RHEB2, 14-3-3 beta/alpha, UDP-D-glucose cytosol, IGF-2, p90Rsk, MEK2 (MAP2K2), c-Myc, IRS-1, PtdIns(3,4,5)P3, PtdIns(4,5)P2, IKK (cat), Erk (MAPK1/3), Hamartin, c-Raf-1, AKT (PKB), PI3K cat class IA, ASK1 (MAP3K5), c-Raf-1, 14-3-3 epsilon, PTEN, 14-3-3 zeta/delta, IGF-1, PI3K reg class IA, p70 S6 kinase1, CREB1, GSK3 alpha/beta, Cyclin D, 220.127.116.11, MEK1 (MAP2K1), Bcl-XL, GRB2, PDK (PDPK1), mTOR, Caspase-9, FOXO3A, Tuberin, 18.104.22.168, Glycogen, I-kB, BAD, 4E-BP1, IGF-1 receptor, H-Ras, IBP, IKK-alpha, GYS1, 22.214.171.124, RPS6, Shc, SOS, NF-kB, Elk-1
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 ( IRS-1 )), 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 14-3-3 proteins.
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 .
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 (MAP3K5). .
IRS proteins, including IRS -3 and IRS-4 however have a negative effect on the anti-apoptotic effects of IGF-1 .