The lens of a mouse at embryonic day 10.5 expressing two proteins (shown in red and green) that are key to its development. Image Credit: Yingyu Mao (CC BY 4.0)
Cells communicate by releasing proteins that bind to receptors on recipient cells, triggering a cascade of events that alter the cell’s behavior. A family of signaling proteins called fibroblast growth factors (FGFs) is critical for various biological processes, especially during embryonic development. While scientists have a good understanding of how FGFs reach their target cells, less is known about the series of events they activate once they bind to a receptor.
Three adaptor proteins – called Frs2, Shp2 and Grb2 – are essential for propagating the FGF signal. First, the activated receptor binds to and adds phosphate groups to Frs2, which then recruits and facilitates the phosphorylation of Shp2 and Grb2. Here, Wang, Li, Mao et al. offer fresh insights into how this complex of molecules transmit the FGF signal through cells during lens development.
First, the team genetically modified the structure and activity of FGF receptors in mice to see how this impacted the formation of their lenses. They found that the membrane-embedded portion of the receptor, which includes the binding site for Frs2, is critical for regulating the consecutive steps of lens development. However, the initial stages of lens formation could still occur when only the Frs2 binding site was mutated. Loss of Grb2 produced a similar effect, suggesting that Frs2 and Grb2 are particularly important for the later stages of lens development.
Previous studies have suggested that Shp2 acts as a bridge between Frs2 and Grb2. To test this theory, Wang, Li, Mao et al. deleted the two sites in Shp2 that are responsible for binding to Grb2 and stopped phosphorylation interactions between the two adaptors. While these changes affected embryo survival, they had only a modest impact on lens development. Further experiments revealed that another adaptor protein called Shc1 can also mediate Grb2 recruitment and activation, and may be responsible for transmitting the FGF signal later in lens development.
This study provides deeper insights into the network of signaling molecules activated by FGFs, uncovering new mechanisms and adaptors involved in this pathway. The findings suggest that the FGF signaling network is highly adaptable, with different components being required at specific stages of development. Future research expanding on this work may lead to the discovery of therapies that target specific organs affected by FGF-related disorders.
