Affinage

STAT5A

Signal transducer and activator of transcription 5A · UniProt P42229

Length
794 aa
Mass
90.6 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAT5A is a latent cytoplasmic transcription factor that couples cytokine, hormone, and growth-factor receptors to sequence-specific gene activation and serves as the obligate, non-redundant mediator of prolactin-driven mammary lobuloalveolar development and lactogenesis (PMID:9009201, PMID:9630227). Activation proceeds through tyrosine phosphorylation by receptor-associated JAK kinases—the JAK2 kinase domain alone is sufficient to bind and phosphorylate STAT5, and the SH2-domain residue R618 is required for this event (PMID:9575217)—as well as by JAK1/JAK3 downstream of IL-2/IL-15 (PMID:7568001); STAT5 is also a direct substrate of the insulin receptor and of oncogenic Flt3-ITD independently of JAK and Src kinases (PMID:9122188, PMID:17356133). Phosphorylated STAT5 dimerizes through reciprocal phosphotyrosine–SH2 contacts (the pharmacologic SH2 inhibitor AC-4-130 blocks dimerization and nuclear entry) and can further tetramerize via N-domain interactions to drive specific outputs such as GM-CSF-induced CCL17 in autoimmune inflammation (PMID:29472718, PMID:34934004); nuclear translocation is promoted by a FAK–Rac1–PAK1 axis in leukemic cells (PMID:25456130). In the nucleus STAT5A binds GAS elements to control target genes including the IL-2 receptor α chain, RANKL, RAD51, and TMPRSS6, and acts through cell-type-specific and autoregulatory mammary enhancers/super-enhancers that amplify Stat5 expression and Wap induction (PMID:9390692, PMID:12952963, PMID:29483142, PMID:24376517, PMID:26446995, PMID:27376239). Transcriptional output is shaped by physical partners—the glucocorticoid receptor (cooperating at non-classical half-sites), Runx1/2/3, HMGN2/HDAC6, and the negative regulator STAP-2/BKS (PMID:8878484, PMID:9442383, PMID:18296717, PMID:27358110, PMID:15611091). Signaling is terminated by the phosphatases PTP1B and Shp-2, which bind phospho-STAT5 and accelerate its dephosphorylation (PMID:10993888, PMID:12615921). Beyond canonical signaling, post-translational modification by serine phosphorylation at S725/S779 and by O-GlcNAcylation is required for its leukemogenic and oncogenic activity (PMID:20508164, PMID:28074064), unphosphorylated STAT5A binds HP1α to stabilize heterochromatin and repress cancer-associated genes (PMID:23733954), and a mitochondrial pool disrupts the pyruvate dehydrogenase complex to promote the Warburg effect (PMID:34148062). STAT5A also has tissue-specific physiological roles in erythroid and adipocyte differentiation, bone mass control, and cardioprotective ischemic preconditioning (PMID:9079629, PMID:12540601, PMID:30429452, PMID:29365089).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1996 High

    Established that STAT5 is not an isolated activator but physically integrates with nuclear hormone receptor signaling, forming a complex with the glucocorticoid receptor that cooperatively shapes transcriptional output.

    Evidence Co-IP, DNA-binding and reporter assays in mammalian cells, with promoter mutagenesis showing dependence on non-classical GR half-sites

    PMID:8878484 PMID:9442383

    Open questions at the time
    • Structural basis of the STAT5-GR interaction not resolved
    • Generality of half-site cooperation beyond the beta-casein promoter not established
  2. 1995 Medium

    Placed STAT5 downstream of IL-2-family cytokine receptors via the JAK1/JAK3 axis, linking tyrosine phosphorylation to DNA-binding complex formation.

    Evidence Phosphorylation assays, EMSA, and JAK immunoprecipitation in human T cells

    PMID:7568001

    Open questions at the time
    • Did not distinguish STAT5A from STAT5B contributions
    • Direct kinase-substrate relationship not reconstituted in vitro
  3. 1997 High

    Genetic knockout defined STAT5A as the principal, non-redundant mediator of prolactin-induced mammary differentiation and lactation, answering whether the near-identical STAT5A/STAT5B paralogs are functionally interchangeable.

    Evidence Stat5a knockout mice, mammary histology, and lactation phenotyping; extended by individual and combined Stat5a/Stat5b knockouts

    PMID:9009201 PMID:9630227

    Open questions at the time
    • Molecular basis for STAT5A vs STAT5B specificity at shared target genes not defined
    • Did not identify the full mammary target gene set
  4. 1997 Medium

    Showed STAT5 is activated by non-JAK receptor kinases, demonstrating direct phosphorylation by the insulin receptor and a requirement downstream of the erythropoietin receptor, broadening STAT5 inputs beyond cytokine JAKs.

    Evidence Yeast two-hybrid, in vitro kinase assay with purified IR domain, in vivo tissue phosphorylation; chimeric EpoR Y→F mutants and dominant-negative STAT5 in erythroleukemia cells

    PMID:9079629 PMID:9122188

    Open questions at the time
    • Physiological weight of IR-direct phosphorylation versus JAK routes unresolved
    • EpoR-STAT5 erythroid role later shown largely Stat5b/redundant in vivo
  5. 1997 High

    Defined a specific STAT5A transcriptional target in immune signaling—the IL-2 receptor alpha chain—linking STAT5A loss to impaired low-affinity IL-2 proliferative responses.

    Evidence Stat5a knockout splenocytes, IL-2Ra expression analysis, and IL-2 dose-response proliferation assays

    PMID:9390692

    Open questions at the time
    • Direct STAT5A occupancy of the IL-2Ra promoter not shown in this study
    • Redundancy with STAT5B not addressed
  6. 1998 Medium

    Dissected the activation mechanism, showing the JAK2 kinase domain is sufficient for STAT5 binding/phosphorylation, the SH2 residue R618 is required, and a single phosphotyrosine-SH2 contact drives dimerization but yields poorly DNA-binding dimers; also separated receptor-driven phosphorylation from nuclear translocation.

