Affinage

STAT5B

Signal transducer and activator of transcription 5B · UniProt P51692

Length
787 aa
Mass
89.9 kDa
Annotated
2026-04-28
100 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAT5B is a latent cytoplasmic transcription factor that is activated by JAK2-dependent tyrosine phosphorylation at Y699 downstream of cytokine receptors for growth hormone, prolactin, IL-2, IL-15, GM-CSF, and EPO, as well as by non-receptor tyrosine kinases including c-Src and BCR/ABL; upon phosphorylation it dimerizes, translocates to the nucleus, and binds GAS elements to drive transcription of target genes including IGF-I, ALS, IGFBP-3, Bcl-XL, SOCS-2, SOCS-3, and CIS (PMID:9231797, PMID:12682066, PMID:14761873, PMID:10428824). Signal termination involves phosphotyrosine phosphatases and proteasome-dependent degradation, while transcriptional output is further tuned by serine phosphorylation at Ser730 and Ser193 (the latter regulated by mTOR and PP2A), bidirectional cross-talk with PPARα and HNF4α, competition with NF-κB for p300/CBP coactivators, and negative feedback through SOCS proteins (PMID:9892011, PMID:11731617, PMID:22442148, PMID:10514468, PMID:10628751). STAT5B has non-redundant roles in NK cell cytolytic function, CD4+CD25high regulatory T cell homeostasis, GH-dependent sexually dimorphic liver gene expression, and restraint of B-cell plasmablast differentiation; germline loss-of-function mutations cause growth hormone insensitivity and immune dysregulation, while dominant-negative missense mutants dimerize with wild-type STAT5B to block its nuclear localization or DNA binding (PMID:9841920, PMID:16920911, PMID:10585399, PMID:35469842, PMID:29844444). Somatic gain-of-function SH2-domain mutations, particularly N642H, increase pY699-SH2 binding affinity and confer dephosphorylation resistance, driving constitutive STAT5B activation in aggressive T-cell and NK-cell lymphomas (PMID:23596048, PMID:25586472, PMID:31175292).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    Establishing that STAT5A and STAT5B are phosphorylation-activated transcription factors that dimerize and bind DNA to drive differentiation-associated gene expression revealed STAT5B as a signal-dependent latent transcription factor.

    Evidence Isoform-specific antibodies, EMSA with supershift, transgenic mouse mammary tissue

    PMID:8961260

    Open questions at the time
    • Upstream kinase not yet identified
    • Individual contributions of STAT5A vs STAT5B not separated
  2. 1997 High

    Demonstrating that JAK2 is required for GH-induced STAT5B tyrosine phosphorylation and that specific GH receptor cytoplasmic tyrosines are needed placed STAT5B directly downstream of the JAK2-GHR complex.

    Evidence GH receptor truncation/mutation constructs in COS and CHO cells, JAK2-deficient cell lines

    PMID:9231797

    Open questions at the time
    • Precise STAT5B recruitment mechanism to receptor not defined
    • Whether JAK2 directly phosphorylates Y699 or acts indirectly not resolved
  3. 1998 High

    Knockout studies and isoform-specific biochemistry revealed non-redundant functions: STAT5B (not STAT5A) is essential for NK cell proliferation/cytolysis downstream of IL-2/IL-15, GM-CSF selectively activates STAT5B in neutrophils, and STAT5B binds GAS elements as homodimers with higher affinity than STAT5A, while only STAT5A forms tetramers.

    Evidence Stat5b−/− mice with NK cell assays; isoform-specific IP/EMSA in neutrophils; purified recombinant protein EMSA and COS-7 transfection

    PMID:9422769 PMID:9605930 PMID:9742102 PMID:9841920

    Open questions at the time
    • Structural basis of isoform-specific receptor recruitment unknown
    • Why STAT5B but not STAT5A is selectively activated in some cell types not mechanistically explained
  4. 1999 High

    A suite of discoveries established how STAT5B signaling is terminated (phosphatases, proteasome, labile inhibitory factor), how continuous vs pulsatile GH patterns produce different STAT5B activation states (explaining sexual dimorphism of liver gene expression), and how c-Src activates STAT5B via a JAK2-independent mechanism that is functionally distinct from cytokine-driven activation.

    Evidence Pharmacological dissection (MG132, pervanadate, cycloheximide, H7) in liver cells; Stat5b−/− mice with pulsatile GH replacement; dominant-negative JAK2 + immunofluorescence in transfected cells

    PMID:10428824 PMID:10585399 PMID:10630411 PMID:9892011 PMID:9973252

    Open questions at the time
    • Identity of the labile protein factor required for signaling termination not determined
    • How Src-phosphorylated nuclear STAT5B fails to activate certain promoters remains unclear
  5. 2000 High

    Showing that STAT5B inhibits NF-κB signaling by competing for limiting p300/CBP coactivators revealed a transcription-independent function of activated STAT5B as a coactivator titrator, broadening its role beyond direct DNA binding.

    Evidence PRL-stimulated reporter assays with p300/CBP rescue, dominant-negative STAT5B, C-terminal deletion mutants

    PMID:10628751

    Open questions at the time
    • Whether this occurs on endogenous NF-κB target genes in vivo not shown
    • Stoichiometry of STAT5B vs NF-κB competition for p300/CBP not quantified
  6. 2001 High

    Identification of Tyr-699 as the essential activating phosphosite plus three additional EGF-induced tyrosine sites (725, 740, 743) that negatively modulate transcription, and of Ser730 as a promoter-context-dependent modulator of transcriptional output, revealed multi-site phosphorylation-based regulation of STAT5B activity.

