FGFR4 p.G388R signaling pathway (Homo sapiens)

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63, 4, 6633, 4, 61Elevated Treg/CD8 T cell ratio in the tumor microenvironment (For genotype rs351855-A/A)IL105STAT372Cell Cycle ProgressionSTAT372STAT37CD3343Regulatory T cellSTAT372CD334STAT337ProliferationTumor cellTumor cellTumor cellTumor cellTumor cellTumor cellTregs6Tregs6Tregs6Tumor cellTregsTumor cell6CD8 T cell1Tumor cellTumor cellTumor cellCD8 T cellTumor cell1Tumor cellTumor cellIL10STAT372STAT37STAT327CD8 T cell2Tumor TIssueLymph NodeProliferationTumor-extrinsic gain-of-function by FGFR4 p.Gly388ArgTumor-intrinsic gain-of-function by FGFR4 p.Gly388ArgTumor Cell


Description

A germline variant rs351855-G/A, 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 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.

Comments

 
A germline variant rs351855-G/A, 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 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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Bibliography

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  1. Raskov H, Orhan A, Christensen JP, Gögenur I; ''Cytotoxic CD8(+) T cells in cancer and cancer immunotherapy.''; Br J Cancer, 2021 PubMed Europe PMC Scholia
  2. 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 PubMed Europe PMC Scholia
  3. Ulaganathan VK, Sperl B, Rapp UR, Ullrich A; ''Germline variant FGFR4  p.G388R exposes a membrane-proximal STAT3 binding site.''; Nature, 2015 PubMed Europe PMC Scholia
  4. Ulaganathan VK, Ullrich A; ''Membrane-proximal binding of STAT3 revealed by cancer-associated receptor variants.''; Mol Cell Oncol, 2016 PubMed Europe PMC Scholia
  5. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A; ''Interleukin-10 and the interleukin-10 receptor.''; Annu Rev Immunol, 2001 PubMed Europe PMC Scholia
  6. Kogan D, Grabner A, Yanucil C, Faul C, Ulaganathan VK; ''STAT3-enhancing germline mutations contribute to tumor-extrinsic immune evasion.''; J Clin Invest, 2018 PubMed Europe PMC Scholia
  7. Yu H, Kortylewski M, Pardoll D; ''Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment.''; Nat Rev Immunol, 2007 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
128235view18:46, 29 January 2024Khanspersconnected interactions
127764view10:00, 3 December 2023EgonwMade three pathways clickable
127743view11:17, 30 November 2023UlaganathanOntology Term : 'fibroblast growth factor signaling pathway' added !
127742view11:16, 30 November 2023UlaganathanOntology Term : 'regulatory T cell' added !
127741view11:16, 30 November 2023UlaganathanOntology Term : 'effector CD8-positive, alpha-beta T cell' added !
127740view11:16, 30 November 2023UlaganathanOntology Term : 'cancer pathway' added !
127725view17:19, 29 November 2023UlaganathanNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
CD334ProteinP22455 (Uniprot-TrEMBL)
Cell Cycle ProgressionPathwayWP179 (WikiPathways)
IL10GeneProductENSG00000136634 (Ensembl)
IL10ProteinP22301 (Uniprot-TrEMBL)
ProliferationPathwayWP179 (WikiPathways)
STAT3ProteinP40763 (Uniprot-TrEMBL)

Annotated Interactions

No annotated interactions
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