    Evidence Yeast reconstitution with integrated reporter, site-directed mutagenesis, stringent co-IP; PRLR phosphotyrosine mutant analysis with subcellular fractionation

    PMID:9516478 PMID:9575217

    Open questions at the time
    • Structural detail of high-affinity DNA-binding dimer geometry not resolved
    • Identity of the nuclear translocation machinery downstream of PRLR Tyr382 unknown
  7. 2003 High

    Identified the phosphatases that terminate STAT5 signaling, establishing PTP1B and Shp-2 as direct, phospho-tyrosine-dependent STAT5 inactivators with functional consequences for transcription and nuclear localization.

    Evidence In vitro phosphatase assays, substrate-trapping co-precipitation, Shp-2-null cells, reporter assays (PTP1B reported 2000)

    PMID:10993888 PMID:12615921

    Open questions at the time
    • Relative in vivo contributions of each phosphatase not ranked
    • Spatial site of dephosphorylation (cytoplasm vs nucleus) not fully defined
  8. 2003 Medium

    Expanded STAT5A's physiological and target-gene repertoire, defining a GAS element in the RANKL promoter, a STAT5A-sufficient adipogenic program, and a STAT5-GR association during differentiation.

    Evidence Dominant-negative JAK2/STAT5 with promoter mapping and COS7 reconstitution; ectopic STAT5A expression with adipogenesis markers and co-IP

    PMID:12540601 PMID:12952963

    Open questions at the time
    • STAT5A vs STAT5B specificity in adipogenesis not mechanistically explained
    • Endogenous-context validation of RANKL regulation limited
  9. 2004 Medium

    Characterized regulatory and co-regulator partners that tune STAT5 activity, identifying STAP-2/BKS as a cytoplasmic negative regulator and (later) Runx1/2/3 as mutual transcriptional antagonists that retain STAT5 in the cytoplasm.

    Evidence Co-IP, domain mapping, intracellular staining, STAP-2-null thymocytes; Runx co-IP, fractionation, DNA-binding and CIS target gene readouts in Ba/F3 cells

    PMID:15611091 PMID:18296717

    Open questions at the time
    • Quantitative impact of these regulators on physiological STAT5 outputs unclear
    • Single-lab co-IP evidence without reciprocal structural validation
  10. 2005 Medium

    Connected STAT5A to G-protein-coupled receptor signaling, showing Src-dependent tyrosine phosphorylation and direct binding to the mu-opioid receptor C-terminal YXXL motif.

    Evidence Co-IP and GST pulldown from brain/COS-7 extracts, MOR motif mutagenesis, Src inhibitor PP1, STAT-responsive reporter

    PMID:15857395

    Open questions at the time
    • Downstream neuronal target genes not identified
    • Physiological relevance in vivo not established
  11. 2010 High

    Distinguished STAT5A's oncogenic from its physiological activity by showing serine phosphorylation at S725/S779 is required for leukemogenesis but dispensable for normal hematopoietic reconstitution.

    Evidence Serine-mutant complementation in Stat5-null cells and bone marrow transplantation leukemia model

    PMID:20508164

    Open questions at the time
    • Kinase(s) responsible for S725/S779 phosphorylation not identified here
    • Mechanism by which serine phosphorylation alters target gene selection unresolved
  12. 2013 Medium

    Revealed a phosphorylation-independent function: unphosphorylated STAT5A binds HP1α to stabilize heterochromatin and repress cancer-associated genes, recasting the unphosphorylated pool as a tumor suppressor.

    Evidence Co-IP, transcriptome profiling, unphosphorylatable STAT5A mutant, and colon cancer xenografts; TMPRSS6 promoter ChIP also defined a direct iron-homeostasis target

    PMID:23733954 PMID:24376517

    Open questions at the time
    • Genome-wide map of unphosphorylated STAT5A/HP1α sites incomplete
    • Switch dynamics between repressive and activating STAT5A pools not defined
  13. 2014 Medium

    Defined nuclear-entry and chromatin-cooperation mechanisms in transformed cells, showing PAK1 drives STAT5 nuclear translocation downstream of FAK-Rac1, and that persistent STAT5 activation recruits p53 to shared promoters.

    Evidence FAK/PAK1 inhibitors with in vivo leukemia models and fractionation; ChIP-seq co-localization of STAT5 and p53 with inhibition experiments

    PMID:24681953 PMID:25456130

    Open questions at the time
    • Whether PAK1-driven translocation is import-receptor independent unknown
    • Functional consequence of STAT5-p53 co-occupancy on individual genes not dissected
  14. 2016 High

    Established that cell-type-specific autoregulatory and super-enhancers, decoded by in vivo CRISPR editing, amplify STAT5 levels and STAT5-dependent gene induction in mammary epithelium, explaining quantitative control of lactation genes.

    Evidence ChIP-seq, DNaseI hypersensitivity, combinatorial CRISPR/Cas9 mutagenesis in mice with transcriptome readouts; additional coactivator (HMGN2/HDAC6) and tissue-specific repressive roles (macrophage Cyp19a1, osteogenic DLX5) defined

    PMID:26446995 PMID:27358110 PMID:27376239 PMID:28606561 PMID:30429452

    Open questions at the time
    • Hierarchy of trans-factors building the super-enhancer not fully resolved
    • Mechanistic basis of repressive vs activating enhancer engagement across tissues unclear
  15. 2017 Medium

    Showed O-GlcNAcylation is a required modification for STAT5 oncogenicity, promoting tyrosine phosphorylation, oligomerization, and transformation, adding a metabolism-linked PTM layer to STAT5 activation.

