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The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor. Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway

Oncogene volume 23, pages 7854–7862 (2004)Cite this article

A Correction to this article was published on 16 December 2022

This article has been updated

Abstract

The insulin-like growth factor-1 receptor (IGF-1R) is crucial for many functions in neoplastic cells, for example, antiapoptosis. Recently, we demonstrated that the cyclolignan PPP efficiently inhibited phosphorylation of IGF-1R without interfering with insulin receptor activity. PPP preferentially reduced phosphorylated Akt, as compared to phosphorylated Erk1/2, and caused apoptosis. Now, we aimed to investigate how PPP inhibits the IGF-1R tyrosine kinase (IGF-1RTK) and the PI3K/Akt apoptotic pathway. Using a baculovirus driven IGF-1RTK we found that PPP interfered with tyrosine phosphorylation in the activation loop of the kinase domain. Specifically, it blocked phosphorylation of tyrosine (Y) 1136, while sparing the two others (Y1131 and Y1135). To explore the impact of inhibition of Y1136 on Akt phosphorylation we transfected P6 cells (overexpressing IGF-1R) and malignant melanoma cells with different IGF-1R mutants, including Y1136F (tyrosine replaced by phenylalanine). Y1136F was found to strongly decrease IGF-1 stimulated phosphorylation of Akt. Conversely, Akt phosphorylation was weakly affected in the Y1131F transfectant. Taken together, our data suggest that the preferential inhibition of phosphorylated Akt, after PPP treatment, may be due to specific inhibition of Y1136. PPP was proven not to interfere directly with Akt or any of its downstream molecules in the apoptotic pathway.

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Acknowledgements

We are greatly indebted to Kristina Garmark for excellent technical assistance and to R Baserga, D LeRoith, WT Miller and S Hubbard for providing us with important reagents and cell lines. Pädraig D'Arcy is thanked for language revision of the manuscript. This study was supported by grants from the Swedish Cancer Society, the Swedish Research Council, the Cancer Society in Stockholm, the Jubilee Fund of King Gustaf V, the Swedish Children Cancer Society and the Karolinska Institute.

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Author notes

  1. Daiana Vasilcanu and Ada Girnita: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology and Pathology, Division of Cellular and Molecular Tumor Pathology, CCK, R8:04, Karolinska Hospital, Stockholm, SE-17176, Sweden

    Daiana Vasilcanu, Ada Girnita, Leonard Girnita, Radu Vasilcanu & Olle Larsson

  2. Department of Clinical Chemistry, Karolinska Hospital, Stockholm, SE-17176, Sweden

    Magnus Axelson

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  1. Daiana Vasilcanu
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Corresponding author

Correspondence to Olle Larsson.

Additional information

The original online version of this article was revised: The authors have become aware of errors in three of the figures (Fig. 1a, Fig. 4c, and Fig. 5a) in this publication. In Fig. 1a, the quality control panel (IGF-1Rb) was incorrectly cropped in the original publication. As a sample quality control was also performed by measuring the protein concentration of each sample, the authors have now chosen to remove this panel. In Fig. 4c, the loading control (Akt) panel for P6 cell line was incorrectly cropped in the original publication. This panel and the corresponding pAkt panel have now been deleted. In Fig. 5a, the loading controls (BAD panels) for BE and R-, detected on the same film were horizontally flipped and swapped through erroneous reverse scanning process. The figure is now corrected. The authors have provided the corrected figures below. These corrections have no impact on the results or conclusions presented in this paper. The authors apologize for the errors, and regret any inconvenience this may have caused for the readers.

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Vasilcanu, D., Girnita, A., Girnita, L. et al. The cyclolignan PPP induces activation loop-specific inhibition of tyrosine phosphorylation of the insulin-like growth factor-1 receptor. Link to the phosphatidyl inositol-3 kinase/Akt apoptotic pathway. Oncogene 23, 7854–7862 (2004). https://doi.org/10.1038/sj.onc.1208065

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