Novel regulators of cell migration
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AbstractCell migration is a multistep process which plays a key role during embryonic development, tissue maintenance and immunological surveillance, but drives also disease progression during cancer. A better and detailed understanding of the molecular processes behind cell migration is therefore necessary to develop targeted therapies against metastatic disease. The work presented in this thesis aimed to gain new insights into mechanisms of normal cell motility and cancer cell migration. Furthermore, a negative-feedback mechanism on activated growth factor receptors controlling cell migration was elucidated. As a starting point, an siRNA screen on normal fibroblasts was performed. Previously not described to have a role in cell migration, the phosphoinositide metabolizing enzymes PI3K class III, PIKfyve and MTMR3 were found to be positive hits. Furthermore, a novel function of their product, PtdIns5P, in cell migration was revealed. In a follow-up study with different cancer cell lines, roles in cancer cell migration and invasion were demonstrated. In the second part of the thesis, a novel negative feedback mechanism in FGF signaling involving the MAPK ERK1 and ERK2 was identified, which also has an impact on cell migration. Altered signaling from FGF receptors is known to be involved in carcinogenesis, since they are regulating a range of biological signals, such as proliferation, survival and migration. Understanding the tight regulation of FGF signaling and its complex signaling cascade has also the potential to contribute to the development of more efficient therapies.
List of papers. Papers I and II are removed from the thesis due to publisher restrictions.
Paper I: Oppelt A, Lobert VH, Haglund K, Mackey AM, Rameh LE, Liestøl K, Schink KO, Pedersen NM, Wenzel EM, Haugsten EM, Brech A, Rusten TE, Stenmark H, Wesche J. (2013) Production of phosphatidylinositol 5- phosphate via PIKfyve and MTMR3 regulates cell migration. EMBO reports 14, 57 - 64. doi:10.1038/embor.2012.183
Paper II: Oppelt A, Haugsten EM, Danielsen HE, Sveen A, Skotheim RI, Wesche J. (2012) Involvement of PIKfyve and MTMR3 in cancer cell migration and invasion. Manuscript.
Paper III: Zakrzewska M, Haugsten EM, Nadratowska-Wesolowska B, Oppelt A, Hausott B, Jin Y, Otlewski J, Wesche J, Wiedlocha A. (2012) ERK-mediated phosphorylation of FGF receptor 1 on Ser777 confers negative feedback on FGF signaling. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signaling (2013) Feb 12;6(262):ra11. doi:10.1126/scisignal.2003087