Heparin-binding growth factor signaling complex (HBGF signaling complex)

Heparin-binding growth factor (HBGF) signaling complexes, primarily represented by the fibroblast growth factor (FGF) family, are essential ternary assemblies consisting of a growth factor ligand, a transmembrane receptor tyrosine kinase (FGFR), and a heparan sulfate proteoglycan (HSPG) cofactor (Schlessinger et al., 2000, Nature). The HSPG component, often heparin or heparan sulfate, facilitates the dimerization of FGFRs upon ligand binding, which triggers intracellular tyrosine kinase activity and downstream signaling pathways such as MAPK/ERK and PI3K/AKT (Ornitz & Itoh, 2015, Wiley Interdiscip Rev Dev Biol). These complexes play critical roles in physiological processes including embryonic development, angiogenesis, and tissue repair (Belov & Mohammadi, 2013, Cold Spring Harb Perspect Biol). Dysregulation of these signaling complexes, often through gene amplification, mutations, or over-expression of ligands, is a major driver in various malignancies, such as urothelial and cholangiocarcinoma, as well as skeletal disorders (Turner & Grose, 2010, Nat Rev Cancer). Consequently, they are significant therapeutic targets, with several small-molecule kinase inhibitors like erdafitinib and pemigatinib approved to disrupt their activity in oncology (FDA, 2019, Balversa Prescribing Information). Therapeutic management often involves monitoring for class-specific effects like hyperphosphatemia, which results from the role of these complexes in renal phosphate regulation (Dyer et al., 2019, ESMO Open). Future directions include the development of more selective inhibitors and antibody-drug conjugates to minimize off-target toxicities while maximizing efficacy in FGF-driven diseases.

Other names

Fibroblast growth factor signaling complexFGF-FGFR-HSPG complexTernary signaling complexHBGF-FGFR complexHeparin-binding growth factor receptor signaling complex

Drugs targeting these complexes primarily act as ATP-competitive inhibitors of the FGFR tyrosine kinase domain, thereby preventing downstream signaling. Other approaches include monoclonal antibodies that block ligand binding or receptor dimerization, and ligand traps that sequester heparin-binding growth factors to prevent their interaction with cell-surface receptors (Dieci et al., 2013, Cancer Treatment Reviews).