Further Development 4.8: Downstream Events of the FGF Signal Transduction Cascade

Cell-to-Cell Communication: Mechanisms of Morphogenesis

Fibroblast growth factors, epidermal growth factors, platelet-derived growth factors, and stem cell factor are all paracrine factors that bind to receptor tyrosine kinase (RTK). Each RTK can bind only one (or one small set) of these ligands, and stable binding requires an additional element, heparan sulfate proteoglycans, or HSPGs (Mohammadi et al. 2005; Bökel and Brand 2013). When RTK-ligand binding occurs, RTK undergoes a conformational change that enables it to dimerize with another RTK. This conformational change stimulates the latent kinase activity of each RTK, and these receptors phosphorylate each other on particular tyrosine residues (see Figure 4.19). Thus, the binding of the paracrine factor to its RTK causes a cascade of autophosphorylation of the cytoplasmic domain of the receptor partners. The phosphorylated tyrosine on the receptor is then recognized by an adaptor protein that serves as a bridge linking the phosphorylated RTK to a powerful intracellular signaling system.

While binding to the phosphorylated RTK through one of the RTK’s cytoplasmic domains, the adaptor protein also activates a G protein, such as Ras. Normally, the G protein is in an inactive, GDP-bound state. The activated receptor stimulates the adaptor protein to activate the GTP exchange factor (GEF; also called guanine nucleotide releasing factor, or GNRP). GEF catalyzes the exchange of GDP with GTP. The GTP-bound G protein is an active form that transmits the signal to the next molecule. After the signal is delivered, the GTP on the G protein is hydrolyzed back into GDP. This catalysis is greatly stimulated by the complexing of the Ras protein with the GTPase-activating protein (GAP). In this way, the G protein is returned to its inactive state, where it can await further signaling. Without the GAP protein, Ras protein cannot efficiently catalyze GTP and so remains in its active configuration for a longer time (Cales et al. 1988; McCormick 1989). Mutations in the RAS gene account for a large proportion of cancerous human tumors (Shih and Weinberg 1982), and the mutations of RAS that make it oncogenic all inhibit the binding of the GAP protein.

The active Ras G protein associates with a kinase called Raf. The G protein recruits the inactive Raf kinase to the cell membrane, where it becomes active (Leevers et al. 1994; Stokoe et al. 1994). Raf kinase activates the MEK protein by phosphorylating it. MEK is itself a kinase, which activates the ERK protein by phosphorylation. In turn, ERK is a kinase that enters the nucleus and phosphorylates certain transcription factors, many of which belong to the Pea3/Etv4 subfamily (Raible and Brand 2001; Firnberg and Neubüser 2002; Brent and Tabin 2004; Willardsen et al. 2014). The end point of the RTK-signaling pathway is the regulation of expression of a variety of different genes, including but not limited to ones involved in the cell cycle.

Literature Cited

Bökel, C. and M. Brand. 2013. Generation and interpretation of FGF morphogen gradients in vertebrates. Curr. Opin. Genet. Dev. 23: 415–422.
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Brent, A. E. and C. J. Tabin. 2004. FGF acts directly on the somitic tendon progenitors through the Ets transcription factors Pea3 and Erm to regulate scleraxis expression. Development 131: 3885–3896.
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Cales, C., J. F. Hancock, C. J. Marshall and A. Hall. 1988. The cytoplasmic protein GAP is implicated as a target for regulation by the ras gene product. Nature 332: 548–551.
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Firnberg, N. and A. Neubüser. 2002. FGF signaling regulates expression of Tbx2, Erm, Pea3, and Pax3 in the early nasal region. Dev. Biol. 247: 237–250.
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Leevers, S. J., H. F. Paterson and C. J. Marshall. 1994. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369: 411–414.
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McCormick, F. 1989. Ras GTPase activating protein: Signal transmitter and signal terminator. Cell 56: 5–8.
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Mohammadi, M., S. K. Olsen and O. A. Ibrahimi. 2005. Structural basis for fibroblast growth factor receptor activation. Cytokine Growth Factor Rev. 16: 107–137.
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Willardsen, M., D. A. Hutcheson, K. B. Moore and M. L. Vetter. 2014. The ETS transcription factor Etv1 mediates FGF signaling to initiate proneural gene expression during Xenopus laevis retinal development. Mech. Dev. 131: 57–67.
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