Received for publication July 12, 2007.
Revised December 3, 2007.
Accepted for publication December 3, 2007.

Insulin-like growth factor type-I receptor (IGF-1R) dependent phosphorylation of ERK1/2 but not Akt (PKB) can be induced by picropodophyllin

Abstract

The initial event upon binding of insulin-like growth factor 1 (IGF-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. Recently, we found that the cyclolignan picropodophyllin (PPP) inhibits phosphorylation of IGF-1R and phosphatidyl-3 kinase (PI3K)/Akt (PKB) 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. Intriguingly, we show here that short treatments with PPP activate the intracellular 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 since PPP is not able to induce ERK phosphorylation in IGF-1R negative cells or in cells in which the receptor is knocked down by siRNA. Moreover, in the absence of Mdm2, an E3 ligase that previously has been shown 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.

Key words: Insulin, MAP Kinase, Mechanisms of cell killing/apoptosis, Membrane targets