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Department of Biochemistry and McGill Cancer Center, McGill University, Montréal, Québec, Canada
3To whom correspondence should be addressed. E-mail: nsonen{at}med.mcgill.ca
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONInsulin-like signaling and...Target of rapamycin signaling...Initiation of translation and...LITERATURE CITED |
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KEY WORDS: • rapamycin • target of rapamycin • insulin-like signaling • translational control
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONInsulin-like signaling and...Target of rapamycin signaling...Initiation of translation and...LITERATURE CITED |
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). The control of translation rates in
eukaryotic cells is critical in many biological processes, including
development, cell growth, cell cycle progression and cell death
(2
). The availability and activity of many eukaryotic
translation factors is modulated in response to a great number of
stimuli and stresses. The target of rapamycin proteins
(TOR),4
also known as FK506-binding protein (FKBP12) and
rapamycin-associated protein (FRAP) or rapamycin and FKBP12 target
(RAFT) (3
), in conjunction with signaling through the
phosphoinositide 3-kinase [PI(3)K] pathway, is believed to play a
central role in signaling to components of the translational apparatus
to facilitate mRNA translation initiation and ribosome biogenesis
(3
). Recent studies in model organisms have yielded
important clues about the biological roles that these signals play in
animal development. We will describe below the studies performed on the
fruit fly Drosophila melanogaster, which support and extend
studies conducted in other organisms including yeast and human. |
Insulin-like signaling and control of cell growth |
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TOPABSTRACTINTRODUCTIONInsulin-like signaling and...Target of rapamycin signaling...Initiation of translation and...LITERATURE CITED |
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Insulin and insulin-like peptides.
The Drosophila genome contains seven Drosophila
insulin-like peptides or dilps (4
). These peptides,
which share sequence and structural similarities with mammalian
insulin, are more similar to the latter than to insulin-like growth
factors 1 and 2. Ectopic overexpression of DILP2, which most closely
resembles insulin, results in larger flies because of an increase in
both cell number and size (4
). Furthermore, DILP2
genetically interacts with a mutant in the unique Drosophila
ortholog of the insulin receptor (DInr; see below), and a mutant in a
downstream serine/threonine kinase, dAkt1 (4
–6
), strongly
suggesting that DILP2 acts partly through this signaling cascade.
Insulin receptor.
The Drosophila genome contains a single ortholog of the
insulin receptor (7
, 8
). Most alleles of DInr
are recessive embryonic or larval lethal, but weak heteroallelic
combinations, or homozygous flies for a partial loss-of-function
mutation are viable, although they display severe developmental delay,
small body size and female sterility (4
, 7
, 8
). The small
body size of DInr mutants is caused by a decrease in both
cell number and size. Conversely, ectopic overexpression of DInr
targeted to the developing eye caused an increase in both size and
number of cells in this organ. These effects are cell autonomous
(4
).
Insulin receptor substrates 1–4 (IRS1–4)/chico.
The insulin receptor substrates (IRS) are adaptor proteins that
interact with the activated insulin receptor (Fig. 1
) and allow other signaling molecules [such as PI(3)K] to dock and
signal to downstream effectors. Drosophila chico encodes a
homologue of the mammalian IRS1–4 (5
). Homozygous viable
mutations in chico give rise to flies smaller than their
wild-type counterparts. Similar to the results with
DInr, this is the result of a reduction in both the number
and the size of the cells and is cell autonomous (5
).
Chico mutants interact genetically with both DInr
and Dp110 [the Drosophila catalytic subunit of PI(3)K; see
below], which is consistent with the notion that this signaling
pathway is involved in the cell-autonomous control of cell growth.
