The Fibroblast Growth Factor (FGF) Signaling Complex
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The fibroblast growth factor (FGF) signaling system is a ubiquitous fast-acting cellular sensor of local environmental changes and mediator of cell-to-cell communication with broad roles in cellular homeostasis in development and adult organs. Through the interaction of heparan sulfate (HS) with both activating FGF polypeptides and transmembrane FGF receptor (FGFR) tyrosine kinases, the system is rigorously modulated by the extracellular matrix and tissue architecture. The heparin-binding property reflects the intimate association of the FGF polypeptides with motifs within HS chains of proteoglycans in the extracellular matrix and in the FGFR signaling complex. The HS and FGFR binding domains in FGFs are composed of secondary and tertiary structures formed from distal sequence domains. Functional analysis by site-directed mutagenesis indicates that heparin binding, FGF receptor (FGFR) binding, and biological activity are intimately associated. FGFs elicit activity by activation of an oligomeric complex of transmembrane receptor tyrosine kinases and HS proteoglycans. The intracellular juxtamembrane region is where the most important intracellular signal transmission relay adaptor (FRS2) and tyrosine kinase substrate associates with FGFR. Membrane-bound co-factors klotho and klotho convert the HS-FGFR1 signaling complex that normally responds to tissue FGFs to mediate cellular homeostasis in development and response to injury into an FGF21- and FGF23-controlled mediator of tissue-specific metabolic homeostasis. The role of the FGF family in specific biological systems, the diverse signaling pathways impacted by the FGF signaling system, and the irreconcilable differences in structural models of the FGF signaling complex are explained in this chapter. 2010 Elsevier Inc. All rights reserved.
