Understanding the Mechanism of Insulin and Insulin-Like Growth Factor (IGF) Receptor Activation by IGF-II

Abstract

BackgroundInsulin-like growth factor-II (IGF-II) promotes cell proliferation and survival and plays an important role in normal fetal development and placental function. IGF-II binds both the insulin-like growth factor receptor (IGF-1R) and insulin receptor isoform A (IR-A) with high affinity. Interestingly both IGF-II and the IR-A are often upregulated in cancer and IGF-II acts via both receptors to promote cancer proliferation. There is relatively little known about the mechanism of ligand induced activation of the insulin (IR) and IGF-1R. The recently solved IR structure reveals a folded over dimer with two potential ligand binding pockets arising from residues on each receptor half. Site-directed mutagenesis has mapped receptor residues important for ligand binding to two separate sites within the ligand binding pocket and we have recently shown that the IGFs have two separate binding surfaces which interact with the receptor sites 1 and 2.Methodology/Principal FindingsIn this study we describe a series of partial IGF-1R and IR agonists generated by mutating Glu12 of IGF-II. By comparing receptor binding affinities, abilities to induce negative cooperativity and potencies in receptor activation, we provide evidence that residue Glu12 bridges the two receptor halves leading to receptor activation.Conclusions/SignificanceThis study provides novel insight into the mechanism of receptor binding and activation by IGF-II, which may be important for the future development of inhibitors of its action for the treatment of cancer.

Insulin resistance and cancer: the role of insulin and IGFs

“…ILP signaling, insulin resistance, and cancer treatment ILP targeting as anticancer strategy ILP signaling via the PI3K/Akt/mTOR pathway is a potential therapeutic target for many cancer types, including breast and prostate cancers (Alvino et al 2011, Tzivion et al 2011. Many drug candidates targeting ILPs have entered clinical trials, and ILP targeting appears to be a promising anticancer strategy.…”

“…Notably, IGF1R signaling may confer chemoresistance to various anticancer agents in solid (Ma et al 2008, Alvino et al 2011, Rowinsky et al 2011) and blood cancers (Ashihara et al 2009, Rowinsky et al 2011.…”

“…Several population-based studies revealed a decrease in cancer risk in diabetic patients assuming antidiabetic agents of the biguanide family such as metformin (Pezzino et al 1982, Suissa 2008, Kiri & Mackenzie 2009). On the other hand, a growing body of evidence indicates an association between type 2 diabetes and an increase in risk of developing breast, prostate, colon, endometrial, and ovarian cancers (Alvino et al 2011, Tan et al 2011, Tzivion et al 2011, Mu et al 2012.…”

“…Such functions are evolutionarily conserved (Duckworth et al 1989, Klusza & Deng 2011, and accordingly, the stimulation of IGF1 axis may represent a common medium for both cancer and diabetes pathogenic processes, together with systemic inflammation and the associated increase in cytokine production (Nunez et al 2006, Dool et al 2011, Faria & Almeida 2012, Ferguson et al 2012, Fernandez-Real & Pickup 2012, Gallagher et al 2012. Except for the IGF2 receptor (IGF2R), following ligand binding, the kinase activity of ILP receptors is activated, leading to the phosphorylation of IR substrates in the cell membrane, which in turn i) activates phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), PI3K/Akt/forkhead box O (FoxO), and Ras/MAPK/extracellular signal-related kinase 1/2 (ERK-1/2) pathways, whose important roles in cancer cell growth and carcinogenesis have been reported (Alvino et al 2011, Tzivion et al 2011; and ii) inactivates glycogen synthase kinase 3b (GSK3b), the inhibitor of the oncogenic b-catenin signaling, through PI3K/Akt signaling pathway, resulting in b-catenin signaling activation that has been associated with cancer stemness and chemoresistance (Fleming et al 2008, Ashihara et al 2009; see Fig. 1).…”

Estudo das alterações na expressão gênica dos ependimomas

“…A circulação de IGF está associada a proteínas (IGFBP -insulin growth factor binding proteins) que apresentam expressão específica dependendo do tecido analisado e do estágio de desenvolvimento desse tecido, e com capacidade de inibir a atividade biológica dos IGFs (Clemmons 1997). Seu receptor, IGF2R, uma glicoproteína transmembrana, regula a quantidade de IGF2 circulante e tecidual por transportar IGF2 para dentro da célula e degradá-la, sendo, também, um imprinted gene expresso quase exclusivamente pelo alelo materno (Alvino, Ong et al 2011). IGF2R tem sido considerado um gene supressor de tumor, com descrição em tumores de mama, cerebrais, osteosarcomas, câncer de próstata, hepatocelular e ovário (Brown, Jones et al 2009).…”