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The PI(3)K regulatory and catalytic subunits (p110 and p85 in mammals)
are recruited to the growth factor receptor (or the IRS) to generate
the second messenger phosphatidylinositol 3,4,5-triphosphate
(PIP3), which in turn is bound by downstream
effectors (Fig. 1
; see below). Mutant alleles of the Dp110 and p60 (the
Drosophila homolog of p85) (9
) subunits of
Drosophila PI(3)K are recessive lethal and display severe
larval growth defect phenotypes (10
). In support of a cell
autonomous role for either gene, homozygous cell clones generated by
FLP/FRT-mediated mitotic recombination exhibit a pronounced
decrease in cell size and also cell number (10
). The
ectopic overexpression of wild-type or constitutively active forms
of PI(3)K in Drosophila tissues (11
) as well as
in the mouse heart (12
) results in enlarged organs. Unlike
the upstream components mentioned above, this effect is caused by an
increase in cell size without any increase in cell number
(4
, 10
). Thus, increased PI(3)K signaling is not sufficient
to increase cell proliferation.
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN).
The phosphatase PTEN was first identified as a tumor suppressor gene
located on chromosome 10q23 (13
). PTEN functions to
antagonize PI(3)K by dephosphorylating the 3' position of
PIP3, which results in a down-regulation of
PI(3)K signaling (Fig. 1)
. Consistent with this notion, ectopic
overexpression of PTEN reduces cell size and number
(14
–16
), whereas homozygous mutant cell clones generated
in several different Drosophila tissues exhibit increased
cell size and number.
Phosphoinositide-dependent kinase 1 and 2 (PDK1/2).
The PDK1/2 serine/threonine kinases are targeted to the cell membrane
by an amino-terminal pleckstrin-homology domain, which allows their
binding to PIP3 produced by the PI(3)K
(17
, 18
). PDK1 was originally identified as an upstream
regulatory kinase of Akt/PKB (19
) and more recently was
shown to directly phosphorylate protein S6 kinase (S6K; Fig. 1
)
(17
, 20
). Drosophila PDK1 mutants are recessive
embryonic lethal, with defective cuticule formation. Signaling through
Akt/PKB is implicated in a cell survival-signaling pathway, and
consistent with dPDK1 acting upstream, dPDK1 mutant embryos
display widespread ectopic apoptosis (19
). Furthermore,
ectopic expression of dAkt1 in dPDK1 mutant embryos strongly
suppresses ectopic apoptosis, supporting the role of dPDK1 signaling to
dAkt1. Consistent with its role in insulin-like signaling,
overexpression of dPDK1 in the eyes and wings of flies causes an
increase in cell size (19
). However, it was not determined
whether this also affects cell number.
Akt/PKB.
The serine/threonine kinase Akt/PKB (Fig. 1)
is also recruited to the
cell membrane through an N-terminal pleckstrin-homology domain.
Upon translocation, the kinase becomes activated through additional
phosphorylation by PDK1/2. Similar to dPDK1 zygotic loss of
function mutants, Drosophila Akt1 (dAkt1) mutants
are embryonic lethal, with defective cuticule formation and display
increased ectopic apoptosis (21
). Ectopic overexpression
of dAkt1 in imaginal discs causes a dramatic increase in cell size
(6
). Furthermore, cell clones homozygous for a
dAkt1 mutation (21
) are drastically reduced in
size (6
). However, in striking contrast to
dilp2, Dlnr, chico and
dPTEN, no effect on cell number is observed because of
ectopic dAkt1 expression.
In summary, although reduced insulin-like signaling reduces both
cell size and number, increasing it has a strong effect on cell size,
but only a modest effect on cell number. Therefore, activation of this
pathway may not be sufficient to activate cell division
(22
).
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Target of rapamycin signaling and control of cell growth |
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TOPABSTRACTINTRODUCTIONInsulin-like signaling and...Target of rapamycin signaling...Initiation of translation and...LITERATURE CITED |
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). TOR lies downstream of PI(3)K and Akt/PKB (Fig. 1)
,
but it is not clear that it functions in a linear signaling cascade,
because TOR is a target in a nutrient-sensing signaling pathway
that does not involve PI(3)K and Akt/PKB (Fig. 1)
(3
).
