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The JAK-STAT Signaling Pathway01:20

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Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
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Analysis of Somatic Hypermutation in the JH4 intron of Germinal Center B cells from Mouse Peyer's Patches
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STAT3 SH2 Domain Aspartic Acid 661 Mutations Activate Immune Gene Programs.

Hye Kyung Lee1, Gyuhyeok Cho2, Jichun Chen3

  • 1Section of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.

Journal of Cellular and Molecular Medicine
|January 13, 2026
PubMed
Summary
This summary is machine-generated.

STAT3 D661 mutations in blood cancers cause varied gain-of-function effects. D661Y and D661V variants show strong activity, impacting T cell viability and immune responses.

Keywords:
D661 variantsSTAT3gain‐of‐functionhematologic malignanciesimmune dysregulation

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Area of Science:

  • Molecular Biology
  • Genetics
  • Immunology

Background:

  • The STAT3 SH2 domain has a conserved aspartic acid residue D661.
  • D661 is a mutational hotspot in hematologic malignancies like T-cell large granular lymphocytic leukemia, myelodysplastic syndromes, and acute lymphoblastic leukemia.

Purpose of the Study:

  • To define the functional consequences of distinct STAT3 D661 variants.
  • To investigate the impact of these variants on STAT3 function and cellular processes.

Main Methods:

  • Computational analysis (AlphaMissense, PolyPhen-2, AlphaFold 3) and structural modeling.
  • In vitro functional assays using Stat3-deficient T cells.
  • In vivo studies using genetically modified mice.

Main Results:

  • All four STAT3 D661 variants (D661Y, D661V, D661N, D661H) were predicted as pathogenic. D661Y and D661V showed stronger predicted promotion of SH2-TAD-mediated dimerization.
  • In vitro, a gain-of-function hierarchy was observed: D661Y ≈ V > H > N, activating STAT3 target genes and immune programs.
  • In vivo, only STAT3 D661H mice were viable, showing altered CD4+ and CD8+ T cell populations and enhanced immune gene expression. D661Y and D661V mutants impaired mouse viability.

Conclusions:

  • A gradient of STAT3 D661 gain-of-function variants was defined, correlating in vitro and in vivo findings.
  • Stronger STAT3 D661 variants (D661Y, D661V) exhibit higher transcriptional activity but lead to impaired mouse viability.