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. 2021 Feb 12;10(2):383. doi: 10.3390/cells10020383

Figure 2.

Figure 2

(A) Balanced agonism. Binding of IGF-I to the IGF-IR induces stimulates both the β-arrestin-1 pathway that leads to MAPK activation and proteasome degradation of the IGF-IR through an ubiquitin-mediated mechanism resulting in a loss of the number of IGF-IRs at cellular membrane. IGF-I binding to the IGF-IR also induces phosphorylation of tyrosine residues and this stimulates the kinase pathway which finally activates AKT. (B) β-arrestin-1-biased agonism. Binding of a biased agonist preferentially increases β-arrestin-1 signaling and this simultaneously inhibits the IGF-IR kinase pathway. Thus, β-arrestin-1-biased agonism results in down-regulation of the IGF-IR and inhibition of AKT signaling, but increases MAPK-mediated cell proliferation and growth (Modified from Salisbury & Tomblin. Insulin/Insulin-like growth factors in cancer: new roles for the aryl hydrocarbon receptor, tumor resistance mechanisms, and new blocking strategies [26].