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Development IGF-RI signaling

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Development IGF-RI signaling

IGF-R1 signaling

The insulin-like growth factor system (IGF system) comprises two receptors:Insulin-like growth factor 1 receptor ( IGF-1 receptor ) and IGF-IIR with theirrespective 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 somaticgrowth by promoting cellular proliferation and differentiation. Additionally, it wasshown that signaling through the IGF-1 receptor plays a critical role in cellsurvival and prevention of programmed cell death. In contrast, the IGF-IIR does notappear to be involved in the regulation of apoptosis [1].

Both IGF-1 and IGF-2 exhibit the high-affinity binding to IGF-1receptor. The IGF binding proteins ( IBP ) bind to both IGF-1 andIGF-2 with high-affinity. Their main role is to modulate actions of freeIGF-1 and IGF-2 [2], [1].

IGF-1 receptor is a transmembrane tyrosine kinase receptor that is highlyhomologous to the insulin receptor (IR). Like IR, IGF-1 receptor consists of a2b2heterotetramers held together by disulfide bridges [1]. IGF-1receptor and IR can also form heterodimers.

Binding of IGF-1 and IGF-2 to the cognate IGF-1 receptorstimulates the intrinsic tyrosine kinase activity of this receptor [1].

Upon IGF binding, the tyrosine kinase activity of IGF-1 receptor leadsto the phosphorylation of several substrates, including the insulin receptor substratefamily of proteins (such as Insulin receptor substrate 1 ( IRS-1 )), SHC (Srchomology 2 domain containing) transforming protein 1 ( Shc ) and some others[3], [4].

Once phosphorylated, these docking proteins activate downstream intracellularsignaling through the Phosphatidylinositol 3-kinase ( PI3K ) or Growth factorreceptor-bound protein 2 ( GRB2 )/ Son of sevenless homolog ( SOS )/v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) pathways thatultimately leads to cellular proliferation [3], [4].

Activation of IGF-1 receptor by its ligand also initiates metabolic cascadesthat result in the stimulation of protein synthesis via activation of Ribosomal proteinS6 kinase, 70kDa, polypeptide 1 ( p70 S6 kinase 1 ), glucose uptake, glycogensynthesis, and lipid storage [4].

As mentioned above, IGF-1 and IGF-2 exhibit strong anti-apoptoticactivity. There are three IGF-1 receptor -induced anti-apoptotic pathways. Themain pathway for the antiapoptotic effect stimulated by IGF-1 receptor is thewell-established IRS-1 -mediated pathway that causes activation of PI3K andV-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ), that leads to thephosphorylation of BCL2-associated agonist of cell death ( BAD ) [5].

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 andBcl-2 protective effect and promotes cell death.

In its phosphorylated form, BAD is sequestered in the cytosol by 14-3-3proteins and cannot bind to antiapoptotic proteins of the Bcl-2 family and thereforecannot induce cell death [5].

Another known anti-apoptotic pathway is mediated by 14-3-3 proteins.

Three members of the 14-3-3 family of proteins (Tyrosine3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta, zeta and epsilonpolypeptides ( 14-3-3 beta/alpha, 14-3-3 zeta/delta, and 14-3-3epsilon ) interact with the IGF-1 receptor, after its autophosphorilation, ina variety of cultured cell types [6].

The 14-3-3 proteins have been implicated in the activation of v-raf-1 murineleukemia viral oncogene homolog 1 ( c-Raf-1 ) [7], [8].

IGF-1 signaling leads to activation of c-Raf-1 to promote itstranslocation to the mitochondria, where mitochondrial c-Raf-1 phosphorylatesBAD, causing its dissociation from antiapoptotic proteins (such as Bcl-2and Bcl-XL ) and its release into the cytosol [5], [6].

Additionally, IGF-1 receptor signaling suppresses the Mitogen-activated proteinkinase kinase kinase 5 ( ASK1 (MAP3K5) )-mediated stimulation of JNK/p38 and theinduction of programmed cell death. ASK1 (MAP3K5) forms a complex with IGF-1receptor. IGF-1 receptor specifically phosphorylates and inhibits ASK1(MAP3K5). [4].

IRS proteins, including IRS -3 and IRS-4 however have a negative effect on theanti-apoptotic effects of IGF-1 [9].