    Evidence O-GlcNAc-site mutagenesis with phosphorylation, oligomerization, and transformation assays in hematopoietic cells

    PMID:28074064

    Open questions at the time
    • O-GlcNAc transferase responsible and modified residues' interplay with serine sites not defined
    • Effect on physiological (non-oncogenic) STAT5 signaling untested
  16. 2018 Medium

    Extended STAT5 function to DNA repair, demonstrating JAK2-dependent STAT5a/b induction of RAD51 is required for homologous recombination and confers radioresistance in prostate cancer.

    Evidence Comet, clonogenic, HR/NHEJ reporter assays, siRNA, xenografts, and patient-derived 3D explants; cardiomyocyte-specific Stat5 KO also defined an ischemic-preconditioning cardioprotective role

    PMID:29365089 PMID:29483142

    Open questions at the time
    • Direct STAT5 occupancy of the RAD51 promoter not detailed here
    • Mechanism linking STAT5 to the apoptotic/HIF-1α program in cardiomyocytes incompletely mapped
  17. 2021 Medium

    Defined oligomerization-state and non-nuclear functions, showing N-domain tetramerization drives a specific cytokine output (CCL17) in autoimmunity and that a mitochondrial STAT5A pool disrupts the pyruvate dehydrogenase complex to enforce the Warburg effect.

    Evidence Tetramer-deficient N-domain knockin mice in EAE with rescue; STAT5A-PDC co-IP, PDC activity and metabolic profiling, hypoxia, and xenografts

    PMID:34148062 PMID:34934004

    Open questions at the time
    • Import mechanism for mitochondrial STAT5A unknown
    • Structural basis distinguishing dimer vs tetramer target selection unresolved
  18. 2021 Medium

    Revealed post-transcriptional and feedback control of STAT5A itself, with YTHDF2-mediated m6A decay of STAT5A mRNA relieving STAT5A-dependent repression of the MAP2K2/ERK pathway, and pY694-STAT5 modulating NPM1/p53 stability.

    Evidence m6A-RIP-seq, RIP-PCR, ChIP-seq/qPCR and functional assays in myeloma; co-IP and ubiquitin-ligase/protein-stability assays for the NPM1-p53 axis

    PMID:28005077 PMID:35075244

    Open questions at the time
    • Generality of STAT5A as an ERK-pathway repressor beyond myeloma unknown
    • Bidirectional STAT5-NPM1 regulation not validated in primary cells
  19. 2025 Medium

    Positioned the JAK2-STAT5 axis as a determinant of dendritic-cell immunogenicity restrained by STAT3, showing STAT3 degradation reprograms DCs toward STAT5-driven anti-tumor T cell priming.

    Evidence STAT3 PROTAC degraders, DC transcriptomics, T cell priming assays, in vivo tumor models

    PMID:40369063

    Open questions at the time
    • Direct STAT5 target genes mediating DC immunogenicity not enumerated
    • Mechanism of STAT3 restraint over JAK2-STAT5 not biochemically defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same protein is partitioned among activating dimers/tetramers, repressive unphosphorylated heterochromatin complexes, and a metabolic mitochondrial pool—and what governs the switch between these states in a given cell—remains unresolved.
  • No unified structural model of dimer/tetramer/monomer interconversion
  • Signals controlling mitochondrial import are unknown
  • Quantitative balance of nuclear-activating vs repressive pools per cell type undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 6 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0000228 nuclear chromosome 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-1266738 Developmental Biology 7 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-1430728 Metabolism 2 R-HSA-4839726 Chromatin organization 1 R-HSA-73894 DNA Repair 1
Partners
GRHP1AJAK2NPM1PTP1BRUNX1SHP2STAP2

