas Genet Cytogenet Oncol Haematol. 2014; 18(5)
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