    Evidence Mass spectrometry + site-directed mutagenesis + reporter assays in EGFR-overexpressing HEK293 and GH-stimulated cells

    PMID:11731617 PMID:11751923

    Open questions at the time
    • Kinase(s) responsible for Y725/740/743 phosphorylation not identified
    • In vivo relevance of Ser730 phosphorylation not tested
  7. 2002 High

    Discovery that STAT5B constitutively shuttles between nucleus and cytoplasm via a CRM1-dependent export pathway independently of cytokine stimulation, with a separate dimerization-dependent import mechanism upon activation, defined two distinct nuclear trafficking modes.

    Evidence Leptomycin B treatment, Y699 dimerization-defective mutant, coiled-coil domain deletions, immunofluorescence in Ba/F3 cells

    PMID:11971004

    Open questions at the time
    • Nuclear import receptor for the monomer pathway not identified
    • Functional consequence of constitutive shuttling remains unclear
  8. 2003 High

    In vivo adenoviral gene transfer demonstrated that STAT5B is necessary and sufficient for GH-stimulated transcription of the IGF-I, ALS, IGFBP-3, SOCS-1, SOCS-2, and CIS genes in liver, establishing it as the master mediator of the hepatic GH-IGF axis.

    Evidence Dominant-negative and constitutively active STAT5B adenoviral vectors delivered to pituitary-deficient rats, with multi-gene expression readouts

    PMID:12682066 PMID:14761873

    Open questions at the time
    • Chromatin-level mechanism of target gene selectivity not determined at this stage
    • Contribution of STAT5A to residual GH responses in liver not fully excluded
  9. 2005 High

    ChIP identification of two distinct STAT5B-occupied GH response elements in the IGF-I locus, each with paired high- and low-affinity sites, provided the first chromatin-level map of STAT5B binding at a key physiological target.

    Evidence Chromatin immunoprecipitation in rat liver, quantitative binding studies, reconstitution reporter assays

    PMID:16339156

    Open questions at the time
    • Whether STAT5B tetramers vs dimers occupy these paired sites in vivo not resolved
    • Enhancer-promoter looping mechanism not addressed
  10. 2006 High

    Multiple studies expanded STAT5B's biological reach: it is required for CD4+CD25high Treg cell accumulation and FOXP3 expression (shown by a human A630P loss-of-function mutation), cooperates with nuclear EGFRvIII on the Bcl-XL promoter in glioblastoma, and mediates thrombin-induced VSMC growth via STAT3 co-association.

    Evidence Patient germline mutation with Treg functional assays; nuclear Co-IP + ChIP + shRNA in glioblastoma cells; dominant-negative STAT5B adenovirus + Co-IP in VSMC

    PMID:16527988 PMID:16920911 PMID:22729867

    Open questions at the time
    • Whether STAT5B directly binds FOXP3 regulatory elements not tested
    • How EGFRvIII translocates to the nucleus to partner with STAT5B not explained
  11. 2012 High

    Identification of Ser-193 as an mTOR-dependent, PP2A-reversed cytoplasmic phosphorylation event required for maximal STAT5B transcriptional activity revealed an additional signaling input that modulates STAT5B before nuclear entry.

    Evidence Mass spectrometry, phospho-specific antibodies, mTOR/PP2A inhibitors, site-directed mutagenesis, HEK293 reconstitution

    PMID:22442148

    Open questions at the time
    • Whether mTOR directly phosphorylates Ser-193 or acts through an intermediate kinase not determined
    • Interplay between Ser-193 and Ser-730 phosphorylation not studied
  12. 2013 High

    Discovery of somatic gain-of-function STAT5B mutations (N642H, Y665F) in the SH2 domain in LGL leukemia established STAT5B as a directly mutated oncogene in human cancer.

    Evidence Exome/transcriptome sequencing of LGL leukemia, targeted amplicon sequencing, transfection of mutant constructs with phosphorylation and transcriptional activity assays

    PMID:23596048

    Open questions at the time
    • Mechanism by which N642H increases phosphorylation persistence not yet biophysically explained
    • Frequency and spectrum of STAT5B mutations across other lymphoid malignancies not yet surveyed
  13. 2015 High

    Biophysical characterization showed that N642H creates enhanced pY699-SH2 binding affinity (SPR) and dephosphorylation resistance, explaining the prolonged phospho-STAT5B persistence observed in N642H-driven lymphomas and providing a structural rationale for oncogenicity.

    Evidence Surface plasmon resonance, molecular modelling, transduction of NK and γδ-T cells, JAK1/2 inhibitor treatment

    PMID:25586472

    Open questions at the time
    • Crystal structure of mutant not yet available at this time
    • Whether dephosphorylation resistance reflects altered phosphatase binding or intrinsic dimer stability not distinguished
  14. 2018 High

    Functional dissection of dominant-negative STAT5B germline mutations showed that distinct mutants fail at different steps (nuclear localization vs DNA binding) yet all retain dimerization capacity, establishing the molecular logic of dominant-negative STAT5B disease.

    Evidence Patient germline mutations, nuclear localization assays, EMSA, dimerization assays, reporter assays

    PMID:29844444

    Open questions at the time
    • Whether heterodimers with STAT5A are also formed and functionally impaired not tested
    • In vivo rescue of dominant-negative phenotype not demonstrated
  15. 2019 High

    Crystal structures of wild-type STAT5B and the N642H mutant revealed alternative SH2 domain conformations and dephosphorylation resistance at the structural level, while functional studies showed STAT5B (not STAT5A) is the major driver of BCR/ABL leukemogenesis by suppressing interferon responses.

    Evidence X-ray crystallography + MD simulations + transgenic/syngeneic mouse models; Stat5b−/− BCR/ABL+ cells + RNA-seq + IFN inhibition rescue

    PMID:30679796 PMID:31175292

    Open questions at the time
    • Full-length phosphorylated dimer structure not yet solved
    • How STAT5B suppresses IFN pathway transcription at the chromatin level not defined
  16. 2022 High

    CRISPR deletion and patient-derived cells showed STAT5B restrains B-cell differentiation into plasmablasts via IL-21-mediated SOCS3 induction and BCL6 repression, expanding STAT5B's non-redundant immune roles to humoral immunity.