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Stat5a is the principal and obligate mediator of prolactin-induced mammary lobuloalveolar development and lactogenesis; targeted deletion of Stat5a in mice abolishes terminal differentiation of mammary epithelium and lactation, despite Stat5b having 96% similarity and a superimposable expression pattern. Gene targeting (knockout mice), mammary gland histology, lactation phenotyping Genes & development High 9009201
1998 Stat5a and Stat5b have essential but often redundant roles in cytokine responses mediated by growth hormone and prolactin; individual and double-knockout mice show that Stat5a is specifically required for prolactin-driven mammary responses while erythropoietin responses are largely unaffected. Individual and combined gene targeting (knockout mice), cytokine response phenotyping Cell High 9630227
1996 STAT5 forms a physical complex with the glucocorticoid receptor (GR); this complex binds DNA independently of classical GRE sequences and enables GR to act as a transcriptional co-activator enhancing STAT5-dependent transcription, while simultaneously diminishing GRE-driven glucocorticoid responses. Co-immunoprecipitation, DNA-binding assays, transcriptional reporter assays, transfection in mammalian cells Nature High 8878484
1997 Stat5a is activated by IL-2 and is specifically required for IL-2-induced upregulation of the IL-2 receptor alpha chain (IL-2Rα/CD25); defective IL-2Rα expression in Stat5a-/- splenocytes leads to markedly decreased proliferative responses to low-affinity IL-2 concentrations. Stat5a knockout mice, splenocyte proliferation assays, IL-2Rα expression analysis, IL-2 dose-response Immunity High 9390692
1995 IL-2 and IL-15 rapidly induce tyrosine phosphorylation of STAT5 (and STAT3) and activate STAT5-containing DNA-binding complexes in human T cells; JAK1 and JAK3 are co-phosphorylated, establishing STAT5 as downstream of the JAK1/JAK3 axis for IL-2 family cytokines. Tyrosine phosphorylation assays, electrophoretic mobility shift assay (EMSA), immunoprecipitation of JAKs in human T cells Proceedings of the National Academy of Sciences of the United States of America Medium 7568001
2000 PTP1B specifically dephosphorylates and inactivates prolactin-activated STAT5a and STAT5b; overexpression of PTP1B inhibits nuclear translocation of STAT5 and suppresses PRL-dependent beta-casein gene transcription; substrate-trapping PTP1B mutants co-precipitate endogenous tyrosine-phosphorylated STAT5. In vitro phosphatase assay, overexpression in COS7 and COMMA-1D mammary cells, retrovirus-mediated overexpression, substrate-trapping co-precipitation, reporter gene assay The Journal of biological chemistry High 10993888
2003 Shp-2 (but not Shp-1) specifically interacts with tyrosine-phosphorylated STAT5A in vivo, accelerates its dephosphorylation, and dephosphorylation of STAT5A is dramatically delayed in Shp-2-deficient cells; interaction is phospho-tyrosine-dependent. Phosphopeptide affinity purification, co-immunoprecipitation, Shp-2-deficient cells, phosphatase assay The Journal of biological chemistry High 12615921
1997 The insulin receptor (IR) directly phosphorylates STAT5 in vitro; insulin stimulates tyrosine phosphorylation and DNA-binding activity of STAT5 in liver, skeletal muscle, and adipose tissue; STAT5b C-terminal domain interacts with the IR cytoplasmic domain identified by yeast two-hybrid. Yeast two-hybrid, in vitro kinase assay with purified IR kinase domain, in vivo tyrosine phosphorylation, EMSA on tissue extracts Proceedings of the National Academy of Sciences of the United States of America High 9122188
2007 Oncogenic Flt3-ITD directly phosphorylates and activates STAT5 independently of Src family kinases and JAK kinases; demonstrated by in vitro kinase assay showing STAT5 as direct Flt3 substrate, and by SOCS1 overexpression (which inhibits IL-3- but not Flt3-ITD-mediated STAT5 activation). In vitro kinase assay, small-molecule kinase inhibitors, Src-deficient cell lines, JAK2/Tyk2-deficient cells, SOCS1 overexpression Blood High 17356133
2003 JAK2 and STAT5a are essential for prolactin-induced RANKL expression in mammary epithelial cells; identified a GAS element in the RANKL promoter conferring PRL responsiveness, demonstrated by dominant-negative mutants of JAK2 and STAT5, and reconstitution of the JAK2/STAT5 pathway in COS7 cells. Dominant-negative mutants, luciferase reporter assay, pathway reconstitution in COS7 cells, promoter deletion analysis The Journal of biological chemistry Medium 12952963
1998 JAK2 kinase domain is sufficient for interaction with and phosphorylation of STAT5; the STAT5 SH2 domain R618K mutation abolishes JAK2-mediated phosphorylation; a single phosphotyrosine-SH2 interaction is sufficient for STAT5 dimerization but produces dimers that bind DNA very inefficiently; C-terminal deletion causes STAT5 hyperphosphorylation. Yeast-based expression system with integrated reporter, site-directed mutagenesis, co-immunoprecipitation under stringent conditions, deletion mutant analysis The Journal of biological chemistry Medium 9575217
1998 Prolactin receptor (PRLR) regulates STAT5 tyrosine phosphorylation and nuclear translocation by two separate mechanisms: phosphorylation is independent of PRLR phosphotyrosines, whereas nuclear translocation specifically requires the C-terminal tyrosine of the PRLR Nb2 form (Tyr382). PRLR phosphotyrosine mutant analysis, overexpression of natural and mutant PRLR forms in HC11 and 293-LA cells, subcellular fractionation, DNA-binding assays The Journal of biological chemistry Medium 9516478
2003 STAT5A, but not STAT5B alone, is sufficient to promote adipogenesis in non-precursor fibroblast cell lines and induces expression of early and late adipogenic markers; STAT5A physically associates with the glucocorticoid receptor during adipogenesis in a regulated manner. Ectopic expression in BALB/c and NIH-3T3 cells, morphological and biochemical adipogenesis markers, co-immunoprecipitation during differentiation Diabetes Medium 12540601
