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.
Raskov H, Orhan A, Christensen JP, Gögenur I; ''Cytotoxic CD8(+) T cells in cancer and cancer immunotherapy.''; Br J Cancer, 2021 PubMedEurope PMCScholia
Ulaganathan VK, Ullrich A; ''Membrane-proximal binding of STAT3 revealed by cancer-associated receptor variants.''; Mol Cell Oncol, 2016 PubMedEurope PMCScholia
Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A; ''Interleukin-10 and the interleukin-10 receptor.''; Annu Rev Immunol, 2001 PubMedEurope PMCScholia
Shao H, Xu X, Mastrangelo MA, Jing N, Cook RG, Legge GB, Tweardy DJ; ''Structural requirements for signal transducer and activator of transcription 3 binding to phosphotyrosine ligands containing the YXXQ motif.''; J Biol Chem, 2004 PubMedEurope PMCScholia
Yu H, Kortylewski M, Pardoll D; ''Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment.''; Nat Rev Immunol, 2007 PubMedEurope PMCScholia
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.
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