Formation of mesoderm and posterior structures in early Xenopus embryos is dependent on fibroblast growth factor

Signals mediated by fibroblast growth factor (FGF) family members are transduced into target cells by tyrosine kinase transmembrane receptors (FGFRs). The FGFR family includes four distinct receptors, FGFR-1, −2, −3 and -4 which share a common general structure. The extracellular domain contains three immunoglobulin-like domains. The first and the second domains are separated by a stretch of acidic amino acids, the acid box. A single transmembrane region joins the extracellular domain to the cytoplasmic domain, which consists of a tyrosine kinase domain and a short C-terminal tail (Green et al., 1996). Activation of FGFR results from ligand induced dimerization and subsequent autophosphorylation, allowing the recruitment of intracellular signaling molecules. Two major signaling pathways downstream of the FGFR have been identified. One involves the recruitment of phospholipase C-γ (PLC-γ) on a single docking phosphotyrosine located in the C-terminal tail (Mohammadi et al., 1992; Peters et al., 1992). Although with a weaker efficiency for FGFR-4, all four members of the FGFR family can cause PLC-γ phosphorylation (Kanai et al., 1997; Shaoul et al., 1995; Vainikka et al., 1994; Wang et al., 1994). A second transduction pathway leads to the activation of mitogenactivated protein kinase (MAPK) via Ras and Raf. Ras activation results from the recruitment of the Grb2/Sos complex to the intracellular domain of the FGFR via a lipidanchored protein, FRS2/SNT-1 which binds to and is phosphorylated by the activated FGFR (Kouhara et al., 1997; Wang et al., 1996). Grb2 recruitment on the FGFR can also be mediated by the adaptor protein Shc (Kanai et al., 1997; Klint et al., 1995; Vainikka et al., 1994). The signals transduced by the different FGFR share some common characteristics but are not identical. Among the four FGFR, FGFR-4 appears to elicit the most divergent responses. For example, FGFR-1 expression promotes FGF1-dependent growth of BaF3 pro-B cells, but not FGFR-4 expression. These differences are correlated with the observation that FGFR-1 strongly induces MAPK phosphorylation in these cells, whereas FGFR-4 only causes a weak activation of MAPK (Wang et al., 1994). In L6E9 rat myoblasts, stimulation of FGFR-1 or FGFR-2 elicits a strong proliferative response with cells becoming rounded. On the contrary, FGFR-4 signals only poorly enhance proliferation while cells remain flattened. Nevertheless, 2865 Journal of Cell Science 113, 2865-2875 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 JCS1302