The insulin-like growth factor system (IGF system) comprises two receptors:
Insulin-like growth factor 1 receptor (IGF-1 receptor) and
IGF-IIR with their respective ligands: Insulin-like growth factors 1 and 2
(IGF-1 and IGF-2) and six
high-affinity IGF binding proteins (IBP).
The principal processes mediated by the IGF system include stimulation of somatic
growth by promoting cellular proliferation and differentiation. Additionally, it was
shown that signaling through the IGF-1 receptor plays a
critical role in cell survival and prevention of programmed cell death. In contrast, the
IGF-IIR does not appear to be involved in the regulation of apoptosis .
Both IGF-1 and IGF-2 exhibit
the high-affinity binding to IGF-1 receptor. The IGF binding
proteins (IBP) bind to both IGF-1
and IGF-2 with high-affinity. Their main role
is to modulate actions of free IGF-1 and
IGF-2 , .
IGF-1 receptor is a transmembrane tyrosine kinase
receptor that is highly homologous to the insulin receptor (IR). Like IR,
IGF-1 receptor consists of a2b2 heterotetramers held
together by disulfide bridges . IGF-1
receptor and IR can also form heterodimers.
Binding of IGF-1 and IGF-2
to the cognate IGF-1 receptor stimulates the intrinsic
tyrosine kinase activity of this receptor .
Upon IGF binding, the tyrosine kinase activity of
IGF-1 receptor leads to the phosphorylation of
several substrates, including the insulin receptor substrate
family of proteins (such as Insulin receptor substrate 1 and 2
(IRS-1 and IRS-2)), SHC (Src
homology 2 domain containing) transforming protein 1 (Shc)
and some others , , .
Once phosphorylated, these docking proteins activate downstream intracellular
signaling through the Phosphatidylinositol 3-kinase (PI3K)
or Growth factor receptor-bound protein 2 (GRB2)/ Son of
sevenless homolog (SOS)/ v-Ha-ras Harvey rat sarcoma viral
oncogene homolog (H-Ras) pathways that ultimately leads to
cellular proliferation , , .
Activation of IGF-1 receptor by its ligand also initiates
metabolic cascades that result in the stimulation of protein synthesis via activation of
Ribosomal protein S6 kinase, 70kDa, polypeptide 1 (p70 S6 kinase
1), glucose uptake, glycogen synthesis, and lipid storage .
As mentioned above, IGF-1 and
IGF-2 exhibit strong anti-apoptotic activity. There are
three IGF-1 receptor -induced anti-apoptotic pathways. The
main pathway for the antiapoptotic effect stimulated by IGF-1
receptor is the well-established
IRS-1-mediated pathway that causes activation of
PI3K and V-akt murine thymoma viral oncogene homolog 1
(AKT(PKB)), that leads to the phosphorylation of
BCL2-associated agonist of cell death (BAD) .
BAD is known to be a heterodimeric partner for both
BCL2-like 1 (Bcl-XL) and B-cell
CLL/lymphoma 2 (Bcl-2). BAD neutralizes
Bcl-XL and Bcl-2 protective
effect and promotes cell death.
In its phosphorylated form, BAD is sequestered in the
cytosol by 14-3-3 proteins and cannot bind to antiapoptotic
proteins of the Bcl-2 family and therefore cannot induce cell death .
Another known anti-apoptotic pathway is mediated by
Three members of the 14-3-3 family of proteins (Tyrosine
3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta, zeta and epsilon
polypeptides (14-3-3 beta/alpha, 14-3-3
zeta/delta, and 14-3-3 epsilon) interact with
the IGF-1 receptor, after its autophosphorilation, in a
variety of cultured cell types .
The 14-3-3 proteins have been implicated in the
activation of v-raf-1 murine leukemia viral oncogene homolog 1
(c-Raf-1) , .
IGF-1 signaling leads to activation of
c-Raf-1 to promote its translocation to the mitochondria,
where mitochondrial c-Raf-1 phosphorylates
BAD, causing its dissociation from antiapoptotic proteins
(such as Bcl-2 and Bcl-XL) and
its release into the cytosol , .
Additionally, IGF-1 receptor signaling suppresses the
Mitogen-activated protein kinase kinase kinase 5 (ASK1
(MAP3K5))-mediated stimulation of JNK/p38 and the induction of programmed
cell death. ASK1 (MAP3K5) forms a complex with
IGF-1 receptor. IGF-1 receptor
specifically phosphorylates and inhibits ASK1
IRS proteins, including IRS-3 and IRS-4 however have a negative effect on the
anti-apoptotic effects of IGF-1 .
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Control of cell survival by IGF signaling pathways.
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Insulin receptor substrate 2 and Shc play different roles in insulin-like growth factor I signaling.
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IGF-I elicits growth of human intestinal smooth muscle cells by activation of PI3K, PDK-1, and p70S6 kinase.
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14-3-3 binding to the IGF-1 receptor is mediated by serine autophosphorylation.
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14-3-3 proteins are required for maintenance of Raf-1 phosphorylation and kinase activity.
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