Spatial organization of FGF receptor 1 by multimeric ligand assemblies
Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinases that together with extracellular fibroblast growth factors (FGFs) transduce signals through the plasma membrane. The FGFRs-FGFs signaling cascades regulate a variety of biological processes, including angiogenesis, embryogenesis, tissue repair and metabolism. Importantly, the aberrant FGFRs-FGFs signaling axis leads to the severe developmental disorders and cancer.
AIM OF THE PROJECT:
The goal of this project is to establish how plasma membrane organization of FGFR1 affects receptor function. By employing different FGFR1 ligands and their configurations in the multimeric ligand assemblies (MLAs), the spatial requirements for FGFR1 activity and internalization will be assessed (Fig. 1). We predict that MLAs will constitute a tool for adjusting FGFR1 activity and thus selective modulation of cell response. FGFR1 dimerization induces FGFR1 internalization. With MLAs we intend to cluster FGFR1 into higher order assemblies to boost receptor endocytosis, which we intend to utilize to enhance selective delivery of cytotoxic drugs into FGFR1 overproducing cancer cells.
Fig. 1. Regulation of FGFR1 oligmeric state and function by natural ligand – FGF1 and multimeric ligand assemblies MLAs designed and prepared in the frame of this project.
RESEARCH TEAM:
Łukasz Opaliński (PhD) – project leader
Natalia Porębska (Msc) – PhD student
Marta Latko (Msc) – PhD student
Marika Kucińska (Bsc) – student
Agata Knapik – volunteer
Project is realized in a collaboration with the group of Prof. Marta Miączyńska from International Institute of Molecular and Cell Biology, Warsaw, Poland
The „Spatial organization of FGF receptor 1 by multimeric ligand assemblies (First TEAM/2017-4/38)” project is carried out within the First TEAM programme of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund.
Budget of the project: 1 999 572 PLN
Project duration: 07.2018 – 06.2021
CONTACT:
Łukasz Opaliński (PhD)
Tel. +48 71375 2631
Publications:
- Pozniak M, Porebska N, Krzyscik MA, Sokolowska-Wedzina A, Jastrzebski K, Zakrzewska M, Otlewski J and Opaliński Ł.The cytotoxic conjugate of highly internalizing engineered tetravalent antibody T-Fc for targeting FGFR1-overproducing cancer cells, Molecular Medicine, 2021.
- Porebska N, Pozniak M, Krzyscik MA, Knapik A, Czyrek A, Kucinska M, Jastrzebski K, Zakrzewska M, Otlewski J and Opaliński Ł.Dissecting biological activities of fibroblast growth factor receptors by coiled-coil-mediated oligomerization of FGF1, International Journal of Biological Macromolecules, 2021.
- Krzyscik M, Sokolowska-Wedzina A, Jendryczko K, Pozniak M, Nawrocka D, Porebska N, Zakrzewska M, Otlewski J, Szlachcic A, Opaliński Ł,Preparation of site-specific cytotoxic protein conjugates via maleimide-thiol chemistryandsortase A-mediated ligation, Journal of Visualized Experiments, 2021.
- Jendryczko K, Chudzian J, Skinder N, Opaliński Ł, Rzeszótko J, Wiedlocha A, Otlewski J, Szlachcic A, FGF2-Derived PeptibodyF2-MMAE Conjugate for Targeted Delivery of Cytotoxic Drugs into Cancer Cells Overexpressing FGFR1, Cancers, 2020.
- Pozniak M, Sokolowska-Wedzina A, Jastrzebski K, Szymczyk J, Porebska N, Krzyscik MA, Zakrzewska M, Miaczynska M, Otlewski J, Opaliński Ł, FGFR1 clustering with engineered tetravalent antibody improves the efficiency and modifies the mechanism of receptor internalization, Molecular Oncology, 2020.
- Nawrocka D, Krzyscik MA, Opaliński Ł, Zakrzewska M, Otlewski J, Stable fibroblast growth factor 2 dimers with high pro-survival and mitogenic potential, International Journal of Molecular Sciences, 2020.
- Sochacka M, Opaliński Ł, Szymczyk J, Zimoch M, Czyrek A, Krowarsch D, Otlewski J and Zakrzewska M, FHF1 is a bona fide fibroblast growth factor that activates cellular signaling in FGFR-dependent manner,Cell Communication and Signaling, 2020.
- Szlachcic A, Sochacka M, Czyrek A, Opaliński Ł, Krowarsch D, Otlewski J, Zakrzewska M, Low Stability of Integrin-Binding Deficient Mutant of FGF1 Restricts Its Biological Activity,Cells, 2019.
- Krzyscik MA, Opaliński Ł, Otlewski J, Novel Method for Preparation of Site-Specific, Stoichiometric-Controlled Dual Warhead Conjugate of FGF2 via Dimerization Employing Sortase A-Mediated Ligation, Molecular Pharmaceutics, 2019.
- Kucińska M, Porębska N, Lampart N, Latko M, Knapik A, Zakrzewska M, Otlewski J, Opaliński Ł,Differential regulation of fibroblast growth factor receptor 1 trafficking and function by extracellular galectins, Cell Communication and Signaling, 2019.
- Porębska N, Latko M, Kucińska M, Zakrzewska M, Otlewski J, Opaliński Ł, Targeting cellular trafficking of fibroblast growth factor receptors as a strategy for selective cancer treatment, Journal of Clinical Medicine, 2019.
- Latko M, Czyrek A, Porębska N, Kucińska M, Otlewski J, Zakrzewska M, Opaliński Ł, Cross-Talk between Fibroblast Growth Factor Receptors and Other Cell Surface Proteins, Cells, 2019.
- Zakrzewska M, Opaliński Ł, Haugsten EM, Otlewski j, Wiedlocha A, Crosstalk between p38 and Erk 1/2 in Downregulation of FGF1-induced signaling,International Journal of Molecular Sciences, 2019.