Antiapoptotic activity of human fibroblast growth factors 1 and 2
The proposal aims to study in detail the anti-apoptotic activity of fibroblast growth factor 1 and 2 (FGF1 and FGF2). Both proteins are powerful mitogens involved in many physiological and pathological processes. They play important role in morphogenesis, differentiation, cell proliferation and migration. FGF1 and FGF2 function through binding to the specific cell surface receptors (FGFRs), possessing tyrosine kinase activity, and induce the activation of downstream signaling pathways, including PLC/PKC, Ras/MAPK and PI3K/Akt cascades.
In contrast to other growth factors, FGF1 and FGF2 are able to cross cell membrane and be translocated into the cytosol and nucleus. The function of translocated FGFs has not been yet described. Our preliminary data and the fact that the stress conditions increase the efficiency of FGF1 and FGF2 translocation indicate a novel intracellular function of these growth factors, completely independent of FGFR tyrosine kinase activity. We suggest that translocated FGF1 and FGF2 provide cell protection against apoptosis induced by various stress factors. Therefore, we hypothesize the existence of two independent anti-apoptotic pathways activated by FGF1 and FGF2, one based on FGFR-dependent signaling and another related to intracellular localization of the growth factors.
Within the project we will perform thorough analysis and characterize both FGF-induced anti-apoptotic routes. We will also evaluate the molecular basis of the differences in the ability to promote cell survival between FGF1 and FGF2. Moreover, we will elucidate consequences of anti-apoptotic activity of FGF1 and FGF2, which might have clinical implications, including induction of chemoresistance in cancer cells.
Project carried out within the Sonata Bis Programme of National Science Centre (2015/18/E/NZ3/00501)
Project duration: 2016-2021
Research team:
Małgorzata Zakrzewska (PhD) – project leader
Katarzyna Służalska (PhD) – post-doc
Agata Lampart (MSc) – PhD student
Martyna Sochacka (MSc) – PhD student
Jakub Szymczyk (MSc) – PhD student
Wiktor Wojsznis (BSc) – student
Dominika Piłat (BSc) – student
Aleksandra Szerszeń (BSc) – student
Publications:
1. Sluzalska KD, Slawski J, Sochacka M, Lampart A, Otlewski J, Zakrzewska M. Intracellular partners of fibroblast growth factors 1 and 2 – implications for functions. Cytokine Growth Factor Rev. 2021;57:93-111. doi: 10.1016/j.cytogfr.2020.05.004
2. Nawrocka D, Krzyscik MA, Opaliński Ł, Zakrzewska M, Otlewski J. Stable Fibroblast Growth Factor 2 Dimers with High Pro-Survival and Mitogenic Potential. Int J Mol Sci. 2020;21(11):4108. doi: 10.3390/ijms21114108
3. Krzyscik MA, Zakrzewska M, Otlewski J. Site-Specific, Stoichiometric-Controlled, PEGylated Conjugates of Fibroblast Growth Factor 2 (FGF2) with Hydrophilic Auristatin Y for Highly Selective Killing of Cancer Cells Overproducing Fibroblast Growth Factor Receptor 1 (FGFR1) Mol Pharm. 2020;17(7):2734-2748. doi: 10.1021/acs.molpharmaceut.0c00419
4. Sochacka M, Opalinski L, Szymczyk J, Zimoch M, Czyrek A, Krowarsch D, Otlewski J, Zakrzewska M. FHF1 is a bona fide fibroblast growth factor that activates cellular signaling in FGFR-dependent manner. Cell Commun Signal. 2020;18(1):69. doi: 10.1186/s12964-020-00573-2
5. Szlachcic, A.; Sochacka, M.; Czyrek, A.; Opalinski, L.; Krowarsch, D.; Otlewski, J.; Zakrzewska, M. Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological Activity. Cells. 2019;8(8):899. doi: 10.3390/cells8080899
6. Kucinska, M.; Porebska, N.; Lampart, A.; Latko, M.; Knapik, A.; Zakrzewska, M.; Otlewski, J. Opalinski, L. Differential regulation of fibroblast growth factor receptor 1 trafficking and function by extracellular galectins. Cell Commun Signal. 2019;17(1):65. doi: 10.1186/s12964-019-0371-1
7. Latko, M.; Czyrek, A.; Porebska, N.; Kucinska, M.; Otlewski, J.; Zakrzewska, M.; Opalinski, L. Cross-Talk between Fibroblast Growth Factor Receptors and Other Cell Surface Proteins. Cells. 2019;8(5):455. doi: 10.3390/cells8050455
8. Zakrzewska, M.; Opalinski, L.; Haugsten, E.M.; Otlewski, J.; Wiedlocha, A. Crosstalk between p38 and Erk 1/2 in Downregulation of FGF1-Induced Signaling. Int J Mol Sci. 2019;20(8):1826. doi: 10.3390/ijms20081826
9. Porebska, N; Latko, M.; Kucinska, M.; Zakrzewska, M.; Otlewski, J.; Opalinski, L. Targeting Cellular Trafficking of Fibroblast Growth Factor Receptors as a Strategy for Selective Cancer Treatment. J Clin Med. 2018;8(1):7. doi: 10.3390/jcm8010007
10. Kostas, M.; Lampart, A.; Bober, J.; Wiedlocha, A.; Tomala, J.; Krowarsch, D.; Otlewski, J.; Zakrzewska M. Translocation of Exogenous FGF1 and FGF2 Protects the Cell against Apoptosis Independently of Receptor Activation. J Mol Biol. 2018;430(21):4087-4101. doi: 10.1016/j.jmb.2018.08.004
11. Opalinski, L.; Szymczyk, J.; Szczepara, M.; Kucinska, M.; Krowarsch, D.; Zakrzewska, M.; Otlewski, J. High Affinity Promotes Internalization of Engineered Antibodies