    Evidence CRISPR KO in B-cell lines, primary cells from STAT5B-null patients, RNA-seq, phospho-flow, in vitro differentiation

    PMID:35469842

    Open questions at the time
    • Direct STAT5B binding at SOCS3 and BCL6 loci in B cells not shown by ChIP
    • Whether enhanced plasmablast formation contributes to autoimmunity in STAT5B-deficient patients not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full-length phosphorylated STAT5B dimer structure, the identity of nuclear import receptors for monomeric STAT5B, the chromatin-level basis for promoter selectivity among STAT5B target genes, and the therapeutic window for selective STAT5B inhibition in N642H-driven lymphomas.
  • Full-length activated dimer crystal structure not available
  • Nuclear import receptor for constitutive monomer shuttling not identified
  • Genome-wide chromatin occupancy comparison of STAT5B vs STAT5A not performed in most cell types

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-74160 Gene expression (Transcription) 7 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4
Partners
BCR-ABLCPEB3EGFRVIIIGHRJAK2SRCSTAT3STAT5A
Complex memberships
EGFRvIII-STAT5B nuclear complexSTAT5A/STAT5B heterodimerSTAT5B homodimer

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 STAT5A and STAT5B are activated by tyrosine phosphorylation in mammary tissue during lactation; upon phosphorylation, they form homo- and heterodimers that bind DNA and drive milk protein gene transcription. Phosphorylation correlates tightly with mammary gland differentiation. Isoform-specific antibodies, EMSA, supershift analysis, transgenic mice Molecular endocrinology High 8961260
1997 GH induces tyrosine phosphorylation of both STAT5A and STAT5B via JAK2 kinase, requiring specific cytoplasmic regions of the GH receptor (C-terminal half; tyrosines 333/338); JAK2 is required for GH-dependent STAT5B tyrosine phosphorylation. Transient transfection in COS cells and CHO cells expressing truncated/mutated GH receptors, JAK2-deficient cell lines, Western blotting Endocrinology High 9231797
1998 STAT5B, but not STAT5A, is essential for NK cell-mediated proliferation and cytolytic activity in response to IL-2 and IL-15; Stat5b-/- mice show diminished IL-2 receptor beta chain expression, reduced NK cell numbers and responsiveness. Stat5b knockout mice, proliferation assays, NK cytolytic activity assays The Journal of experimental medicine High 9841920
1998 The CIS gene promoter contains paired STAT binding elements that bind STAT5 tetramers; STAT5A (but not STAT5B) can form tetrameric complexes on adjacent STAT sites, representing a biochemical distinction between the two isoforms. STAT5B binds as a homodimer with higher affinity than STAT5A. EMSA with nuclear extracts and purified recombinant proteins, transient transfection with STAT5A/B expression vectors, COS-7 cell model Molecular and cellular biology High 9742102
1998 GM-CSF selectively activates JAK2, STAT3, and STAT5B (not STAT5A, STAT1, STAT2, STAT4, or STAT6) in human neutrophils; only the 92-kDa STAT5B isoform undergoes tyrosine phosphorylation and increased DNA binding in response to GM-CSF. Immunoprecipitation, Western blot, EMSA with isoform-specific antibodies The Journal of biological chemistry High 9422769
1998 STAT5A and STAT5B bind to a single GAS-like element (ALS-GAS1) in the mouse acid-labile subunit (ALS) promoter in a GH-dependent manner, mediating GH-induced transcription of the ALS gene in hepatocytes. Promoter deletion analysis, luciferase reporter assays, EMSA with supershift using STAT5 antibodies, primary rat hepatocytes and H4-II-E hepatoma cells Molecular endocrinology High 9605930
1998 GH and PRL activate STAT5B via JAK2 tyrosine phosphorylation in Leydig cells, inducing STAT5B nuclear translocation and DNA binding to GAS elements; the response is cell-type specific (immature but not adult primary Leydig cells respond to GH). Immunoprecipitation, Western blot, EMSA, primary rat Leydig cells and MA-10 mouse Leydig tumor cells Endocrinology Medium 9528973
1999 STAT5b mediates GH-induced expression of SOCS-2 and SOCS-3 mRNA in liver but not in mammary gland, demonstrating tissue-specific STAT5b-dependent feedback regulation of GH signaling. STAT5b knockout mice, GH treatment, Northern blot/mRNA quantification Molecular and cellular endocrinology High 10630411
1999 Src kinase activates STAT5B by tyrosine phosphorylation leading to its nuclear translocation, but this occurs by a mechanism distinct from JAK-mediated cytokine activation: src-mediated STAT5B nuclear translocation does not depend on JAK2, is selective for STAT5B over STAT5A, and is mediated by C-terminal sequences of STAT5B. Src-activated STAT5B does not drive beta-casein promoter transcription despite nuclear translocation. Dominant-negative JAK2 overexpression, indirect immunofluorescence, co-transfection reporter assays The Journal of biological chemistry High 10428824
