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Upon ligand engagement, the single-pass transmembrane receptor tyrosine kinases (RTKs) dimerize to transmit qualitatively and quantitatively different intracellular signals that alter the transcriptional landscape and thereby determine the cellular response. The molecular mechanisms underlying these fundamental events are not well understood. Considering recent insights into the structural biology of fibroblast growth factor signaling, we propose a threshold model for RTK signaling specificity in which quantitative differences in the strength/longevity of ligand-induced receptor dimers on the cell surface lead to quantitative differences in the phosphorylation of activation loop (A-loop) tyrosines as well as qualitative differences in the phosphorylation of tyrosines mediating substrate recruitment. In this model, quantitative differences on A-loop tyrosine phosphorylation result in gradations in kinase activation, leading to the generation of intracellular signals of varying amplitude/duration. In contrast, qualitative differences in the pattern of tyrosine phosphorylation on the receptor result in the recruitment/activation of distinct substrates/intracellular pathways. Commensurate with both the dynamics of the intracellular signal and the types of intracellular pathways activated, unique transcriptional signatures are established. Our model provides a framework for engineering clinically useful ligands that can tune receptor dimerization stability so as to bias the cellular transcriptome to achieve a desired cellular output.

Mammalian fibroblast growth factor (FGF) signaling is intricately regulated via selective binding interactions between 18 FGF ligands and four FGF receptors (FGFR1–4), three of which (FGFR1–3) are expressed as either epithelial (“b”) or mesenchymal (“c”) splice isoforms. The FGF7 subfamily, consisting of FGF3, FGF7, FGF10, and FGF22, is unique among FGFs in that its members are secreted exclusively by the mesenchyme, and specifically activate the “b” isoforms of FGFR1 (FGFR1b) and FGFR2 (FGFR2b) present in the overlying epithelium. This unidirectional mesenchyme-to-epithelium signaling contributes to the development of essentially all organs, glands, and limbs. Structural analysis has shown that members of the FGF7 subfamily achieve their restricted specificity for FGFR1b/FGFR2b by engaging in specific contacts with two alternatively spliced loop regions in the immunoglobulin-like domain 3 (D3) of these receptors. Weak basal receptor-binding affinity further constrains the FGF7 subfamily’s specificity for FGFR1b/2b. In this review, we elaborate on the structural determinants of FGF7 subfamily receptor-binding specificity, and discuss how affinity differences among the four members for the heparin sulfate (HS) co-receptor contribute to their disparate biological activities.

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