Downstream signaling through TOR is inhibited by the macrolide
rapamycin, which forms a gain-of-function complex with FKBP12 that
interacts with TOR; this results in G1 arrest and
dephosphorylation of two of its targets: ribosomal protein S6K and
eIF4E-binding proteins (4E-BPs; see below). However, many lines of
evidence suggest that the kinase activity of TOR is not affected by
rapamycin (24
, 25
), implying that the drug affects other
aspects of TOR function, such as binding to a phosphatase
(26
). A current model for TOR signaling posits that under
optimal nutritional conditions, TOR transmits a permissive signal to
downstream effectors, which in turn allows for the transmission of the
growth promoting signal elicited by insulin-like signaling. In a
nutrient-deficient environment or in the presence of rapamycin, TOR
transmits no signal and insulin signaling is blunted.
Mutations of Drosophila TOR have recently been described to
exhibit important effects on cell growth and proliferation
(27
, 28
). Homozygous dTOR mutants hatch
normally, but larvae are severely growth delayed. The larvae live for
up to 30 -d, but die without pupating. Consistent with the growth
promoting activity of the insulin-like signaling pathway,
homozygous dTOR mutant cell clones are reduced in size
(27
, 28
). Furthermore, similar to rapamycin-treated
yeast and mammalian cells, cells homozygous for mutant alleles of
dTOR display an altered cell cycle phasing, with an
increased number of cells in the G1 phase
relative to the S and G2 phases
(27
). Mutations in dTOR are epistatic to PI(3)K signaling:
while homozygous dPTEN mutant cell clones display increased growth,
cell clones homozygous for both dPTEN and dTOR mutations are identical
to dTOR mutant cells, indicating that dTOR is necessary for effective
PI(3)K signaling.
In the yeast Saccharomyces cerevisiae, treatment with
rapamycin mimics the effects of starvation and results in the
modulation of the activity of genes involved in a switch from a
nutrient rich to a poor, nitrogen-depleted environment
(29
–35
). In Drosophila, amino acid deprivation
elicits a series of distinctive changes, such as reduction in nucleolar
area (synonymous with reduced ribosome biogenesis), aggregation of
lipid vesicles in the larval fat body and cell-specific cell cycle
arrest (36
). Consistent with these observations, clones of
dTOR mutant cells from the wing imaginal disc display
reduced nucleolar area (27
). dTOR mutant cell
clones in the fat body are phenotypically identical to starved fat body
cells (27
). Finally, mutant clones induced in the larval
endoreplicative tissues, the fat body and the salivary glands, which
undergo successive rounds of DNA replication without concomitant cell
divisions, show the characteristic cell cycle arrest that accompanies
starvation (27
, 28
). Together, these data strongly support
a role for dTOR in nutrient sensing and suggest that under sufficient
nutritional conditions, dTOR transmits a positive growth signal.
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Initiation of translation and effectors of TOR signaling |
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TOPABSTRACTINTRODUCTIONInsulin-like signaling and...Target of rapamycin signaling...Initiation of translation and...LITERATURE CITED |
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). The m7GpppX cap
structure (where X is any nucleotide) is present at the 5' termini of
all nuclear transcribed mRNAs and is responsible for directing the
translational machinery to the 5' of the mRNA. The cap is recognized by
the cap-binding protein eIF4E, a component of the eIF4F complex,
which also contains eukaryotic translation initiation factor 4G (eIF4G)
and the RNA helicase eIF4A (Fig. 2
) (2
, 37
). The eIF4G is a large scaffold protein that
interacts with other components of the translational machinery,
including the ribosome-associated eIF3 and eIF4A
(2
, 38
). Upon binding of eIF4F to the cap, eIF4A, along
with eukaryotic translation initiation factor 4B (eIF4B), a protein
that strongly stimulates the activity of eIF4A, unwinds the inhibitory
secondary structures present in the 5' untranslated region of the mRNA
(Fig. 2)
(2
). Through its interaction with eIF3, eIF4G
recruits the 40S ribosomal subunit to the mRNA. The ribosome is then
thought to scan in a 5' to 3' direction until it reaches an initiation
codon in the proper context (39
, 40
). The initiation
factors then dissociate from the small ribosomal subunit, the 60S
ribosomal subunit joins and protein synthesis begins. The
phosphorylation of an increasing number of proteins involved in the
regulation of translation initiation is modulated by the PI(3)K,
Akt/PKB and TOR-signaling pathway. The best-characterized
substrates are described in detail below.