2004 Physical interaction between STAP-2/BKS and STAT5 occurs via the PH- and SH2-like domains of STAP-2/BKS binding the C-terminal region of STAT5; STAP-2/BKS co-localizes with STAT5 in the cytoplasm of resting cells and dissociates upon STAT5 phosphorylation; overexpression of STAP-2/BKS diminishes cytokine-induced STAT5 tyrosine phosphorylation and transcriptional activation. Co-immunoprecipitation, intracellular staining, mutational analysis, STAP-2/BKS-deficient mice thymocytes, overexpression assays The Journal of biological chemistry Medium 15611091
2013 Unphosphorylated STAT5A binds to heterochromatin protein 1α (HP1α) and stabilizes heterochromatin; expression of unphosphorylatable STAT5A produces similar global gene repression as HP1α overexpression, with most co-repressed genes implicated in cancer development; expressing unphosphorylated STAT5A or HP1α inhibits colon cancer xenograft growth. Co-immunoprecipitation, transcriptome profiling, mouse xenograft models, unphosphorylatable STAT5A mutant expression Proceedings of the National Academy of Sciences of the United States of America Medium 23733954
2010 Serine phosphorylation of Stat5a at residues 725 and 779 is a prerequisite for oncogenic/leukemogenic transformation; mutating these serines abolishes the leukemogenic potential of constitutively active Stat5a in bone marrow transplants, while normal hematopoietic reconstitution functions are preserved. Site-directed mutagenesis of Stat5a serine residues, genetic complementation in Stat5-null cells, in vivo bone marrow transplantation leukemia model Blood High 20508164
1997 STAT5 activation correlates with and is required for erythropoietin receptor (EpoR)-mediated erythroid differentiation; EpoR Tyr343 or Tyr401 independently activates STAT5 and induces erythroid differentiation; dominant-negative STAT5 suppresses EPO-dependent erythroid differentiation. Chimeric EpoR mutants with Y→F substitutions, dominant-negative STAT5 overexpression, globin expression assay in erythroleukemia ELM-I-1 cells The Journal of biological chemistry Medium 9079629
2003 LMW-PTP associates with and dephosphorylates STAT5 in megakaryocytic cells; interaction involves the C-terminal domain of STAT5 (not exclusively the phosphotyrosine-active site interaction), identifying LMW-PTP as a STAT5 phosphatase. Co-immunoprecipitation in DAMI megakaryocytic cells, phosphatase assay, domain mapping Biochemical and biophysical research communications Low 14637146
2008 STAT5 physically interacts with Runx1, Runx2, and Runx3 via its DNA-binding domain and α-helix loop; STAT5 retains Runx proteins in the cytoplasm; STAT5-Runx interaction mutually inhibits transcriptional activity of both, and Runx proteins inhibit STAT5 DNA-binding activity. Co-immunoprecipitation, reporter assay, subcellular localization (nuclear/cytoplasmic fractionation), DNA-binding assay, endogenous target gene (CIS) expression in Ba/F3 cells Journal of biochemistry Medium 18296717
2017 O-GlcNAcylation of STAT5 promotes its tyrosine phosphorylation, oligomerization, and oncogenic transactivation; a hyperactive STAT5 mutant lacking O-GlcNAcylation shows decreased tyrosine phosphorylation, oligomerization, transactivation potential, and complete loss of oncogenic transformation capacity. O-GlcNAcylation site mutagenesis, tyrosine phosphorylation assays, oligomerization assays, oncogenic transformation assays in hematopoietic cells Leukemia Medium 28074064
2014 In oncogenic FLT3/KIT-driven leukemic cells, FAK activates Rac1 via RacGEF Tiam1, which activates PAK1; PAK1 promotes nuclear translocation of Stat5; pharmacologic inhibition of PAK1 inhibits Stat5 nuclear translocation and prolongs survival of leukemic mice. FAK/PAK1 pharmacologic inhibitors, in vivo leukemia mouse models, subcellular fractionation, survival analysis of leukemic mice Cell reports Medium 25456130
2016 HDAC6 deacetylates the STAT5a coactivator HMGN2 at lysine K2; deacetylated HMGN2 promotes STAT5a-mediated transcription and breast cancer growth; HDAC6 inhibition enhances HMGN2 acetylation with concomitant reduction in STAT5a-mediated signaling. HDAC6 inhibition in vitro and in vivo, acetylation site identification (K2), co-immunoprecipitation, chromatin assays, breast cancer xenograft models Molecular cancer research : MCR Medium 27358110
2014 Persistent (but not transient) STAT5 activation recruits p53 to chromatin; genome-wide ChIP shows STAT5 and p53 co-localize at 463 proximal promoter positions in transformed hematopoietic cells; chromatin binding of p53 at these sites is dependent on persistent STAT5 activation. ChIP-seq, ChIP, reporter assay, STAT5 and p53 inhibition, patient MPN platelet gene expression Oncogene Medium 24681953
2016 A mammary-specific intergenic enhancer between the Stat5a and Stat5b loci contains STAT5-binding motifs and drives positive autoregulatory feedback; CRISPR/Cas9 deletion of STAT5-binding sites reduces Stat5 levels in mammary epithelium by ~80% and correspondingly reduces STAT5-dependent gene expression. ChIP-seq, DNaseI hypersensitivity, CRISPR/Cas9 genome editing in mice, transcriptome analysis Nucleic acids research High 26446995
2016 The mammary Wap super-enhancer contains a functional hierarchy of STAT5A-binding sites; combinatorial CRISPR/Cas9 mutation of all constituent enhancers is required for the full ~1000-fold induction of Wap expression during pregnancy; disabling STAT5, NFIB, and ELF5 binding sites in the proximal enhancer incapacitates the entire super-enhancer. ChIP-seq (STAT5A, GR, H3K27ac, MED1), CRISPR/Cas9 combinatorial mutagenesis in mice, reporter assays Nature genetics High 27376239
2021 A mitochondrial fraction of STAT5A interacts with the pyruvate dehydrogenase complex (PDC), disrupts PDC integrity, inhibits PDC activity, and promotes the Warburg effect; mitochondrial translocation of STAT5A increases under hypoxic conditions and promotes tumor growth in vivo. Co-immunoprecipitation of STAT5A with PDC subunits, PDC activity assays, glycolysis/OXPHOS metabolic profiling, hypoxia treatment, xenograft tumor models Cell death & disease Medium 34148062
