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A Connection between the Microtubule System and ERK activation;Picropodophyllin, an Inhibitor of the IGF-1 receptor, and IGF-1 Destabilize Microtubules and Activate ERK
Stockholm University, Faculty of Science, The Wenner-Gren Institute . (Uno Lindberg Group, Department of Microbiology, Tumor Biology, and Cell Biology, Karolinska Institutet, Stockholm, Sweden)
(English)Manuscript (Other academic)
Abstract [en]

Insulin-like growth factor-1 receptor (IGF-1R) is important for growth and survival of cancer cells, but is not obligatory for growth of normal cells. This has led to attempts to target this receptor to terminate growth of malignant cells. The cyclolignan, picropodophyllin (PPP), has proven useful in inhibiting signalling through the IGF-1R. PPP inhibits IGF-1R autophosphorylation and activation of PI3-kinase/Akt, but it activates ERK in an IGF-1R dependent manner, and causes IGF-1R downregulation. Interestingly, ERK activation and IGF-1R downregulation by IGF-1 and PPP both require ubiquitination of IGF-1R by the E3-ligase Mdm2. In this context, beta-arrestin1 acts as an adapter protein bringing Mdm2 to IGF-1R. How beta-arrestin is recruited to the receptor is unknown. It was recently reported, however, that beta-arrestins bind to microtubules (MT), and that this interaction likely influences signaling via G-protein coupled receptors (GPCRs). This paper reports that the ligand IGF-1 and PPP both have distinct effects on the organization of MT in cultured cells as seen by indirect immunofluorescence, and corroborated by biochemical analysis, demonstrating that IGF-1, as well as PPP, induce MT reorganization and depolymerization. Likely, subsequent association of beta-arrestin1:Mdm2 to the IGF-1R is required for ERK activation, receptor ubiquitination and internalization/downregulation.

Keyword [en]
PPP, tubulin, betA-arrestin, cell cycle regulation, PI3-Kinase, Akt, microfilament system
Research subject
URN: urn:nbn:se:su:diva-27758OAI: diva2:217753
Övriga författare: 10 st. Andra Institutioner: Department of Oncology and Pathology, CCK R8:04, Karolinska Institutet, SE-171 76 Stockholm, Sweden och Department of Clinical Chemistry, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden. Available from: 2009-05-15 Created: 2009-05-15 Last updated: 2010-01-14Bibliographically approved
In thesis
1. Tropomyosin in Normal and Malignant Cells and the Action of Picropodophyllin on the Microfilament and Microtubule Systems
Open this publication in new window or tab >>Tropomyosin in Normal and Malignant Cells and the Action of Picropodophyllin on the Microfilament and Microtubule Systems
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cell motility is a fundamental process, enabling cells to migrate, for instance during embryogenesis, tissue repair and defense. Force is generated by two protein systems, which also participate in cell proliferation, control macromolecular and organelle distribution and determine the fine structure of the cell interior. The major components of these are actin and tubulin, respectively, and they are referred to as the microfilament and the microtubule systems. This thesis focuses on tropomyosin, one of many microfilament associated proteins coupled to actin dynamics and organization and expressed in several isoform variants. Altered distribution and isoform expression of tropomyosin are signatures of malignant cells and are dealt with in the current thesis. The presence of tropomyosin isoforms in protruding lamellipodia of migrating cells is demonstrated, and a method to fractionate tropomyosin depending on its organization in an easily extractable, and a more tightly bound cytoplasmic form is presented. Analysis of the loosely associated tropomyosin fraction by gel filtration chromatography revealed that most of the tropomyosins in this fraction exist in a multimeric form. It was also observed that the distribution of tropomyosin varied between non-transformed and transformed cells with most of the isoforms enriched in the loosely bound fraction in the latter category of cells. Possibly this reflects the extensive reorganization of the microfilament system observed in cancer cells and which, depending on the context, can be normalized by introduction of certain tropomyosin isoforms.

Many anti-cancer drugs target the microtubule system, inhibit cell division and promote apoptosis. Here it is shown that picropodophyllin, which has promising anticancer properties has a destabilizing effect on microtubules and via the microfilament system causes cells to detach from their substratum. Furthermore, picropodophyllin interferes with stimulation of the insulin-like growth factor receptor, which is involved in growth stimulation, differentiation and survival and whose expression is up-regulated in cancer cells.   

Place, publisher, year, edition, pages
Stockholm: The Wenner-Gren Institute, Stockholm University, 2009. 44 p.
Tropomyosin, Actin, Picropodophyllin, Tubulin, Cell motility, Cancer
National Category
Cell and Molecular Biology
Research subject
urn:nbn:se:su:diva-27767 (URN)978-91-7155-895-4 (ISBN)
Public defence
2009-06-17, Sal E306, Arrheniuslaboratorierna, Svante Arrhenius väg 14-18, Stockholm, 09:30 (English)
Available from: 2009-05-27 Created: 2009-05-18 Last updated: 2009-06-04Bibliographically approved

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