Germline variant FGFR4  p.G388R exposes a membrane-proximal STAT3 binding site

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• The fibroblast growth factor receptor FGFR4 (CD334) gene harbors a common single-nucleotide polymorphism, rs351855 (c.1162G>A), resulting in a glycine to arginine substitution (p.Gly388Arg) in the transmembrane domain.
• This variant has been genetically associated with numerous cancers, including bone, breast, colon, prostate, skin, lung, head and neck, soft-tissue sarcomas, and non-Hodgkin lymphoma, but the underlying mechanism remains unclear.

Purpose of the Study:

• To elucidate the molecular mechanism by which the FGFR4 p.Gly388Arg variant contributes to cancer development and progression.
• To investigate the role of this variant in signal transducer and activator of transcription 3 (STAT3) signaling pathways.

Main Methods:

• Analysis of the structural impact of the p.Gly388Arg substitution on the FGFR4 transmembrane domain.
• Investigation of STAT3 binding site exposure and recruitment to the inner cell membrane.
• Validation using Fgfr4 single nucleotide polymorphism knock-in mice and transgenic cancer models (breast and lung).

Main Results:

• The p.Gly388Arg substitution exposes a membrane-proximal cytoplasmic STAT3 binding site (Y(390)-(P)XXQ(393)).
• This motif enhances STAT3 tyrosine phosphorylation by recruiting STAT3 proteins to the inner cell membrane, a phenomenon observed in germline variants.
• In vivo studies in mouse models confirmed enhanced STAT3 signaling driven by the FGFR4 Arg388 variant, correlating with accelerated cancer progression.

Conclusions:

• The study identifies a molecular mechanism linking the common FGFR4 rs351855 variant to accelerated cancer progression through enhanced STAT3 signaling.
• Germline variants in cell-surface molecules that recruit STAT3 to the inner cell membrane represent a significant risk factor for cancer prognosis and disease progression.