2005 STAT5A physically interacts with and is tyrosine-phosphorylated upon activation of the mu-opioid receptor (MOR) via a Src-dependent mechanism; the YXXL motif (aa 336-339) in the MOR C-terminal tail is required for STAT5A binding; Src inhibitor PP1 abolishes opioid-dependent STAT5A phosphorylation. Co-immunoprecipitation, GST pulldown from rat brain/COS-7 extracts, site-directed mutagenesis of MOR YXXL motif, Src inhibitor PP1, STAT-responsive reporter gene Journal of neurochemistry Medium 15857395
2018 STAT5a/b is required for RAD51 expression and homologous recombination (HR) DNA repair in prostate cancer via JAK2-dependent induction of Rad51 mRNA; genetic knockdown of STAT5a/b suppresses HR but not NHEJ, and pharmacologic STAT5 inhibition sensitizes prostate cancer to radiation. Comet assay, clonogenic survival assay, HR/NHEJ reporter assays, RAD51 expression analysis, STAT5a/b siRNA knockdown, xenograft in vivo models, patient-derived 3D explant cultures Clinical cancer research Medium 29483142
2021 STAT5A negatively regulates MAP2K2 transcription by occupying its promoter, thereby decreasing ERK phosphorylation; YTHDF2 m6A reader promotes STAT5A mRNA degradation by binding its m6A modification site, thus relieving STAT5A-mediated suppression of the MAP2K2/ERK pathway in multiple myeloma. m6A-RIP-seq, RIP-PCR, ChIP-seq, ChIP-qPCR, siRNA knockdown/overexpression, in vitro and in vivo proliferation assays Oncogene Medium 35075244
2018 Cardiomyocyte-specific Stat5 knockout abolishes late remote ischemic preconditioning (RIPC)-induced cardioprotection against myocardial I/R injury; RIPC requires Stat5 to activate anti-apoptotic signaling (Bcl-2, Bcl-xL), suppress cytochrome c/caspase-3, and activate HIF-1α, IL-10, AKT, and PI3K in cardiac tissue. Cardiomyocyte-specific Stat5 conditional knockout (Stat5fl/fl; Tnnt2Cre), myocardial infarct size measurement, apoptosis assays, Western blot of signaling proteins Cardiovascular research Medium 29365089
2013 TMPRSS6 expression is directly regulated by STAT5, which binds a STAT5 element in the Tmprss6 promoter; inflammation suppresses TMPRSS6 by reducing STAT5 phosphorylation through a Bmp-Smad-independent mechanism, thereby secondarily increasing hepcidin to regulate iron homeostasis. ChIP (STAT5 binding to Tmprss6 promoter), in vitro IL-6 treatment, in vivo LPS injection in mice, STAT5 phosphorylation assays PloS one Medium 24376517
2016 STAT5 binds directly to the Cyp19a1/aromatase promoter in macrophages to suppress its transcription; loss of STAT5 in macrophages leads to enhanced stromal aromatase expression, increased IL-6, delayed ductal elongation, and enhanced ductal branching during mammary gland development. Myeloid-specific Stat5 conditional knockout mice, ChIP (STAT5 binding to Cyp19a1 promoter), mammary gland whole-mount analysis, quantitative gene expression Developmental biology Medium 28606561
2016 STAT5 inhibition suppresses STAT5 activation, dimerization, and nuclear translocation; the SH2 domain inhibitor AC-4-130 directly binds STAT5 and blocks its SH2-mediated dimerization, establishing the SH2 domain as essential for STAT5 activation and nuclear translocation in AML cells. Direct STAT5 binding assay, STAT5 dimerization assay, nuclear translocation assay, pharmacologic SH2 domain inhibitor, AML cell lines and patient samples in vitro and in vivo Leukemia Medium 29472718
2021 STAT5 tetramerization (mediated by N-domain interactions) promotes GM-CSF-induced CCL17 production by monocyte-derived cells, which in turn facilitates integrin VLA-4-dependent pathogenic Th17 cell extravasation in experimental autoimmune encephalomyelitis; STAT5 N-domain double knockin (tetramer-deficient) mice have reduced EAE pathogenesis. STAT5 tetramer-deficient knockin mice (N-domain mutations), EAE model, flow cytometry, cytokine production assays, CCL17 rescue experiments Proceedings of the National Academy of Sciences of the United States of America Medium 34934004
2019 STAT5A directly regulates FABP5 transcription by binding to the FABP5 promoter, thereby promoting fatty acid metabolic reprogramming and tumorigenesis in gastric cancer cells. Luciferase reporter assay, ChIP-qPCR, STAT5A knockdown, lipid content measurements, xenograft tumor models European review for medical and pharmacological sciences Low 31646566
2016 STAT5A inhibition de-represses DLX5 expression in bone marrow stromal cells, enhancing osteogenesis; STAT5A knockout mice show increased trabecular and cortical bone mass and prevention of age-related bone loss; STAT5A deletion enhances fracture repair in a murine model. STAT5A siRNA knockdown in hBMSCs, STAT5A conditional knockout mice, micro-CT bone analysis, fracture callus histology Cell death & disease Medium 30429452
2016 Phosphorylated STAT5 (pY694) downregulates NPM1 by impairing the BRCA1-BARD1 ubiquitin ligase that controls NPM1 stability; decreased NPM1 levels suppress p53 expression, enhancing cell survival; NPM1 conversely negatively regulates STAT5 phosphorylation and preserves unphosphorylated STAT5. Co-immunoprecipitation, knockdown/overexpression, ubiquitin ligase activity assays, p53 expression analysis Cell death & disease Medium 28005077
1997 GR and STAT5 interaction requires intact DNA-binding sites for both factors; GR sites used for synergism with STAT5 at the beta-casein gene promoter are non-classical half-palindromic sites that do not function independently, establishing a novel mode of transcriptional cooperation dependent on both activated STAT5 and GR. Reporter gene assays in HC11 and COS-7 cells, promoter deletion/mutation analysis, gel shift assay Immunobiology Medium 9442383
2025 STAT3 restrains the JAK2-STAT5 transcriptional pathway in dendritic cells, thereby suppressing immunogenic DC function; STAT3 degradation by PROTACs reprograms the DC transcriptional network toward STAT5-driven immunogenicity, enhancing T cell priming and anti-tumor immunity. PROTAC STAT3 degraders, transcriptomic profiling of dendritic cells, T cell priming assays, in vivo tumor models Nature Medium 40369063

