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Figure 1.
Simplified description of the insulin/IGF-1 signal transduction (IIS) pathway in invertebrates and mammals. In the invertebrate C.elegans, multiple insulin/IGF-1 like ligands (INS1–38) bind to a single common receptor (DAF-2). After ligand binding, the signal is transduced from the activated receptor, either directly or via the insulin receptor substrate homolog protein-1 (IST-1) to the phosphatidylinositol 3-kinase (PI-3K) AGE-1 (ageing alteration-1)/AAP-1 [9], which converts phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol 3,4,5-trisphosphate (PIP3). Elevated levels of the second messenger PIP3 activate the 3-phosphoinositide dependent protein kinase-1 (PDK1) and the protein kinases B (PKB1-2 also known as AKT1–2), thus leading to the phosphorylation of DAF-16, a homolog of mammalian FoxO family of transcription factors by PKB1–2/AKT1–2. In mammals, three different insulin/IGF-1 receptor ligands are present: insulin, IGF-1 and IGF-2, which can bind to the insulin receptor isoforms A or B (IRA–B) or the IGF-1 receptor (IGF-1R). Upon ligand binding, activated insulin or IGF-1 receptors phosphorylate several intracellular substrates, including IR substrates (IRS1–4) and the Src-homology-2-containing protein (Shc). The phosphorylated substrates provide specific docking sites for intracellular effectors, including the p85 regulatory subunit of PI-3K and Growth-factor-receptor-bound protein-2 (Grb2). PI-3K converts PIP2 in the second messenger PIP3. Elevated levels of the second messenger activate PDK1 and PKB1–3 (also known as AKT1–3), which culminates, amongst others, in the phosphorylation the mammalian FoxO family of transcription factor members Foxo1a, 3a, 4, 6. Grb2 recruits the GDP/GTP exchange factor Son-of-Sevenless (SOS), upon which the small G-protein Ras is converted in its active conformation, leading to the activation of successively the intracellular kinases Raf (part of the family of mitogen activated protein kinase (MAPK) kinase kinases), Mitogen activated protein kinase/Extracellular-signal-regulated-Kinase kinases MEK1–2 (part of the family of MAPK kinases) and Extracellular-signal-Regulated-Kinases ERK1–2 (part of the family of MAPKs), culminating in the activation of transcription, amongst others, via the transcription factor ELK1 (member of ETS oncogene family).
Table 1.
Life span extension in different species with alteration in insulin/IGF-1 signaling
C .elegans | D. melanogaster | M. musculus | Affected IIS component |
|---|
|
|
Prop1df/df↑ |
Prophet of Pit1 |
|
|
Pit1dw/dw↑ |
Pituitary-specific positive transcription factor 1 |
|
|
GHRHRlit/lit↑ |
Growth hormone release hormone receptor |
|
|
GHR−/−↑ |
Growth hormone receptor |
ins-1↓, ins-7↑ |
|
|
Insulin-like ligand |
|
|
Klotho−/−↓ |
Inhibitor of intracellular insulin/IGF-1 signaling (amongst others) |
daf-2↑ |
dInsR↑ |
FIRKO↑
IGF-1R+/−↑♀ |
(fat) insulin receptor
IGF-1 receptor |
|
CHICO↑ |
Irs1−/−↑♀
Irs2+/−↑ or ↔
bIRS2−/−↑bIRS2+/−↑ |
Insulin receptor substrate
(brain) insulin receptor substrate 2 |
|
|
p66Shc−/−↑ |
P66 isoform of the Src-homology-2-domain containing transforming protein |
age-1↑ |
|
|
phosphatidylinositol 3-kinase catalytic subunit |
aap-1↑ |
|
|
phosphatidylinositol 3-kinase regulatory subunit |
daf-18↓ |
dPTEN↓ |
|
phosphatase and tensin homolog PTEN |
pdk-1↑ |
|
|
3-phosphoinositide dependent protein kinase-1 |
pkb-1/pkb-2↑ |
|
|
protein kinases B 1–2 |
daf-16↓ |
|
|
FoxO family of transcription factors |
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Arrows indicate the effects of mutations or RNAi on lifespan:
↑: increased lifespan,
↓: decreased lifespan,
↔: no chance in life span. In some mutants, effects on life span are only observed in the female (♀) sex.
The organization of the IIS pathway in the fruit fly Drosophila melanogaster shows strong similarities to that in C. elegans, and consists of multiple extracellular ligands which bind to a common single transmembrane insulin/IGF-1 tyrosine kinase receptor to induce a cascade of intracellular phosphorylation events, culminating in the phosphorylation and nuclear exclusion of dFOXO [14]. In Drosophila, numerous subtle loss of function mutations have been associated with enhanced lifespan (Table 1), including those in the insulin receptor (InR) [15] and its substrate (CHICO) [16]. Interestingly, the observed effects on longevity were found to be more pronounced in the female sex. Interestingly, foxo null mutant flies were found incapable of adjusting their circadian rhythms under low doses of paraquat and showed an enhanced age-related decline in their ability to maintain circadian rhythms [17].
