FGF homologous factors are secreted from cells to induce FGFR‐mediated anti‐apoptotic response

• Published in: The FASEB journal 2023-07, Vol.37 (7), p.e23043-n/a
• Main Authors: Biadun, Martyna, Sochacka, Martyna, Karelus, Radoslaw, Baran, Karolina, Czyrek, Aleksandra, Otlewski, Jacek, Krowarsch, Daniel, Opalinski, Lukasz, Zakrzewska, Malgorzata
• Format: Article
• Language: English
• Subjects: anti‐apoptotic response; FGF11; FGF12; FGF13; FGF14; FGFs; FHFs; Fibroblast Growth Factors - metabolism; Phosphorylation; Protein Processing, Post-Translational; Receptors, Fibroblast Growth Factor - genetics; Receptors, Fibroblast Growth Factor - metabolism; secretion; Signal Transduction - physiology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202300324R

FGF homologous factors (FHFs) are the least described group of fibroblast growth factors (FGFs). The FHF subfamily consists of four proteins: FGF11, FGF12, FGF13, and FGF14. Until recently, FHFs were thought to be intracellular, non‐signaling molecules, despite sharing structural and sequence similarities with other members of FGF family that can be secreted and activate cell signaling by interacting with surface receptors. Here, we show that despite lacking a canonical signal peptide for secretion, FHFs are exported to the extracellular space. Furthermore, we propose that their secretion mechanism is similar to the unconventional secretion of FGF2. The secreted FHFs are biologically active and trigger signaling in cells expressing FGF receptors (FGFRs). Using recombinant proteins, we demonstrated their direct binding to FGFR1, resulting in the activation of downstream signaling and the internalization of the FHF‐FGFR1 complex. The effect of receptor activation by FHF proteins is an anti‐apoptotic response of the cell. Fibroblast growth factor homologous factors (FHFs) are the least described subfamily of FGF proteins. Until recently, FHFs were thought to be intracellular, non‐signaling molecules. Here, we show for the first time that despite lacking a canonical secretion signal, FHFs are exported to the extracellular space. Furthermore, we propose that their secretion mechanism is similar to that of unconventional secretion of FGF2. Extracellular FHFs are able to bind directly to FGFR, resulting in activation of downstream signaling and an anti‐apoptotic response.