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 1020 9630227
1997 Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes & development 939 9009201
1996 Functional interactions between Stat5 and the glucocorticoid receptor. Nature 544 8878484
2012 STAT5 is a potent negative regulator of TFH cell differentiation. The Journal of experimental medicine 411 22271576
1995 Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proceedings of the National Academy of Sciences of the United States of America 317 7568001
2008 Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes & development 287 18347089
2000 The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 281 10851055
2016 Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nature genetics 219 27376239
1997 An indirect effect of Stat5a in IL-2-induced proliferation: a critical role for Stat5a in IL-2-mediated IL-2 receptor alpha chain induction. Immunity 207 9390692
2018 Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer. Leukemia 204 29728695
1999 Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation. Cytokine & growth factor reviews 200 10743504
2007 Activation mechanisms of STAT5 by oncogenic Flt3-ITD. Blood 176 17356133
2015 STAT5 in Cancer and Immunity. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 139 26716518
2000 A cytosolic protein-tyrosine phosphatase PTP1B specifically dephosphorylates and deactivates prolactin-activated STAT5a and STAT5b. The Journal of biological chemistry 139 10993888
2018 Pharmacologic inhibition of STAT5 in acute myeloid leukemia. Leukemia 133 29472718
2003 Stat5 expression is critical for mast cell development and survival. Blood 126 12714518
2009 Reciprocal effects of STAT5 and STAT3 in breast cancer. Molecular cancer research : MCR 115 19491198
2004 STAT5 activation underlies IL7 receptor-dependent B cell development. Journal of immunology (Baltimore, Md. : 1950) 114 15067053
1997 Stat5 is a physiological substrate of the insulin receptor. Proceedings of the National Academy of Sciences of the United States of America 113 9122188
2010 The role of Stat5 transcription factors as tumor suppressors or oncogenes. Biochimica et biophysica acta 108 20969928
2003 Receptor activator of NF-kappaB ligand induction via Jak2 and Stat5a in mammary epithelial cells. The Journal of biological chemistry 98 12952963
2003 STAT5A promotes adipogenesis in nonprecursor cells and associates with the glucocorticoid receptor during adipocyte differentiation. Diabetes 96 12540601
2003 Identification of Shp-2 as a Stat5A phosphatase. The Journal of biological chemistry 94 12615921
2008 Mutations in the STAT5A gene are associated with embryonic survival and milk composition in cattle. Journal of dairy science 93 18218766
2019 STAT3 and STAT5 Activation in Solid Cancers. Cancers 92 31557897
2000 Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice. Oncogene 91 10851049
2020 Suppressing STAT5 signaling affects osteosarcoma growth and stemness. Cell death & disease 79 32094348
2020 Involvement of STAT5 in Oncogenesis. Biomedicines 77 32872372
1997 STAT5 activation correlates with erythropoietin receptor-mediated erythroid differentiation of an erythroleukemia cell line. The Journal of biological chemistry 77 9079629
2019 Direct Targeting Options for STAT3 and STAT5 in Cancer. Cancers 76 31817042
2014 Critical role for mast cell Stat5 activity in skin inflammation. Cell reports 76 24412367
2004 Deregulation of Stat5 expression and activation causes mammary tumors in transgenic mice. International journal of cancer 74 15382041
2008 Maximal STAT5-induced proliferation and self-renewal at intermediate STAT5 activity levels. Molecular and cellular biology 72 18779318
2001 Stat5a regulates T helper cell differentiation by several distinct mechanisms. Blood 69 11290598
1998 Prolactin receptor regulates Stat5 tyrosine phosphorylation and nuclear translocation by two separate pathways. The Journal of biological chemistry 67 9516478
2013 Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth. Proceedings of the National Academy of Sciences of the United States of America 65 23733954
2020 Pharmacological Inhibition of Oncogenic STAT3 and STAT5 Signaling in Hematopoietic Cancers. Cancers 62 31963765
2010 STAT5 in B cell development and leukemia. Current opinion in immunology 61 20227268
2009 Phospho-STAT5 and phospho-Akt expression in chronic myeloproliferative neoplasms. British journal of haematology 61 19747364
2007 STAT5 signaling in normal and pathologic hematopoiesis. Frontiers in bioscience : a journal and virtual library 61 17485261
2021 STAT5 as a Key Protein of Erythropoietin Signalization. International journal of molecular sciences 59 34281163
2017 O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies. Leukemia 54 28074064
2019 Structural Implications of STAT3 and STAT5 SH2 Domain Mutations. Cancers 53 31717342
2014 Regulation of Stat5 by FAK and PAK1 in Oncogenic FLT3- and KIT-Driven Leukemogenesis. Cell reports 53 25456130
2006 Stat5 expression is required for IgE-mediated mast cell function. Journal of immunology (Baltimore, Md. : 1950) 53 16920984
2010 Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation. Blood 50 20508164
2004 Physical and functional interactions between STAP-2/BKS and STAT5. The Journal of biological chemistry 50 15611091
2007 Constitutive activation of Flt3 and STAT5A enhances self-renewal and alters differentiation of hematopoietic stem cells. Experimental hematology 49 17379095
2018 STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair. Clinical cancer research : an official journal of the American Association for Cancer Research 48 29483142
2015 An autoregulatory enhancer controls mammary-specific STAT5 functions. Nucleic acids research 48 26446995
2018 EGFRvIII-Stat5 Signaling Enhances Glioblastoma Cell Migration and Survival. Molecular cancer research : MCR 46 29724813
