An FGFR4 substitution promotes STAT3 signaling by revealing a membrane-proximal STAT3 binding site.
Major finding: An FGFR4 substitution promotes STAT3 signaling by revealing a membrane-proximal STAT3 binding site.
Mechanism: Variant rs351885-G/A results in a substitution that alters the FGFR4 transmembrane segment.
Impact: STAT3 inhibitors may be effective in patients with cancer who have the germline rs351885-A SNP.
The rs351885-G/A single-nucleotide polymorphism (SNP) results in an amino-acid substitution (p.Gly388Arg) in the transmembrane domain of FGFR4. The Arg388 allele occurs in about 50% of patients with cancer and is associated with a poor prognosis. However, the mechanism by which it promotes tumorigenesis is unknown. To investigate the role of the FGFR4 p.Gly388Arg variant, Ulaganathan and colleagues generated a knock-in mouse with the mouse homolog of the p.Gly388Arg allele (p.Gly385Arg). These mice had no obvious phenotypic defects, but cultured mouse embryonic fibroblasts (MEF) had an increased proliferation rate. Bioinformatics analyses of the FGFR transmembrane domain identified a STAT3 YXXQ binding motif in close proximity to the amino acid substitution, partially overlapping with the transmembrane region. The glycine to arginine substitution exposed this STAT3 binding site, positioning it proximal to the membrane, and resulted in increased STAT3 activity in both mouse and human cells expressing the Arg388 variant. Knock-in MEFs homozygous for the p.Gly385Arg allele exhibited a higher dependency on STAT3 for survival, suggesting addiction to enhanced STAT3 signaling. STAT3 was activated by an FGFR4 Arg388 variant lacking the tyrosine kinase domain, and targeting of STAT3 to the inner plasma membrane was sufficient to increase its activation. Mutations in FGFR4 that moved the STAT3 binding site away from the plasma membrane reduced STAT3 phosphorylation and cell proliferation, suggesting that proximity of the STAT3 binding site to the plasma membrane is essential for its phosphorylation and activity. Consistent with these findings, in mouse models of breast and lung cancer harboring the FGFR4 variant, the Arg385 allele was associated with enhanced STAT3 activity and proliferation. Taken together, these findings demonstrate that the rs351885-G/A SNP results in an FGFR4 p.Gly388Arg substitution that exposes a membrane-proximal STAT3 binding site, thereby promoting STAT3 activation. This result suggests that STAT3 inhibitors may have potential in treating patients with cancer who have the rs351885-G/A SNP.