1999 Termination of GH pulse-induced STAT5b signaling requires synthesis of a labile protein factor (sensitive to cycloheximide), proteasome activity (sensitive to MG132), and phosphotyrosine phosphatase activity (sensitive to pervanadate); serine kinase inhibitor H7 sustains JAK2 signaling to STAT5b. CWSV-1 rat liver cell line, pharmacological inhibitors (cycloheximide, MG132, pervanadate, H7), GH pulse protocols Molecular endocrinology High 9892011
1999 STAT5b is essential for GH pulse-dependent activation of male-specific liver P450 gene expression (CYP2D9) and body weight gain; STAT5b-deficient mice are GH pulse-resistant, demonstrating STAT5b is the key intracellular mediator of pulsatile GH effects in liver. STAT5b knockout mice, hypophysectomy + pulsatile GH replacement, liver gene expression analysis The Journal of biological chemistry High 10585399
1999 Continuous (female-pattern) GH exposure down-regulates JAK2-STAT5b signaling in liver cells through enhanced dephosphorylation of both STAT5b and GHR-JAK2, with the JAK2 dephosphorylation leading to receptor internalization/degradation. CWSV-1 liver cell line, pharmacological inhibitors (pervanadate, proteasome inhibitors), continuous vs. pulsatile GH treatment protocols Molecular endocrinology High 9973252
1999 GH-activated STAT5b inhibits PPARalpha transcription by targeting the ligand-independent AF-1 transactivation domain of PPARalpha; a constitutively active STAT5b mutant does not inhibit PPARalpha, and SOCS-3 abolishes the inhibitory response. Transient transfection, luciferase reporter assays, GAL4-chimeric receptor constructs, constitutively active and dominant-negative STAT5b mutants The Journal of biological chemistry High 10514468
2000 STAT5a (but not STAT5b, STAT1–4, or STAT6) is potently activated by Flt3 ligand (FL) downstream of Flt3 receptor kinase without Jak activation; FL does not stimulate hematopoietic progenitor proliferation in Stat5a-/- mice but does in Stat5b-/- mice, demonstrating functional non-redundancy. Baf3/Flt3 stable cell line, EMSA, Stat5a-/- and Stat5b-/- mouse bone marrow progenitor assays The Journal of experimental medicine High 10974037
2000 PRL-inducible STAT5b inhibits NFκB-mediated signaling independently of STAT5b-DNA interactions but requiring the carboxyl terminus of STAT5b and nuclear translocation; the inhibition is reversed by overexpression of p300/CBP coactivator, suggesting competition for limiting coactivators. Transient transfection, luciferase reporter assays, dominant-negative STAT5b, p300/CBP overexpression Molecular endocrinology High 10628751
2001 EGF activates STAT5b at three novel tyrosine sites (Tyr-725, Tyr-740, Tyr-743) in addition to Tyr-699; Tyr-699 is absolutely required for transcriptional activation while tyrosines 725, 740, 743 may negatively regulate transcription. EGF-induced STAT5b activation requires EGFR overexpression. Metabolic labeling, site-directed mutagenesis, luciferase reporter assays, stable EGFR-overexpressing HEK293 cells The Journal of biological chemistry High 11751923
2001 STAT5b serine phosphorylation at Ser730 contributes to GH-stimulated transcriptional activity in a promoter context-dependent manner; mutation of Ser730 to Ala reduces reporter activity ~50% at an isolated STAT5-binding site but causes ~2-fold higher activity at the intact beta-casein promoter. Mass spectrometry, site-directed mutagenesis, GH-stimulated luciferase reporter assays, serine kinase inhibitor H7 Molecular endocrinology High 11731617
2002 STAT5B mediates synergism between EGFR and c-Src: EGF-induced STAT5b tyrosine phosphorylation requires EGFR Tyr845 (a c-Src phosphorylation site), and dominant-negative STAT5b abolishes EGF-induced DNA synthesis, placing STAT5b downstream of the EGFR/c-Src axis. Tyrosine-to-phenylalanine receptor mutants, dominant-negative STAT5b, kinase-defective c-Src, luciferase reporter assays, DNA synthesis assays in human breast tumor cell lines The Journal of biological chemistry High 12429742
2002 STAT5B shuttles between nucleus and cytoplasm via two distinct mechanisms: (1) a constitutive, cytokine-independent monomer import (requiring the coiled-coil domain, sensitive to leptomycin B indicating CRM1-dependent export), and (2) a cytokine-stimulated, tyrosine phosphorylation/dimerization-dependent import. Leptomycin B treatment, STAT5B Tyr699 mutant (dimerization-defective), deletion mutants, immunofluorescence in Ba/F3 cells Journal of immunology High 11971004
2003 STAT5b is a key component of GH-stimulated IGF-I gene transcription in vivo: dominant-negative STAT5b completely prevents GH-stimulated IGF-I gene transcription in rat liver, while constitutively active STAT5b drives IGF-I expression in the absence of hormone. In vivo adenovirus-mediated gene transfer to pituitary-deficient rats, IGF-I mRNA quantification, constitutively active and dominant-negative STAT5b The Journal of biological chemistry High 12682066
2003 A Stat5b mutation (L327M) in NOD mice reduces DNA-binding affinity (Leu327 is the first residue in the STAT DNA-binding domain, conserved in all STATs), leading to decreased expression of Stat5b-regulated target genes IL-2Rβ and Pim1. Sequencing, homology modeling, DNA-protein binding assays, Western blotting The Journal of biological chemistry Medium 14701862
