Signaling by FGF Receptors

There are more than 20 FGFs, and the best studied of these are FGF-1 and FGF-2. The FGFs signal via four FGF RTKs, FGFR-1 to FGFR-4, and variants of these receptors arise by alternative splicing. These receptors have a similar overall structure, with extracellular domains containing two or three immunoglobulin repeats and an alternatively spliced sequence rich in acidic residues and serines, the acidic box. The intracellular domains comprise a juxtamem-

Figure 1 Overview of VEGFR-2 Signaling. Schematic representation of VEGFR-2 illustrating main sites of tyrosine phosphorylation. Shaded boxes in the intracellular portion of the receptor denote the kinase domain. Signaling intermediates, PLCg, Grb2, FAK, and VRAP, known to interact with VEGFR-2, are shown adjacent to the phosphotyrosine residues to which they bind. Arrows indicate downstream pathways reported in endothelial cells to be initiated from signaling molecules recruited to VEGFR-2. VEGFR-2-activated pLCg acts on phosphatidylinositol 4,5-bisphosphate to generate DAG and the Ca++ mobilizing second messenger inositol 1,4,5-trisphosphate (IP3). Increased intracellular Ca++ may also occur via an IP3-independent route.

Figure 1 Overview of VEGFR-2 Signaling. Schematic representation of VEGFR-2 illustrating main sites of tyrosine phosphorylation. Shaded boxes in the intracellular portion of the receptor denote the kinase domain. Signaling intermediates, PLCg, Grb2, FAK, and VRAP, known to interact with VEGFR-2, are shown adjacent to the phosphotyrosine residues to which they bind. Arrows indicate downstream pathways reported in endothelial cells to be initiated from signaling molecules recruited to VEGFR-2. VEGFR-2-activated pLCg acts on phosphatidylinositol 4,5-bisphosphate to generate DAG and the Ca++ mobilizing second messenger inositol 1,4,5-trisphosphate (IP3). Increased intracellular Ca++ may also occur via an IP3-independent route.

brane region, tyrosine kinase domain with kinase insert, and carboxy-terminal tail. In contrast to the VEGFR family, receptors for FGF are expressed by a wide range of cell types. FGFR-1 has been shown clearly to have a role in microvessel formation and maintenance. FGFs stimulate endothelial proliferation, migration, and organization into capillary tubes.

Activation of FGFR-1 results in phosphorylation of the juxtamembrane Y463, Y583/585 in the kinase insert, Y653/654, Y730, and in the carboxy-tail Y766. Several signaling pathways are activated by FGFR-1, including the PI-3K pathway and stimulation of Src family kinases. The best-elucidated pathways are those leading to PKC activation and ERK1/2 stimulation, linking FGFR-1 to endothelial proliferation. Phosphorylation of Y766 is important for both of these pathways. This phosphotyrosine provides a site for recruitment and activation of PLCg, leading to generation of inositol 1,4,5-trisphosphate (IP3) and DAG with subsequent PKC stimulation.

FGFR-1 is linked to the Ras/ERK1/2 pathway and proliferation via a multisubstrate adaptor FRS2. In some studies, this adaptor has been found constitutively associated with the juxtamembrane region of FGFR-1 via the FRS2 PTB domain, although in a phosphotyrosine-independent manner. Activation of FGFR-1 results in markedly increased phosphorylation of FRS2, creating recruitment sites for Grb2 and Shp2. Grb2 is associated with the guanine nucleotide exchange factor SOS that activates Ras, thereby initiating the Raf/ERK1/2 cascade. In endothelial cells, stimulation of FRS2 phosphorylation by FGFR-1 requires the adaptor protein Shb that binds to phosphorylated Y766 in FGFR-1. This adaptor does not interact directly with FRS2 but associates with Shp2, providing an indirect link. Further work will determine the mechanism by which Shb mediates FGFR-1 phosphorylation of FRS2. These signaling events are illustrated in Figure 2. Additional, undefined pathways exist in endothelial cells for FGFR-1 activation of the ERK1/2 pathway.

In several cell types, the adaptor protein Gab1 is recruited to FGFR-1-activated FRS2 via its interaction with the SH3 domain of Grb2. FGFR-activated phosphorylation of Gab1 then creates a binding site for the SH2 domain of the p85 regulatory subunit of PI-3K, resulting in activation of PI-3K and Akt. Although not yet directly demonstrated, it is likely that a similar pathway is responsible for the FGF-activation of PI-3K/Akt in endothelial cells.

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