A Sprouty4 Mutation Identified in Kallmann Syndrome Increases the Inhibitory Potency of the Protein towards FGF and Connected Processes.

Abstract

Kallmann syndrome is the result of innate genetic defects in the fibroblast growth factor (FGF) regulated signaling network causing diminished signal transduction. One of the rare mutations associated with the syndrome alters the Sprouty (Spry)4 protein by converting the serine at position 241 into a tyrosine. In this study, we characterize the tyrosine Spry4 mutant protein in the primary human embryonic lung fibroblasts WI-38 and osteosarcoma-derived cell line U2OS. As demonstrated in a cell signaling assay, Spry4 gains the capability of inhibiting FGF, but not epithelial growth factor (EGF)-induced signaling as a consequence of the tyrosine substitution. Additionally, migration of normal embryonic lung fibroblasts and osteosarcoma-derived cells is potently inhibited by the tyrosine Spry4 variant, while an effect of the wildtype Spry4 protein is hardly measureable. Concerning cell proliferation, the unaltered Spry4 protein is ineffective to influence the WI-38 cells, while the mutated Spry4 protein decelerates the cell doubling. In summary, these data emphasize that like the other mutations associated with Kallmann syndrome the described Spry4 mutation creates a hyperactive version of a selective inhibitory molecule and can thereby contribute to a weakened FGF signaling. Additionally, the study pinpoints a Spry4 variation expanding the applicability of Spry4 in a potential cancer therapy.

• Authors: Astrid Stütz, Anna Z M Kamptner, Hedwig Sutterlüty
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 4 (Feb 21 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33670044 (Publication Type: Journal Article)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Nerve Tissue Proteins
• SPRY4 protein, human
• Fibroblast Growth Factor 2
• Tyrosine
• Epidermal Growth Factor

Topics

• Cell Line
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Epidermal Growth Factor (pharmacology)
• Fibroblast Growth Factor 2 (pharmacology)
• Fibroblasts (drug effects, metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Kallmann Syndrome (genetics)
• Lung (pathology)
• MAP Kinase Signaling System (drug effects)
• Mutation (genetics)
• Nerve Tissue Proteins (genetics)
• Osteosarcoma (pathology)
• Phosphorylation (drug effects)
• Signal Transduction
• Tyrosine (metabolism)