ArticleBlood2023
Aberrant function of pathogenic STAT3 mutant proteins is linked to altered stability of monomers and homodimers.
Article in Blood, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 20 citations in OpenAlex.
- Colitis-Associated Colorectal Cancer-STAT3 Inhibition as a Preventive Strategy.International journal of molecular sciences · 2026Article
- RNF220 mediates K63-linked polyubiquitination of STAT3 and aggravates pathological cardiac hypertrophy.Cell death and differentiation · 2026Article
- The X Factor in Immunity: Sex Differences Shaped by the X Chromosome.Immunological reviews · 2026Review
- Real-time visualization of STAT activation in live cells using genetically encoded biosensors.Nature chemical biology · 2026Article
- Psoralen and Isopsoralen fromPharmaceuticals (Basel, Switzerland) · 2026Article
- STAT3 signaling in cancer: mechanisms and targeting therapeutic.Frontiers in immunology · 2026Review
- STAT3 SH2 Domain Aspartic Acid 661 Mutations Activate Immune Gene Programs.Journal of cellular and molecular medicine · 2026Article
- T-cell lymphoma-associated STAT3 variants impose a type 1 regulatory-like phenotype.Frontiers in immunology · 2026Article
- STAT3 Inhibition to Treat Ulcerative Colitis-Associated Colorectal Cancer.International journal of molecular sciences · 2025Article
- STAT3 haploinsufficiency is associated with autosomal dominant hyper-IgE syndrome.Science advances · 2025Article
- STAT3 Signaling Pathway in Health and Disease.MedComm · 2025Review
- Effect of SNORD113-3/ADAR2 on glycolipid metabolism in glioblastoma via A-to-I editing of PHKA2.Cellular & molecular biology letters · 2025Article
- Key Role of STAT3 in Osteoarthritis: From Pathogenic Mechanisms to Targeted Therapy.International journal of nanomedicine · 2025Review
- Visomitin Attenuates Pathological Bone Loss by Reprogramming Osteoclast Metabolism via the STAT3/LDHB Axis.Research (Washington, D.C.) · 2025Article
- IRG1/Itaconate inhibits proliferation and promotes apoptosis of CD69Apoptosis : an international journal on programmed cell death · 2024Article
- Asymmetric post-translational modifications regulate the nuclear translocation of STAT3 homodimers in response to leukemia inhibitory factor.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- Article
- Signal Transducer and Activator of Transcription Proteins at the Nexus of Immunodeficiency, Autoimmunity and Cancer.Biomedicines · 2023Review
- Fluorinated andPharmaceutics · 2023Article
- DRUGGING "UNDRUGGABLE" DISEASE-CAUSING PROTEINS: FOCUS ON SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) 3.Transactions of the American Clinical and Climatological Association · 2022Article
Corrections and comments
- Erratum issued
Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
STAT3 mutations, predominantly in the DNA-binding domain (DBD) and Src-homology 2 domain (SH2D), cause rare cases of immunodeficiency, malignancy, and autoimmunity. The exact mechanisms by which these mutations abrogate or enhance STAT3 function are not completely understood. Here, we examined how loss-of-function (LOF) and gain-of-function (GOF) STAT3 mutations within the DBD and SH2D affect monomer and homodimer protein stability as well as their effect on key STAT3 activation events, including recruitment to phosphotyrosine (pY) sites within peptide hormone receptors, tyrosine phosphorylation at Y705, dimerization, nuclear translocation, and DNA binding. The DBD LOF mutants showed reduced DNA binding when homodimerized, whereas the DBD GOF mutants showed increased DNA binding. DBD LOF and GOF mutants showed minimal changes in other STAT3 functions or in monomer or homodimer protein stability. However, SH2D LOF mutants demonstrated reduced conformational stability as either monomers or homodimers, leading to decreased pY-peptide recruitment, tyrosine phosphorylation, dimerization, nuclear localization, and DNA binding. In contrast, cancer-causing SH2D GOF mutants showed increased STAT3 homodimer stability, which increased their DNA binding. Of note, a small-molecule inhibitor of STAT3 that targets the tyrosine phosphopeptide-binding pocket within the STAT3 SH2D potently inhibited cell proliferation driven by STAT3 SH2D GOF mutants. These findings indicate that the stability of STAT3 protein monomer and homodimer is critical for the pathogenesis of diseases caused by SH2D LOF and GOF mutations and suggest that agents that modulate STAT3 monomer and/or homodimer protein stability may have therapeutic value in diseases caused by these mutations.
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