Abstract
The initial event upon binding of insulin-like growth factor 1 to the insulin-like growth factor type-I receptor (IGF-1R) is auto-phosphorylation 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.
Footnotes
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This study was supported by grants from the Swedish Cancer Society, the Cancer Society in Stockholm, the Swedish Research Council, the Swedish Children Cancer Society, Ingabritt and Arne Lundberg's Research Foundation, International Union Against Cancer International Cancer Technology Transfer Fellowship, Alex and Eva Wallström's Foundation, and the Karolinska Institute.
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ABBREVIATIONS: IGF-1R, insulin-like growth factor type-I receptor; PPP, picropodophyllin; PI3K, phosphatidyl inositol-3 kinase; siRNA, small interfering RNA; SBS, substrate binding site; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; WT, wild type; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; DN, double negative; IRS, insulin receptor substrate.
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↵1 Current affiliation: Department of Otolaryngology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Received July 11, 2007.
- Accepted December 3, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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