Trial lecture - time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Marta Miaczynska, International Institute of Molecular and Cell Biology in Warsaw, Poland
- Second opponent: PhD Espen Stang, Oslo University Hospital
- Third member and chair of the evaluation committee: Professor II Ben Davidson, University of Oslo
Chair of defence
Associate Professor June Helen Myklebust, University of Oslo
Principal Supervisor
Research group leader Antoni Wiedlocha, Oslo University Hospital
Summary
Cells have developed mechanisms to ensure that appropriate signaling is achieved and continued for the proper period of time. Deregulation of receptor signaling can result in diseases, including development of cancer. Among known mechanisms that tightly regulate Fibroblast Growth Factor Receptor (FGFR) signaling are endocytosis, pathway-specific regulatory proteins, phosphatases and negative feedback loops.
In this work we identified novel mechanisms that regulate FGFR signaling. We have found that ERK1/2-mediated phosphorylation of serine 780 in FGFR2 creates a negative feedback loop leading to reduced tyrosine phosphorylation and signaling. We also showed that cells expressing a mutated version of serine 780 migrated faster than cells expressing wild-type FGFR2 suggesting a possible role of serine 780 in cancer progression. Next, performance of APEX2-based proximity labelling assay combined with proteomic analysis led to the identification of the MAPK-specific regulatory protein, SPRED2, as an FGFR1 interactor. Our results indicate multiple roles for SPRED2 in FGFR1 signaling and endocytosis. Using proximity-dependent biotin labeling assay combined with proteomic analysis we also identified the tyrosine phosphatase PTPRG as a regulator of FGFR1 activity. We found that PTPRG is a major phosphatase of FGFR and might have future clinical relevance as a predictor of outcome upon treatment with FGFR inhibitors in patients with FGFR aberrations. All the regulatory mechanisms enable cells to avoid erroneous receptor signaling that can lead to atypical cellular behavior and eventually diseases.
Additional information
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