2003 Constitutive activation of Stat5b contributes to squamous cell carcinogenesis in vivo; Stat5b antisense blockade inhibits tumor growth and abrogates Stat5 target gene expression in xenografts. EGFR links to Stat5b in vivo. Antisense oligonucleotide blockade in xenograft model, gene expression analysis Cancer research Medium 14583472
2004 In vivo, dominant-negative STAT5b completely inhibits GH-stimulated transcription of IGF-I, IGFBP-3, ALS, SOCS-1, SOCS-2, and CIS genes in rat liver, but has little effect on SOCS-3. Constitutively active STAT5b drives IGF-I, ALS, and IGFBP-3 without hormone but minimally affects SOCS family induction. In vivo adenovirus-mediated gene transfer to pituitary-deficient male rats, gene expression analysis, dominant-negative and constitutively active STAT5b American journal of physiology. Endocrinology and metabolism High 14761873
2004 STAT5b and HNF4alpha exhibit bidirectional cross-talk in liver: HNF4alpha inhibits STAT5b transcriptional activity by blocking GH-stimulated JAK2 tyrosine phosphorylation (not STAT5b dephosphorylation), while STAT5b synergistically enhances HNF4alpha activity at the ApoCIII promoter. Transient transfection reporter assays in HepG2 cells, dominant-negative phosphatase 1B, pervanadate treatment, Western blot for JAK2 and STAT5b phosphorylation The Biochemical journal High 16584384
2005 Stat5b binds two distinct GH response elements in the rat IGF-I locus in vivo in a GH-dependent manner (chromatin immunoprecipitation); each element contains one high-affinity and one lower-affinity Stat5b site; paired Stat5b sites in intron 2 are more than twice as effective as the 5'-distal element in driving transcription. Chromatin immunoprecipitation (ChIP), quantitative protein-DNA binding studies, biochemical reconstitution reporter assays The Journal of biological chemistry High 16339156
2006 STAT5b is required for the in vivo accumulation and regulatory function of CD4+CD25high T regulatory cells; STAT5b(A630P) missense mutation in a patient leads to low FOXP3 expression, impaired Treg suppression, and reduced CD25 expression in response to IL-2. Patient study with homozygous STAT5b missense mutation, flow cytometry, functional Treg assays, in vitro IL-2 stimulation Journal of immunology High 16920911
2006 STAT5b mediates neurotensin-induced mitogenesis in prostate cancer cells via a c-Src/EGFR Tyr845/STAT5b pathway; mutant forms of EGFR (Y845F) or STAT5b, or catalytic inhibitors of EGFR, c-Src, and MMPs, abrogate NT-induced DNA synthesis. Site-directed mutant EGFR and STAT5b expression, selective kinase inhibitors, BrdU incorporation/cell counting, PC3 prostate cancer cells Oncogene High 16862179
2006 Thrombin activates STAT5B (not STAT5A) to induce Hsp27 and FGF-2 expression in vascular smooth muscle cells (VSMC), mediating VSMC growth and motility; STAT5B associates with STAT3 in response to thrombin. Dominant-negative adenoviral STAT5B/STAT5A constructs, siRNA against Hsp27, dominant-negative STAT3, co-immunoprecipitation, VSMC growth and motility assays Circulation research High 16527988
2006 Nuclear EGFRvIII forms a complex with phosphorylated STAT5b, binds DNA, and cooperates with STAT5b to regulate the Bcl-XL promoter; STAT5b knockdown reduces Bcl-XL levels and sensitizes glioblastoma cells to cisplatin. Co-immunoprecipitation of nuclear EGFR-STAT5b, ChIP on Bcl-XL and Aurora A promoters, shRNA knockdown, cisplatin sensitivity assays International journal of cancer High 22729867
2006 Glucocorticoids recruit STAT5B to the P4 promoter of bcl-X in lymphoid cells where it acts as a persistent repressor; inhibition of STAT5 activity converts glucocorticoid-induced repression to activation, associated with stable GR and RNA Pol II recruitment. ChIP, transient transfection reporter assays, STAT5 inhibition in S49 T cells and mouse thymocytes The Journal of biological chemistry Medium 16959781
2010 CPEB3 interacts with STAT5b in the nucleus and inhibits its transcriptional activity without disrupting STAT5b dimerization, DNA binding, or nuclear localization; EGFR is a direct transcriptional target of STAT5b in neurons, negatively regulated by CPEB3. Co-immunoprecipitation of CPEB3-STAT5b, STAT5b knockdown, reporter assays, NMDA receptor activation, neuronal CPEB3 nuclear accumulation Nucleic acids research High 20639532
2010 ZFP36L1 negatively regulates erythroid differentiation of CD34+ hematopoietic stem cells by directly binding the 3'-UTR of STAT5b mRNA and triggering its degradation, thereby down-regulating STAT5b protein and suppressing erythroid colony formation. ZFP36L1 overexpression, siRNA knockdown, 3'-UTR binding assay, erythroid colony formation assay Molecular biology of the cell High 20702587
2010 Stat5b has a predominant role over Stat5a in promoting prostate cancer cell viability and tumor growth; inhibition of Stat5a/b induces massive cancer cell death and reduces subcutaneous and orthotopic tumor growth in vivo, while Stat3 dominates metastasis promotion. siRNA knockdown, subcutaneous and orthotopic xenograft models, RNA-seq gene expression profiling The American journal of pathology High 20167868