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The 4E-BPs constitute a family of low-molecular-weight proteins that
interact with eIF4E. Upon binding to eIF4E they prevent its interaction
with the scaffold protein eIF4G and inhibit cap-dependent
translation initiation (Fig. 2)
(3
). Translational
repression by 4E-BP is relieved by the phosphorylation of a set of
serine and threonine residues that causes 4E-BP dissociation from
eIF4E. Phosphorylation of 4E-BP occurs in response to extracellular
stimuli via the PI(3)K, Akt/PKB and TOR-signaling pathway. The
modulation of 4E-BP activity by this pathway is a hierarchical process:
TOR first phosphorylates two threonine residues located N-terminal
to the eIF4E-binding site of 4E-BP (Thr37 and Thr46 in mammalian
4E-BP1) (41
). Phosphorylation of these residues is only
mildly modulated by serum, insulin or rapamycin treatment
(41
). However, they serve as priming sites for the
subsequent phosphorylation of at least two additional sites located
downstream of the 4E-binding site (Ser65 and Thr70 in 4E-BP1)
(42
). The phosphorylation of Ser65 and Thr70 is clearly
dependent on both TOR and PI(3)K signaling, because it is robustly
enhanced upon serum and insulin treatment and is effectively blunted by
rapamycin, wortmannin or LY294002 treatment (42
–45
).
Drosophila contains a single 4E-BP homolog, d4E-BP, whose
binding to deIF4E is modulated by insulin and is sensitive to both
LY294002 and rapamycin (46
). Ectopic overexpression of a
highly active form of d4E-BP causes reduction in cell size and
coexpression of d4E-BP with growth promoting genes on the
PI(3)K-signaling pathway antagonizes their effect on growth
(46
). These results are consistent with d4E-BP being a
downstream effector of both TOR and PI(3)K signaling (Fig. 1)
.
S6K.
The S6Ks (Fig. 1
; there are two human homologues) (47
)
regulate the translation of mRNAs with a 5' terminal oligopyrimidine
tract (5'TOP): a stretch of 4–14 pyrimidines in ribosomal protein
mRNAs and mRNAs coding for components of the translational machinery
(48
). S6K activity is inhibited by PI(3)K inhibitors and
rapamycin (49
). Similar to the regulation of 4E-BPs,
PI(3)K and TOR signaling to S6K can be separated: deletion of an
N-terminal S6K1 sequence confers rapamycin resistance to the
protein, but, nevertheless, it remains sensitive to PI(3)K inhibitors
(50
, 51
).
Phosphorylation of Drosophila S6K (dS6K) is sensitive to
rapamycin treatment (52
, 53
). The dS6K deletion
mutants are viable, but only 25% of expected homozygous mutants hatch,
with a 3-d delay in development (54
). The homozygous
dS6K mutants are severely reduced in size, attributed to a
reduction in cell size. Morphometric analysis of eyes and wings
revealed that they contain the same number of cells as wild-type
flies (54
). Interestingly, ectopic expression of a
constitutively active form of S6K in dTOR hypomorphic
mutants is sufficient to rescue the growth arrest phenotype
(27
). Although the rescued animals are still
smaller than wild-type flies, these data strongly suggest that dS6K
is a major target, acting downstream of dTOR.
Similar to the fly mutants, knockout mice for one of the two S6K genes,
S6K1, are smaller in size and are delayed in growth but do not display
other morphological differences (47
). The insulin
secreting ß-cells of the pancreas are very sensitive to the lack of
S6K1, because S6K1-deficient mice are glucose intolerant because their
ß-cells are reduced in size (but not number), which causes reduced
insulin synthesis (55
). Better understanding of S6K
signaling in mice will be gained once the second S6K isoform, S6K2, is
also deleted.
eIF4B.
