Insulin/IGF signaling pathways

Regulation of Drosophila imaginal disc growth by the insulin/IGF signalling pathway... 

Some mutants of D. melanogaster with extended lifespans have a defective insulin / IGF signaling pathway. The methuselah mutant, whose lifespan is 35% greater than average, appears to involve a G-protein-coupled transmembrane receptor. Mutation of an insulin receptor homolog extends lifespan, apparently by causing a juvenile hormone deficiency. Drosophila lifespan is also lengthened by mutation of a transmembrane dicarboxylate transporter or by overexpression of a protein repair carboxyl methyltransferase (p. 594). ... 

There are several alternative pathways associated with the balance between proliferation and apoptosis that are affected by lycopene treatment, especially the insulin-like growth factor (IGF) signaling pathway. Another is the possibility that lycopene or one of its breakdown products has retinoid activity. Kotake-Nara et al. compared acyclo-retinoic acid, an in vitro oxidation product of lycopene, to four actively researched anticarcinogenic retinoids. Acycloretinoic acid was found to more actively reduce PC-3 and DU-145 cell viabilities (but not LNCaP) through apoptosis in a medium already containing small amounts of natural retinoids. But study concentrations were 20 pM, far above physiologically relevant lycopene concentrations, let alone the smaller concentration of one of its breakdown products. Acycloretinoic acid had a very low affinity for the retinoid X receptors (RXR) and retinoic acid receptors (RAR) receptors (Kotake-Nara et al. 2002). 

Fig. 2. Insulin and IGF-1 receptors. Receptor domains are described on the left and the percentage of homology is indicated. Tyrosine residues undergoing phosphorylation upon receptor activation is also shown. Binding of the ligand to the extracellular a-subunits leads to autophosphorylation of specific tyrosine residues on the intracellular part of the 3-subunits through a transphosphorylation mechanism that results in the activation of their tyrosine kinase domain. This enable the receptor kinase to phosphorylate intermediate docking proteins which subsequently recruit various intracellular proteins. This results in the activation of downstream signaling pathways (Adapted from Lamothe et al., 1998 and Butler et al., 1998).

Barbieri, M., Bonale, M., Franceschi, C., and Paolisso, G. 2003. Insulin/IGF-I-signaling pathway an evolutionarily conserved mechanism of longevity from yeast to humans. Am J Physiol Endocrinol Metab, 285, El064-El 071. 

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