2012 STAT5b Ser-193 is a novel cytokine-induced phosphorylation site identified by mass spectrometry; it is phosphorylated rapidly in the cytoplasm prior to nuclear translocation, requires mTOR kinase and PP2A dephosphorylates it, and is required for maximal STAT5b transcriptional activity. Mass spectrometry, phospho-specific antibodies, mTOR and PP2A inhibitors, site-directed mutagenesis, EMSA, reporter assays, HEK293 reconstitution The Journal of biological chemistry High 22442148
2013 Somatic STAT5B mutations (Y665F, N642H) in the SH2 domain increase STAT5 tyrosine phosphorylation and transcriptional activity in LGL leukemia cells, representing the first somatic STAT5 gain-of-function mutations discovered in human cancer. Exome and transcriptome sequencing, targeted amplicon sequencing, transfection of mutant constructs with phosphorylation and transcriptional activity assays Blood High 23596048
2015 STAT5B N642H mutation in the SH2 domain causes markedly increased binding affinity of phosphotyrosine-Y699 with the mutant histidine (surface plasmon resonance), prolonged persistence of phospho-STAT5B, and increased binding to target sites, conferring growth advantage to NK and γδ-T cells. Molecular modelling, surface plasmon resonance, next-generation sequencing, transduction of cell lines and primary NK cells, JAK1/2 inhibitor treatment Nature communications High 25586472
2015 The STAT5b SH2 domain can be selectively inhibited over STAT5a (>50-fold) by the natural product-inspired small molecule Stafib-1 (Ki=44 nM); binding site validated by point mutant functional analysis. In vitro SH2 domain binding assay, point mutant analysis, tumor cell phosphorylation inhibition Angewandte Chemie High 25702814
2017 Cryptochromes regulate IGF-1 production by controlling JAK2-dependent STAT5B phosphorylation at Y699 in liver and skeletal muscle; CRY deficiency reduces STAT5B Y699 phosphorylation without reducing JAK2 phosphorylation, placing CRY function downstream of JAK2 in the GH-STAT5B-IGF-1 axis. Cry-deficient mice, phospho-specific antibodies, IGF-1 ELISA, qPCR Molecular biology of the cell High 28100634
2017 Musculin (MSC) expressed in human Th17 cells in an RORγt-dependent manner upregulates PPP2R2B (PP2A regulatory subunit), which dephosphorylates STAT5B Ser-193, thereby reducing STAT5B transcriptional activity and IL-2 responsiveness in Th17 cells. Th17 cell expression analysis, PP2A inhibitor experiments, Ser-193 phosphorylation assay, gene reporter assays European journal of immunology High 28612433
2018 Dominant-negative STAT5B missense mutants are tyrosine phosphorylated but fail to localize to the nucleus or fail to bind canonical DNA response elements; each retains the ability to dimerize with wild-type STAT5B, thereby disrupting wild-type STAT5B transcriptional function through dominant-negative mechanism. Patient germline mutations, nuclear localization assays, EMSA for DNA binding, dimerization assays, transcriptional reporter assays Nature communications High 29844444
2018 cAMP-PKA signaling upregulates STAT5B in human trophoblast cells, and STAT5B knockdown decreases FSK-induced cell fusion and expression of syncytialization markers (CGB, syncytin2, GCM1, OVOL1), establishing STAT5B as a positive regulator of trophoblast syncytialization. siRNA knockdown of STAT5B, microarray, qPCR, syncytialization functional assays in BeWo cells Journal of cellular biochemistry Medium 29377304
2019 Crystal structures of human STAT5B and STAT5B-N642H reveal alternative SH2 domain conformations; biophysical data suggests the N642H mutant can adopt hyper-activated and hyper-inactivated states with resistance to dephosphorylation; MD simulations support sustained interchain cross-domain interactions in the N642H anti-parallel dimer. X-ray crystallography (human STAT5B and N642H crystal structures), biophysical assays, molecular dynamics simulations, transgenic mouse model, in vivo syngeneic transplant model Nature communications High 31175292
2019 STAT5B (not STAT5A) is the major STAT5 isoform driving BCR/ABL-induced leukemogenesis; STAT5B-deficient BCR/ABL+ cells show enhanced IFN-α and IFN-γ signatures, and IFN pathway inhibition rescues BCR/ABL+ colony formation of Stat5b-/- cells, demonstrating that STAT5B enables transformation by suppressing IFN responses. STAT5A/B-deficient BCR/ABL-expressing cells, RNA-seq, colony formation assays, IFN inhibition rescue experiments Leukemia High 30679796
2022 STAT5B restrains human B-cell differentiation into plasmablasts via IL-21 signaling; STAT5B deletion in B cells diminishes IL-21-mediated SOCS3 induction and BCL6 repression, leading to enhanced plasmablast generation and class switching. CRISPR-mediated STAT5B deletion in B-cell lines, primary lymphocytes from STAT5B-null patients, RNA-seq, phospho-flow cytometry, in vitro differentiation assays The Journal of allergy and clinical immunology High 35469842

