FGFR4 p.G388R signaling (Homo sapiens)

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11, 3, 5151, 3, 52Elevated Treg/CD8 T cell ratio in the tumor microenvironment (For genotype rs351855-A/A)IL104STAT376Cell cycle progressionSTAT376STAT37CD3345Regulatory T cellSTAT376CD3345STAT37ProliferationTumor cellTumor cellTumor cellTumor cellTumor cellTumor cellTregs1TregsTregs11Tumor cellTregs1Tumor cellCD8 T cell2Tumor cellTumor cellTumor cellCD8 T cell2Tumor cellTumor cellTumor cellIL10STAT376STAT376STAT376CD8 T cellTumor 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, 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.

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Bibliography

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  1. 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
  2. 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
  3. Ulaganathan VK, Ullrich A; ''Membrane-proximal binding of STAT3 revealed by cancer-associated receptor variants.''; Mol Cell Oncol, 2016 PubMed Europe PMC Scholia
  4. 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
  5. 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
  6. 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
  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
134737view22:32, 26 July 2024EweitzOntology Term : 'neoplastic cell' added !
134736view22:31, 26 July 2024EweitzOntology Term : 'CL:0001064' removed !
134683view21:53, 25 July 2024EweitzStandardize font name
134682view21:52, 25 July 2024EweitzModified description
134681view21:51, 25 July 2024EweitzModified description
134680view21:51, 25 July 2024EweitzRemove misplaced description
134679view21:49, 25 July 2024EweitzRemove duplicate comments
134678view21:47, 25 July 2024EweitzSimplify, standardize case
134677view21:45, 25 July 2024EweitzEconomize layout
134676view21:36, 25 July 2024EweitzFix typo, standardize case
129739view01:50, 22 May 2024EweitzOntology Term : 'malignant cell' added !
129738view01:49, 22 May 2024EweitzModified title
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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