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S6K is not the only kinase for rpS6 (
Pende et al., 2004
). Indeed, rpS6 can be
phosphorylated by RSK (p90 ribosomal S6 kinase), via the Ras-Raf-MEK-
ERK signaling (
Roux et al., 2007
) (
Fig. 6.3
). Being the substrate of both S6K
and RSK, which are kinases that are known to upregulate protein synthesis,
it was once believed that rpS6 promoted protein translation. It is because
upon stimulation of cells by growth factors, mitogens and/or nutrients, rpS6
phosphorylation was positively correlated to translational activation of a class
of mRNAs having characteristic 5′ terminal oligopyrimidine (TOP) tract,
as both events took place simultaneously. These mRNAs, known as TOP
mRNAs, are responsible for encoding numerous translational apparatus.
Hence, based on the fact that rpS6 is a subunit of ribosome that undergoes
phosphorylation during protein synthesis upregulation, rpS6 was thought
to be responsible for stimulating the translation of TOP mRNAs (
Meyuhas,
2000
). Furthermore, translational activation of TOP mRNAs upon stimula-
tion by mitogens was abolished by rapamycin treatment in some cell lines
seemingly reinforced the above hypothesis (
Hornstein et al., 2001
). This
concept, however, has been challenged by subsequent studies. First, in several
cell lines, only a minor or no suppression of TOP mRNAs translation was
found after rapamycin treatment, regardless of a complete activation block-
age of S6K or its substrate rpS6 by rapamycin (
Tang et al., 2001
). Moreover,
in amino acid starved cells, neither phosphorylation of rpS6 nor activation
of S6K1 was sufficient to stimulate the translation of TOP mRNAs, whereas
overexpression of dominant negative S6K1 which inhibited the activity of
S6K1 and rpS6 phosphorylation failed to cause translational repression of
TOP mRNAs in amino acid refed cells (
Tang et al., 2001
). Besides, even in
dividing lymphoblastoids that S6K1 was active and rpS6 was phosphory-
lated, translation of TOP mRNAs was constitutively repressed (
Stolovich
et al., 2005
). Furthermore, in some cell lines, the relief of translation repres-
sion of TOP mRNAs by LiCl was found to be independent of S6K and
rpS6 (
Stolovich et al., 2005
). Collectively, these studies indicate that rpS6
phosphorylation is
not
indispensable for translational activation of TOP
mRNAs and this possibility was validated by a study demonstrating that
in mice expressing knockin nonphosphorylatable rpS6 (rpS6
p-/-
), normal
TOP mRNAs translation was detected (
Ruvinsky et al., 2005
). In short, it is
increasingly clear that translational activation of TOP mRNAs is not medi-
ated by rpS6 phosphorylation, and there is growing evidence to show that
cell growth and even protein synthesis are not upregulated by phosphory-
lated rpS6, at least not in all mammalian cells. This notion is supported by
studies using conditional rpS6 knockout mice or rpS6
p−/−
mice. It has been
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