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells. Nature communications 327 25586472
2008 Interpretation of cytokine signaling through the transcription factors STAT5A and STAT5B. Genes & development 284 18347089
2000 The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 280 10851055
1998 Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. The Journal of experimental medicine 256 9841920
2013 Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood 247 23596048
1996 Activation of Stat5a and Stat5b by tyrosine phosphorylation is tightly linked to mammary gland differentiation. Molecular endocrinology (Baltimore, Md.) 214 8961260
1999 Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation. Cytokine & growth factor reviews 198 10743504
2006 Cutting edge: Decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency. Journal of immunology (Baltimore, Md. : 1950) 181 16920911
2000 Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling. The Journal of experimental medicine 171 10974037
2003 Acute control of insulin-like growth factor-I gene transcription by growth hormone through Stat5b. The Journal of biological chemistry 161 12682066
1995 Transcription factors Stat3 and Stat5b are present in rat liver nuclei late in an acute phase response and bind interleukin-6 response elements. The Journal of biological chemistry 152 8530402
2006 Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics 135 17030597
2002 STAT5b, a Mediator of Synergism between c-Src and the Epidermal Growth Factor Receptor. The Journal of biological chemistry 127 12429742
1998 A sequence of the CIS gene promoter interacts preferentially with two associated STAT5A dimers: a distinct biochemical difference between STAT5A and STAT5B. Molecular and cellular biology 124 9742102
1998 Granulocyte-macrophage colony-stimulating factor-activated signaling pathways in human neutrophils. Selective activation of Jak2, Stat3, and Stat5b. The Journal of biological chemistry 104 9422769
2012 The STAT5b Pathway Defect and Autoimmunity. Frontiers in immunology 100 22912632
1999 STAT5b mediates the GH-induced expression of SOCS-2 and SOCS-3 mRNA in the liver. Molecular and cellular endocrinology 100 10630411
1999 Differential effects of prolactin and src/abl kinases on the nuclear translocation of STAT5B and STAT5A. The Journal of biological chemistry 98 10428824
2003 Constitutive activation of Stat5b contributes to carcinogenesis in vivo. Cancer research 95 14583472
2017 HIV-1-mediated insertional activation of STAT5B and BACH2 trigger viral reservoir in T regulatory cells. Nature communications 93 28887441
2011 STAT5b deficiency: lessons from STAT5b gene mutations. Best practice & research. Clinical endocrinology & metabolism 90 21396575
2012 Mapping the growth hormone--Stat5b--IGF-I transcriptional circuit. Trends in endocrinology and metabolism: TEM 89 22361342
2018 Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nature communications 86 29844444
1999 STAT5b-deficient mice are growth hormone pulse-resistant. Role of STAT5b in sex-specific liver p450 expression. The Journal of biological chemistry 82 10585399
2003 A functional polymorphism in a STAT5B site of the human PPAR gamma 3 gene promoter affects height and lipid metabolism in a French population. Arteriosclerosis, thrombosis, and vascular biology 80 12588773
1995 STAT3 and STAT5B are targets of two different signal pathways activated by hematopoietin receptors and control transcription via separate cytokine response elements. The Journal of biological chemistry 77 7559477
2006 Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. The Journal of clinical endocrinology and metabolism 75 16787985
2004 In vivo regulation of growth hormone-stimulated gene transcription by STAT5b. American journal of physiology. Endocrinology and metabolism 75 14761873
2006 Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway. Oncogene 73 16862179
2018 Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia. Leukemia 70 30573779
2005 Characterization of distinct Stat5b binding sites that mediate growth hormone-stimulated IGF-I gene transcription. The Journal of biological chemistry 70 16339156
2000 Stat5b inhibits NFkappaB-mediated signaling. Molecular endocrinology (Baltimore, Md.) 70 10628751
2015 STAT5B deficiency: Impacts on human growth and immunity. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 68 26703237
2014 Identification of STAT5A and STAT5B target genes in human T cells. PloS one 68 24497979
2014 Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma. Cell death and differentiation 67 24440911
1999 Insulin inhibits growth hormone signaling via the growth hormone receptor/JAK2/STAT5B pathway. The Journal of biological chemistry 67 10224108
1999 STAT5b down-regulates peroxisome proliferator-activated receptor alpha transcription by inhibition of ligand-independent activation function region-1 trans-activation domain. The Journal of biological chemistry 67 10514468
1997 Growth hormone-induced tyrosyl phosphorylation and deoxyribonucleic acid binding activity of Stat5A and Stat5B. Endocrinology 65 9231797
1999 Termination of growth hormone pulse-induced STAT5b signaling. Molecular endocrinology (Baltimore, Md.) 64 9892011
2010 Transcription factor Stat3 stimulates metastatic behavior of human prostate cancer cells in vivo, whereas Stat5b has a preferential role in the promotion of prostate cancer cell viability and tumor growth. The American journal of pathology 63 20167868
2019 Structural and functional consequences of the STAT5BN642H driver mutation. Nature communications 62 31175292
2002 Stat5B shuttles between cytoplasm and nucleus in a cytokine-dependent and -independent manner. Journal of immunology (Baltimore, Md. : 1950) 59 11971004
2001 Serine phosphorylation of GH-activated signal transducer and activator of transcription 5a (STAT5a) and STAT5b: impact on STAT5 transcriptional activity. Molecular endocrinology (Baltimore, Md.) 59 11731617
1998 Binding of STAT5a and STAT5b to a single element resembling a gamma-interferon-activated sequence mediates the growth hormone induction of the mouse acid-labile subunit promoter in liver cells. Molecular endocrinology (Baltimore, Md.) 58 9605930
2014 Uncovering the pathogenesis of large granular lymphocytic leukemia-novel STAT3 and STAT5b mutations. Annals of medicine 57 24512550
1999 PPARgamma ligand-dependent induction of STAT1, STAT5A, and STAT5B during adipogenesis. Biochemical and biophysical research communications 57 10448095
2001 Novel activation of STAT5b in response to epidermal growth factor. The Journal of biological chemistry 54 11751923
1999 Down-regulation of liver JAK2-STAT5b signaling by the female plasma pattern of continuous growth hormone stimulation. Molecular endocrinology (Baltimore, Md.) 54 9973252
2015 Nanomolar inhibitors of the transcription factor STAT5b with high selectivity over STAT5a. Angewandte Chemie (International ed. in English) 53 25702814
2017 Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation. Molecular biology of the cell 52 28100634
