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November 20, 2014
The fibroblast growth factors are a family of proteins known as cell signaling molecules
At top left: After a fibroblast growth factor binds to a cell, it triggers two potential sequences of events. Under typical conditions, it sets off a cascade of chemical reactions that eventually cause cells to divide, and even to differentiate into tissues and organs. In the other, shown in the image at the above left, it’s processed and then marked for eventual disassembly. With this internal breakdown process, the cell achieves a balance—once the cell acquires a critical mass of a fibroblast growth factor, the excess is marked for elimination. The process begins with the fibroblast growth factor (FGF) attaching to a special site, or receptor, on the cell surface, something like the way a key fits into a lock. The receptor changes shape, setting off the reactions that trigger the cell into such actions as dividing or giving rise to an organ or tissue type. At some point, sufficient FGF has bound to receptors on the cell surface. In response, pocket-like structures form on the cell’s surface. The cell surface changes shape—it involutes, like the surface of a water-filled balloon with a finger in it. This sunken-in structure contains many such FGF-receptor pairs. Eventually, this involution pinches off inside the cell, forming a spherical structure known as an endosome. Like a bathysphere ferrying ocean researchers to the sea depths, the endosome conveys the FGF-receptor duplexes deep into the cell. During their journey, the endosomes encounter a protein complex, called Endosomal Sorting Complex Required for Transport II—ESCRT-II, for short. When it’s functioning normally, ESCRT-II processes the endosome, reducing it in size. The details of just how ESCRIT-II processes the endosome aren’t fully understood. Once this processing takes place, the endosome fuses with another cellular body, called a lysosome. The lysosome disassembles the endosome, degrading it and its contents—FGF and its receptor.
At bottom left: The researchers discovered that, in the mouse strain they bred for the study, a mutation in a gene for a key subunit of ESCRT-II impairs the ability of ESCRT-II to do its job. This gene contains the information needed to make vacuolar protein sorting protein 25, or Vps25. The mutant Vps25 protein interferes with ESCRT-II’s ability to do its job. Because the endosomes aren’t sufficiently processed, the lysosomes have trouble breaking them apart. As a result, endosomes accumulate inside the cell. Fewer endosomes form at the cell surface, and FGF-receptor pairs accumulate on the surface because they can’t be removed rapidly enough. This situation creates an imbalance—increasing the amount of FGF bound to receptors on the cell surface. The end result in the mice with the Vps25 mutation is polydactyly.