3. Fibroblast Growth Factors: do reverse signals exist?
Fibroblast growth factor (FGF) signaling impacts a number of different cellular functions important for supporting embryonic development. FGF ligands are polypeptide growth factors that bind to cell surface fibroblast growth factor receptors (FGFRs). These receptor ligands trigger tyrosine kinase activity associated with the intracellular domains of their receptors, and thereby activate signaling responses within cells. In early embryos, FGF signaling controls mesoderm induction and patterning, cell growth, migration, and differentiation; while later functions include organ formation and maintenance, neuronal differentiation and survival, wound healing, and malignant transformation. In vertebrates, nevertheless, the system remains quite complex with over 120 FGF-FGFR combinations possible. Studies in Drosophila have yielded valuable insights into the functions of many signaling pathways during development, as this system is amenable to molecular and genetic techniques as well as to live in vivo imaging. Drosophila, with only three FGF-FGFR combinations acting, offers a simpler system to study FGF signaling.
In a recent study, we identified structural features providing this information for one ligand of the FGF family named Pyramus (Pyr) (see Stepanik, Sun et al. Curr Biol 2020). These features control the dynamics of how the Pyramus signal is sent, thereby expanding the range of information that can be transferred from Pyramus to its receptor. One feature, a transmembrane domain, acts to tether the signaling portion of Pyramus to its cell of origin, thereby limiting how far the signal can travel. The second feature, known as a degron, leads to destruction of Pyramus when it is attached, and therefore strongly limits the amount of Pyramus produced until it is removed. This is the first study to identify these structural features in any FGF ligand (22 FGFs are present in humans alone). Importantly, this study demonstrates how these features affect the signaling properties of Pyramus as it is being utilized during development, by providing a local, concentrated signal (via the tether), and a signal that is sent in a precise direction (via the degron) at a precise time, which is especially critical when building complex three-dimensional tissues in an organism.
