FGFR4 p.G388R signaling pathway (WP5428)

Homo sapiens

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A germline variant, rs351855-G/A, in FGFR (c.1162G>A, p.Gly388Arg), activates the proximal STAT3 signaling pathway. This germline receptor variant, FGFR p.Gly388Arg, recruits STAT3 to inner cell membranes, resulting in increased levels of STAT3 tyrosine phosphorylation. This heritable variant-specific signaling pathway enhances both tumor-intrinsic proliferation and tumor-extrinsic immune evasion within the tumor microenvironment. The tumor-intrinsic molecular function is driven by elevated levels of tyrosine-phosphorylated STAT3 in tumor cells, promoting cell division and enhancing proliferation. Meanwhile, the tumor-extrinsic molecular function is influenced by increased levels of tyrosine-phosphorylated STAT3 in regulatory T cells and CD8 T cells. This activates the STAT3 signaling pathway predominantly in Tregs and alters the Treg/CD8 T cell ratio in lymphoid organs, thereby limiting immune surveillance within the tumor microenvironment.

Authors

Ulaganathan , Egon Willighagen , and Kristina Hanspers

Activity

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Organisms

Homo sapiens

Communities

Annotations

Pathway Ontology

cancer pathway fibroblast growth factor signaling pathway

Cell Type Ontology

regulatory T cell effector CD8-positive, alpha-beta T cell

Participants
Query Drugst.One

Label Type Compact URI Comment
IL10 GeneProduct ensembl:ENSG00000136634
IL10 Protein uniprot:P22301
STAT3 Protein uniprot:P40763
STAT3 Protein uniprot:P40763
STAT3 Protein uniprot:P40763
CD334 Protein uniprot:P22455
STAT3 Protein uniprot:P40763
CD334 Protein uniprot:P22455
STAT3 Protein uniprot:P40763
STAT3 Protein uniprot:P40763
STAT3 Protein uniprot:P40763
STAT3 Protein uniprot:P40763

References

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  4. Germline variant FGFR4  p.G388R exposes a membrane-proximal STAT3 binding site. Ulaganathan VK, Sperl B, Rapp UR, Ullrich A. Nature. 2015 Dec 24;528(7583):570–4. PubMed Europe PMC Scholia
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