Mechanism of FGFR3 activation (Source: Nature Communications)
Fibroblast growth factor receptors (FGFRs or FGF receptors) are expressed in the plasma membrane of many key cell types in mammals, and their activity plays a crucial role in the development of bone and tissue. Pathogenic mutations in these receptors disrupt normal receptor activity and are known to be responsible for a wide spectrum of abnormalities and illnesses, from dwarfism to bladder cancer.
“Numerous tyrosine kinase inhibitors are on the market as drugs targeting activity of FGF receptors but such drugs have not shown great success,” says Dr. Sarvenaz Sarabipour, a postdoctoral researcher at Johns Hopkins University. “This is largely due to the fact that the mechanism of action of the receptors remains unknown and attempts across many fields to unravel the receptor-ligand specificity have revealed little information.”
FGF receptors, like other cell surface receptors, sense extracellular clues or growth factors and generate distinct signals, initiating cascades of protein-protein interactions inside a cell. The transmitted signals control all aspects of cell fate and are central to the formation of malignant cells.
Sarabipour—in collaboration with Dr. Kalina Hristova, Marlin U. Zimmerman Jr. Faculty Scholar and professor of materials science and engineering at Johns Hopkins University—has found a direct, significant correlation between structure and activation for FGF receptors in response to FGF ligands. Their findings have been reported in the January 2016 issue of Nature Communications.
Using quantitative imaging on FGF receptors, Sarabipour and Hristova found that the FGF receptors responded distinctly to FGF1 and FGF2 ligands. Their results show that while the receptors interact and activate each other in the absence of ligands, ligand binding induces conformational changes in the receptor structure, which regulates and maximizes FGFR activity. They further found that a pathogenic mutation in FGFR3 responsible for Crouzon syndrome and bladder cancer mimics the FGF2-bound receptor dimer structure ensuring maximum receptor activation and signaling.
“Understanding the mechanism of action of FGFRs and other receptor tyrosine kinases in the absence and presence of their ligands will generate invaluable information for design of new RTK-targeted therapeutics,” says Sarabipour
This work has been funded by grants from the National Institute of Health.