Translocation of FGF1 and FGF2 to the cytosol and nucleus
Many growth factors and cytokines elicit a variety of responses in target cells and it is not clear how the necessary signals are transmitted. A multitude of bacterial and plant toxins act by transferring an enzymatically active protein into the cytosol. Therefore, translocation of exogenous growth factors into the cytosol and nucleus could be an efficient mode of signal transduction, but it is not generally accepted that growth factors and cytokines enter the cytosol and nucleus. Based on the evidence that fibroblast growth factor 1 (FGF1) and fibroblast growth factor 2 (FGF2) do enter the cell, we are going to characterize the mechanism for translocation of the growth factors into the cell and to elucidate which cellular responses are elicited by this process. We have identified a short amino acid sequence in the C-terminus of FGFR1 that is required for translocation and we are going to identify cellular proteins interacting with this sequence. After appearance in the cytosol, FGF1 is transported to the nucleus where it remains until it becomes phosphorylated and is expelled from the nucleus. We try to identify which proteins are bound to the growth factor in the these two locations. The main approaches is based on the use of the C-terminal tail of the FGFR and FGF1 in a unphosphorylated and in a phosphomimetic state as bites for "fishing" interacting proteins out of a cellular lysate. mass spectrometry. Since FGFs is one of the crucial factor in the development of several major cancer forms, such as breast cancer and prostate cancer, we hope that the results will reveal new possibilities for treatment.
Research supported by PNRF-87-AI-1/07 grant from Norway through the Norwegian Financial Mechanism within the Polish-Norwegian Research Fund.:
Antoni Więdłocha Group
Department of Biochemistry
Institute for Cancer Research
The Norwegian Radium Hospital
Oslo University Hospital
Montebello, 0310 Oslo, Norway
Antoni Więdłocha (Oslo University Hospital) "Rola kompleksu HSP90/CDC37 w utrzymaniu złośliwego fenotypu białaczki KG1" (Feb 25, 2010, University of Wroclaw).
Anna Szlachcic (University of Wroclaw) "FGF-1 conjugates for cancer therapy" (Oct 8, 2010, Oslo Univesrity Hospital).
Antoni Więdłocha (Oslo University Hospital) "Activation and termination of fibroblast growth factor (FGF) induced cellular signaling - role of heat shock response elements" (Nov 3, 2010, Wrocław University).
Małgorzata Zakrzewska (University of Wroclaw) "The role of MAP kinases, Erk1 and 2 in direct downregulation of FGFR1" (Jan 28, 2011, Oslo University Hospital).
„Intracellular life of FGF1” hold in Zakopane in Poland, June 10-13, 2010.
„FGF and FGFR binding partners” hold in Svalbard in Norway, June 5-10, 2011.