2006 Stat5 in the mammary gland: controlling normal development and cancer. Journal of cellular physiology 44 16883580
2017 STAT5-Interacting Proteins: A Synopsis of Proteins that Regulate STAT5 Activity. Biology 43 28287479
2013 STAT5A/B gene locus undergoes amplification during human prostate cancer progression. The American journal of pathology 43 23660011
2008 The different functions of Stat5 and chromatin alteration through Stat5 proteins. Frontiers in bioscience : a journal and virtual library 41 18508657
2005 Haploinsufficiency identifies STAT5 as a modifier of IL-7-induced lymphomas. Oncogene 41 15870688
2025 STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity. Nature 40 40369063
1998 Jak2-Stat5 interactions analyzed in yeast. The Journal of biological chemistry 40 9575217
2017 STAT5 and CD4 + T Cell Immunity. F1000Research 39 28163905
1997 Mechanism of interaction between the glucocorticoid receptor and Stat5: role of DNA-binding. Immunobiology 39 9442383
2019 Evaluating STAT5 Phosphorylation as a Mean to Assess T Cell Proliferation. Frontiers in immunology 38 31024554
2022 YTHDF2 promotes multiple myeloma cell proliferation via STAT5A/MAP2K2/p-ERK axis. Oncogene 37 35075244
2018 Stat5-dependent cardioprotection in late remote ischaemia preconditioning. Cardiovascular research 37 29365089
1997 Cytokine receptor-independent, constitutively active variants of STAT5. The Journal of biological chemistry 37 9374508
2008 Physical and functional interactions between STAT5 and Runx transcription factors. Journal of biochemistry 36 18296717
2020 High activation of STAT5A drives peripheral T-cell lymphoma and leukemia. Haematologica 35 31123029
2018 Brain STAT5 signaling modulates learning and memory formation. Brain structure & function 35 29460051
2016 HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth. Molecular cancer research : MCR 35 27358110
2019 The RAGE/STAT5/autophagy axis regulates senescence in mesangial cells. Cellular signalling 34 31158467
2014 Persistent STAT5 activation in myeloid neoplasms recruits p53 into gene regulation. Oncogene 34 24681953
2008 STAT5 contributes to antiapoptosis in melanoma. Melanoma research 33 19011510
2016 FYN expression potentiates FLT3-ITD induced STAT5 signaling in acute myeloid leukemia. Oncotarget 32 26848862
1998 Erythropoietin receptor and STAT5-specific pathways promote SKT6 cell hemoglobinization. Blood 31 9694697
2021 Mitochondrial STAT5A promotes metabolic remodeling and the Warburg effect by inactivating the pyruvate dehydrogenase complex. Cell death & disease 30 34148062
2013 STAT5 in hematopoietic stem cell biology and transplantation. JAK-STAT 30 24498540
2023 Batf stabilizes Th17 cell development via impaired Stat5 recruitment of Ets1-Runx1 complexes. The EMBO journal 29 36917143
2003 LMW-PTP associates and dephosphorylates STAT5 interacting with its C-terminal domain. Biochemical and biophysical research communications 29 14637146
2005 Signal transducer and activator of transcription 5 (STAT5), a crucial regulator of immune and cancer cells. Current drug targets. Immune, endocrine and metabolic disorders 28 16375697
2021 Tetramerization of STAT5 promotes autoimmune-mediated neuroinflammation. Proceedings of the National Academy of Sciences of the United States of America 27 34934004
2019 Growth hormone/STAT5 signaling in proopiomelanocortin neurons regulates glucoprivic hyperphagia. Molecular and cellular endocrinology 27 31494175
2017 Essential roles of stat5.1/stat5b in controlling fish somatic growth. Journal of genetics and genomics = Yi chuan xue bao 27 29246863
2016 Phosphorylated STAT5 regulates p53 expression via BRCA1/BARD1-NPM1 and MDM2. Cell death & disease 27 28005077
2014 BCR-ABL affects STAT5A and STAT5B differentially. PloS one 27 24836440
2018 GSK3-activated STAT5 regulates expression of SFRPs to modulate adipogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 29579399
2018 Inhibition of STAT5A promotes osteogenesis by DLX5 regulation. Cell death & disease 26 30429452
2015 A positive feedback loop between prolactin and STAT5 promotes angiogenesis. Advances in experimental medicine and biology 26 25472543
2005 STAT5A interacts with and is phosphorylated upon activation of the mu-opioid receptor. Journal of neurochemistry 26 15857395
2023 Dynamic chromatin accessibility licenses STAT5- and STAT6-dependent innate-like function of TH9 cells to promote allergic inflammation. Nature immunology 25 37106040
2021 Disruption of STAT5A and NMI signaling axis leads to ISG20-driven metastatic mammary tumors. Oncogenesis 24 34078871
2016 Differential cytokine sensitivities of STAT5-dependent enhancers rely on Stat5 autoregulation. Nucleic acids research 24 27694626
2021 A centric view of JAK/STAT5 in intestinal homeostasis, infection, and inflammation. Cytokine 23 33482575
2021 STAT5a Confers Doxorubicin Resistance to Breast Cancer by Regulating ABCB1. Frontiers in oncology 23 34336684
2018 Targeting STAT5 or STAT5-Regulated Pathways Suppresses Leukemogenesis of Ph+ Acute Lymphoblastic Leukemia. Cancer research 23 30154155
2016 Brain STAT5 signaling and behavioral control. Molecular and cellular endocrinology 23 27118133
2013 STAT5 acetylation: Mechanisms and consequences for immunological control and leukemogenesis. JAK-STAT 23 24416653
2002 Stat5: an essential regulator of mast cell biology. Molecular immunology 23 12217382
2019 STAT5A reprograms fatty acid metabolism and promotes tumorigenesis of gastric cancer cells. European review for medical and pharmacological sciences 22 31646566
2018 JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes. Neuroendocrinology 22 30376668
2017 STAT5 deletion in macrophages alters ductal elongation and branching during mammary gland development. Developmental biology 22 28606561
2013 Inflammation regulates TMPRSS6 expression via STAT5. PloS one 22 24376517

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