Insulin-Like Growth Factor Type-I Receptor-Dependent Phosphorylation of Extracellular Signal-Regulated Kinase 1/2 but not Akt (Protein Kinase B) Can Be Induced by Picropodophyllin

Abstract

The initial event upon binding of insulin-like growth factor 1 to the insulin-like growth factor type-I receptor (IGF-1R) is autophosphorylation of tyrosine residues within the activation loop of the kinase domain followed by phosphorylation of other receptor tyrosine residues and the subsequent activation of the intracellular signaling cascades. We found recently that the cyclolignan picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and phosphatidyl-3 kinase/Akt (protein kinase B) signaling molecules without interfering with the highly homologous insulin receptor. Furthermore, PPP causes regression of tumor grafts and substantially prolongs the survival of animals with systemic tumor disease. It is of interest that we show here that short treatments with PPP activate the intracellular extracellular signal-regulated kinase (ERK) signaling. Our data suggest that PPP induces IGF-1R ubiquitination and in turn activates ERK1/2. The PPP-induced ERK activation requires IGF-1R because PPP is not able to induce ERK phosphorylation in IGF-1R-negative cells or in cells in which the receptor is knocked down by small interfering RNA. Moreover, in the absence of Mdm2, an E3 ligase that has been shown previously to be involved in IGF-1R ubiquitination, the phosphorylation of ERK did not occur. Thus, apart from inhibiting the receptor activity, PPP can induce IGF-1R ubiquitination and stimulate ERK in an Mdm2-dependent manner. This response could contribute to the apoptotic effect of PPP.

β-Arrestin–biased agonism as the central mechanism of action for insulin-like growth factor 1 receptor–targeting antibodies in Ewing’s sarcoma

“…The IGF-1 will activate these functional responses in a balanced manner, whereas a biased agonist (like CP) would favor one response over another (e.g., β-arr1 over kinase). This model accommodating all experimental data described for the IGF-1R targeting antibodies is also fully supported by our previous findings demonstrating that IGF-1R signaling is not exclusively dependent on its kinase activity and can be activated in a biased manner via β-arr1 by IGF-1R inhibitors or by natural biased agonists (39)(40)(41)(42).…”

Identification of c-Cbl as a New Ligase for Insulin-like Growth Factor-I Receptor with Distinct Roles from Mdm2 in Receptor Ubiquitination and Endocytosis

“…The interplay between Mdm2 and c-Cbl in the ubiquitination of IGF-IR may be important in cancer biology and requires further investigation. In addition, the identification and functional characterization of new E3 ligases ubiquitinating growth regulatory molecules are important because therapeutic targeting of substrate-specific E3 ligases is likely to represent a new strategy in cancer treatment (39)(40)(41).…”

Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor

“…This model is validated by studies demonstrating that IGF-1R signaling could be activated in a "biased manner" via β-arr by IGF-1R inhibitors as well as by natural "biased" agonists (17,18). By searching for therapies inhibiting only one type of IGF-1R activity (e.g., kinase activity), many potential drugs that cause alternative downstream effects, the "biasing agonists" have not yet been considered.…”