The phosphorylation of eIF4B (Figs. 1
and 2)
is stimulated by serum,
insulin and phorbol esters (56
), and it can be
phosphorylated in vitro by a number of kinases, including S6K1
(57
). Interestingly, eIF4B possesses at least one
phosphorylation site that is sensitive to rapamycin and the PI(3)K
inhibitors. Furthermore, eIF4B is a direct target of S6Ks (Raught, B.,
Gingras, A.-C., Peiretti, F. and Hershey, J.W.B., unpublished results).
The Drosophila genome does not contain an eIF4B homolog, but
a homolog of a protein with a similar function, eIF4H
(58
, 59
), is present (CG4429).
eIF4G.
In mammals, there are two eIF4G (Fig. 1
and 2)
homologs, both of which
are phosphoproteins (60
). The phosphorylation of the
eIF4GI homolog on three residues of in the C-terminal hinge region
is modulated by serum or insulin stimulation and is inhibited by the
PI(3)K inhibitors and rapamycin (60
). The function of
phosphorylation is unclear at present, and the identity of the
kinase(s) is unknown. The Drosophila genome contains two
homologs of eIF4G (CG10811 and CG10192) (61
).
There is an important distinction between the effects on growth
elicited by the dilp/DInr/chico and
dPTEN genes versus those of the
Dp110/dAkt1/dS6K genes. Modulation of
signaling by all these proteins has an effect on both cell size and
number. However, increased signaling elicited by dilp, DInr, chico or
dPTEN has a marked effect on both cell size and number, whereas the
effects of Dp110, dAkt1 and dS6K influence primarily cell size. These
results suggest that insulin-like peptides are signaling to
multiple signal transduction pathways to influence organ growth. This
hypothesis is supported by the observation that the IRS1–4 homolog
chico contains binding sites for the Drk/Grb2 adaptor proteins involved
in Ras/MAPK signaling (5
) and that MAPK is activated in
extracts of fly head expressing an activated form of DInr
(4
). Thus, the pathway branches at the level of the
receptor, with the PI(3)K cascade transmitting a growth promoting
signal, and the MAPK pathway is likely transmitting a proliferation
signal (4
).
Recently, the Drosophila homologs of the genes of the
tuberous sclerosis complex, tuberous sclerosis complexes 1 and 2
(Tsc1/2), were described as negative regulators of cell
growth and proliferation (62
, 63
). In mammals, mutations in
either of these genes cause benign tumors that contain giant cells
(62
, 63
). Interestingly, Tsc1 and 2 are epistatic to the
DInr, dPTEN and dAkt, but dS6K is epistatic to Tsc1/2
(62
, 63
). This implies that Tsc1/2 antagonizes growth at a
still to be defined level, between Akt and S6K (Fig. 1)
.
In summary, studies in Drosophila have yielded important results that further our understanding of how cell growth and proliferation are modulated by insulin-like signaling through PI(3)K, Akt/PKB and TOR. Moreover, they established the translational machinery as one of its major targets.
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FOOTNOTES |
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2 Work in the investigator’s laboratory is
supported by grants from the Canadian Institute of Health Research, the
National Cancer Institute of Canada, the Howard Hugues Medical
Institute and the Human Frontier Science Program. M.M. is a recipient
of a Cancer Research Society studentship. N.S. is a Canadian Institute
of Health Research Distinguished Scientist and a Howard Hugues Medical
Institute Scholar.
4 Abbreviations used: 4E-BP, eIF4E binding
protein; eIF, eukaryotic translation initiation factor; FLP/FRT, FLP
recombinase and its target FRT sequence; FKBP12, FK506-binding protein;
FRAP, FKBP12 and rapamycin-associated protein; IRS, insulin
receptor substrate; IRS1–4, insulin receptor substrates 1–4; PDK1/2,
phosphoinositide-dependent kinases 1 and 2; PI(3)K,
phosphoinositide 3-kinase; PIP3, phosphatidylinositol
3,4,5-triphosphate; PKB, protein kinase B; PTEN, phosphatase and tensin
homolog deleted on chromosome 10; S6K, ribosomal protein S6 kinase;
TOR, target of rapamycin; Tsc1/2, tuberous sclerosis complex 1 and 2.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONInsulin-like signaling and...Target of rapamycin signaling...Initiation of translation and...LITERATURE CITED |
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