2010 A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings. European journal of endocrinology 49 20538865
2003 Down-regulation of STAT5b transcriptional activity by ligand-activated peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma. Molecular pharmacology 49 12869640
2020 STAT3 and STAT5B Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features. Cancers 48 33255665
2012 Methylsulfonylmethane suppresses breast cancer growth by down-regulating STAT3 and STAT5b pathways. PloS one 47 22485142
2019 Twins with different personalities: STAT5B-but not STAT5A-has a key role in BCR/ABL-induced leukemia. Leukemia 45 30679796
2016 Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome. PloS one 45 26959237
2004 Simultaneous, bidirectional inhibitory crosstalk between PPAR and STAT5b. Toxicology and applied pharmacology 45 15364543
2023 STAT5b: A master regulator of key biological pathways. Frontiers in immunology 44 36755813
2013 Differentiating the roles of STAT5B and STAT5A in human CD4+ T cells. Clinical immunology (Orlando, Fla.) 44 23773921
2022 Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia. Blood cancer journal 43 35210405
2017 Rational development of Stafib-2: a selective, nanomolar inhibitor of the transcription factor STAT5b. Scientific reports 43 28400581
2016 Disruption of STAT5b-Regulated Sexual Dimorphism of the Liver Transcriptome by Diverse Factors Is a Common Event. PloS one 43 26959975
2002 The structure of human STAT5A and B genes reveals two regions of nearly identical sequence and an alternative tissue specific STAT5B promoter. Gene 42 12039059
2010 A novel role of CPEB3 in regulating EGFR gene transcription via association with Stat5b in neurons. Nucleic acids research 39 20639532
2012 Nuclear EGFRvIII-STAT5b complex contributes to glioblastoma cell survival by direct activation of the Bcl-XL promoter. International journal of cancer 38 22729867
2000 Thrombopoietin induces the generation of distinct Stat1, Stat3, Stat5a and Stat5b homo- and heterodimeric complexes with different kinetics in human platelets. Experimental hematology 38 10720694
2012 STAT5b as molecular target in pancreatic cancer--inhibition of tumor growth, angiogenesis, and metastases. Neoplasia (New York, N.Y.) 37 23097626
2003 A mutant Stat5b with weaker DNA binding affinity defines a key defective pathway in nonobese diabetic mice. The Journal of biological chemistry 37 14701862
2013 JAK2-STAT5B pathway and osteoblast differentiation. JAK-STAT 36 24470975
2018 Regulation of human trophoblast cell syncytialization by transcription factors STAT5B and NR4A3. Journal of cellular biochemistry 35 29377304
2006 Novel role for STAT-5B in the regulation of Hsp27-FGF-2 axis facilitating thrombin-induced vascular smooth muscle cell growth and motility. Circulation research 35 16527988
2005 Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells. Experimental & molecular medicine 35 16155412
2000 Pulsatility of growth hormone (GH) signalling in liver cells: role of the JAK-STAT5b pathway in GH action. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society 34 10984246
2017 STAT5B: A Differential Regulator of the Life and Death of CD4+ Effector Memory T Cells. Journal of immunology (Baltimore, Md. : 1950) 32 29187589
2012 Signal transducer and activator of transcription 5b (Stat5b) serine 193 is a novel cytokine-induced phospho-regulatory site that is constitutively activated in primary hematopoietic malignancies. The Journal of biological chemistry 32 22442148
2009 A novel role for signal transducer and activator of transcription 5b (STAT5b) in beta1-integrin-mediated human breast cancer cell migration. Breast cancer research : BCR 32 19630967
2020 Human growth disorders associated with impaired GH action: Defects in STAT5B and JAK2. Molecular and cellular endocrinology 31 33122102
2010 ZFP36L1 negatively regulates erythroid differentiation of CD34+ hematopoietic stem cells by interfering with the Stat5b pathway. Molecular biology of the cell 30 20702587
2004 Characterization of the human STAT5A and STAT5B promoters: evidence of a positive and negative mechanism of transcriptional regulation. FEBS letters 30 15043997
2007 Hypoxia activates the IGF-1 expression through STAT5b in human HepG2 cells. Biochemical and biophysical research communications 28 17509524
2017 Essential roles of stat5.1/stat5b in controlling fish somatic growth. Journal of genetics and genomics = Yi chuan xue bao 27 29246863
2015 Signal transducer and activator of transcription 5B (STAT5B) modulates adipocyte differentiation via MOF. Cellular signalling 27 26388045
2022 STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis. The Journal of allergy and clinical immunology 26 35469842
2021 miR-146a enhances regulatory T-cell differentiation and function in allergic rhinitis by targeting STAT5b. Allergy 26 34716993
2014 BCR-ABL affects STAT5A and STAT5B differentially. PloS one 26 24836440
2010 Constitutively active Stat5A and Stat5B promote adipogenesis. Environmental health and preventive medicine 26 21431790
2008 Enhancement of hypoxia-induced apoptosis of human breast cancer cells via STAT5b by momilactone B. International journal of oncology 26 18695876
2006 Signalling cross-talk between hepatocyte nuclear factor 4alpha and growth-hormone-activated STAT5b. The Biochemical journal 26 16584384
2018 Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation. Frontiers in immunology 23 29988287
2002 Diabetic LDL inhibits cell-cycle progression via STAT5B and p21(waf). The Journal of clinical investigation 23 11781356
2016 Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion. Oncology reports 22 27035235
2015 Phosphorylation of Capsaicinoid Derivatives Provides Highly Potent and Selective Inhibitors of the Transcription Factor STAT5b. ACS chemical biology 22 26469307
2013 Constitutive activation of STAT5A and STAT5B regulates IgM secretion in Waldenstrom's macroglobulinemia. Blood 21 24335105
2007 Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation. European journal of endocrinology 21 17287404
2017 Musculin inhibits human T-helper 17 cell response to interleukin 2 by controlling STAT5B activity. European journal of immunology 19 28612433
2012 Coffee polyphenols change the expression of STAT5B and ATF-2 modifying cyclin D1 levels in cancer cells. Oxidative medicine and cellular longevity 19 22919439
2006 Retracted: Glucocorticoids repress bcl-X expression in lymphoid cells by recruiting STAT5B to the P4 promoter. The Journal of biological chemistry 18 16959781
2006 Constitutively active STAT5b induces cytokine-independent growth of the acute myeloid leukemia-derived MUTZ-3 cell line and accelerates its differentiation into mature dendritic cells. Journal of immunotherapy (Hagerstown, Md. : 1997) 17 16531819
1999 EGF-induced activation of Stat1, Stat3, and Stat5b is unrelated to the stimulation of DNA synthesis in cultured hepatocytes. Biochemical and biophysical research communications 17 10329425
1998 Lactogenic hormone-inducible phosphorylation and gamma-activated site-binding activities of Stat5b in primary rat Leydig cells and MA-10 mouse Leydig tumor cells. Endocrinology 17 9528973