Affinage

STAT5B

Signal transducer and activator of transcription 5B · UniProt P51692

Length
787 aa
Mass
89.9 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 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

STAT5B is a latent cytoplasmic transcription factor that converts cytokine and growth-factor receptor engagement into GAS-element–driven gene expression, functioning downstream of prolactin, IL-2, growth hormone, and other receptors (PMID:7568026, PMID:8631883, PMID:9231797). Receptor-associated JAK kinases phosphorylate STAT5B on Tyr-699, which is required for dimerization and is the obligate step for cytokine-induced nuclear import; in resting cells STAT5B shuttles constitutively as a monomer via a CRM1-dependent export route, whereas activated dimers use a distinct Tyr-699/coiled-coil–dependent import mechanism (PMID:8631883, PMID:11971004). Maximal transcriptional output further requires a cytoplasmic, mTOR-sensitive Ser-193 phosphorylation that precedes nuclear translocation (PMID:22442148). STAT5B and the paralog STAT5A diverge functionally: a single DNA-binding-domain residue (Gly-433 in STAT5B versus Glu in STAT5A) sets differential GAS-site preference, and STAT5B is selectively required for growth-hormone–driven, sex-specific liver gene expression while STAT5A governs prolactin-induced mammary development (PMID:9852045, PMID:9630227, PMID:10585399). Through these activities STAT5B controls NK-cell proliferation and cytolytic function via IL-2Rβ, IFN-γ–induced IGF-1 production, and restraint of IL-21–driven B-cell differentiation through SOCS3 and BCL6 induction (PMID:9841920, PMID:14570891, PMID:35469842). Signaling is terminated by phosphotyrosine dephosphorylation, with PTP1B acting as a direct STAT5B phosphatase, together with serine-kinase- and proteasome-dependent feedback (PMID:9892011, PMID:10993888). STAT5B drives leukemic transformation, in part by suppressing IFN-α/γ responses in BCR/ABL+ cells, and recurrent activating mutations—notably N642H in the SH2 domain—prolong phospho-STAT5B persistence by increasing phosphotyrosine–SH2 affinity and conferring dephosphorylation resistance, as defined by surface plasmon resonance and crystal structures of wild-type and mutant protein (PMID:25586472, PMID:31175292, PMID:30679796). Dominant-negative missense mutations in STAT5B cause growth hormone insensitivity by impairing either nuclear localization or DNA binding while still dimerizing with and poisoning wild-type protein (PMID:29844444).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    Established STAT5B as a sequence-specific transcriptional activator acting downstream of cytokine receptor signaling, answering whether the cloned factor could directly drive hormone-induced transcription.

    Evidence cDNA cloning, in vitro GAS-site DNA-binding assays, and prolactin-receptor reporter reconstitution in COS cells

    PMID:7568026

    Open questions at the time
    • Did not define the upstream kinase or activation residues
    • No endogenous target genes identified
  2. 1996 High

    Defined the receptor architecture and the obligate dimerization residue, showing STAT5B activation requires JAK3/IL-2Rβ docking tyrosines and STAT5B Tyr-699.

    Evidence COS-7 reconstitution with dominant-negative constructs and tyrosine point mutants of IL-2Rβ and STAT5B; EMSA in lymphocytes

    PMID:8631883 PMID:8961260

    Open questions at the time
    • Did not address how the two paralogs differ functionally
    • Mechanism of nuclear import not yet defined
  3. 1997 High

    Placed STAT5B activation downstream of JAK2 at the growth hormone receptor, establishing the GHR cytoplasmic determinants required for phosphorylation.

    Evidence GHR truncation/mutation constructs and JAK2-deficient cell line rescue with Western blotting and EMSA

    PMID:9231797

    Open questions at the time
    • Did not separate STAT5B from STAT5A physiological roles
    • In vivo GH consequences untested
  4. 1998 High

    Resolved paralog specificity, showing a single DNA-binding-domain residue (Gly-433) governs differential GAS-site preference and that STAT5A and STAT5B have non-redundant tissue roles.

    Evidence Chimeric proteins and point mutagenesis with EMSA; individual and double Stat5a/Stat5b knockout mice

    PMID:9630227 PMID:9841920 PMID:9852045

    Open questions at the time
    • Mechanistic basis for tissue-restricted requirement unresolved
    • How a single residue rewires target selection in vivo not mapped
  5. 1999 High

    Defined STAT5B as the essential mediator of pulsatile GH-driven, sex-specific liver gene expression and dissected the multi-step termination of GH signaling.

    Evidence Hypophysectomized STAT5b-deficient mice with pulsatile GH replacement and liver P450 readouts; rat liver cell models with cycloheximide, MG132, pervanadate, and H7 inhibitors

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

    Open questions at the time
    • Identity of the labile feedback protein not established
    • Specific serine kinase and phosphatase not molecularly identified
  6. 2000 High

    Identified PTP1B as a direct STAT5B phosphatase that terminates signaling and blocks nuclear translocation, and flagged CrkL as a STAT5B-associated adapter.

    Evidence In vitro phosphatase assays and substrate-trapping PTP1B co-precipitation in mammary cells; co-IP of CrkL from TPO-stimulated platelets

    PMID:10720694 PMID:10993888

    Open questions at the time
    • Other STAT5B phosphatases not excluded
    • CrkL association based on single-method co-IP at this stage
  7. 2002 High

    Distinguished the two nuclear-trafficking modes of STAT5B and extended its activation to EGFR/Src signaling, broadening the input space beyond classical cytokines.

    Evidence Leptomycin B, Tyr-699 and deletion mutants with fractionation in Ba/F3 cells; EGFR/Src tyrosine mutants with DNA-synthesis assays

    PMID:11971004 PMID:12429742

    Open questions at the time
    • Import receptor for the dimer-dependent route not identified
    • Physiological relevance of monomer shuttling unresolved
  8. 2003 Medium

    Demonstrated isoform-selective STAT5B function in IFN-γ–induced IGF-I production and that a DNA-binding-domain mutation weakens target gene expression.

    Evidence Primary human fibroblasts with functional vs non-functional STAT5B and IGF-I mRNA readouts; NOD mouse L327M mutant with EMSA and target gene analysis

    PMID:14570891 PMID:14701862

    Open questions at the time
    • STAT5A non-redundancy mechanism in IGF-I regulation not fully defined
    • L327M findings from a single genetic background
  9. 2006 Medium

    Established CrkL as a functional cofactor that enhances STAT5B DNA binding, rescuing a binding-defective mutant.

    Evidence Co-IP and recombinant CrkL profection with EMSA in NOD and congenic backgrounds

    PMID:16505237

    Open questions at the time
    • Structural basis of CrkL-enhanced binding not defined
    • Single-lab finding
  10. 2012 High

    Identified Ser-193 as an mTOR-sensitive cytoplasmic phosphorylation site required for maximal STAT5B transcriptional activity, adding a serine-dependent layer to activation.

    Evidence Mass spectrometry, phospho-specific antibodies, mTOR/PP2A inhibitors, and site-directed mutagenesis in HEK293 reconstitution with EMSA/reporters

    PMID:22442148

    Open questions at the time
    • Specific Ser-193 kinase not identified
    • How Ser-193 phosphorylation augments transcription mechanistically unclear
  11. 2017 Medium

    Connected STAT5B to circadian and Th17 regulatory inputs, placing CRY downstream of JAK2 in IGF-1 control and defining a RORγt→MSC→PP2A axis that dephosphorylates Ser-193.

    Evidence Cry-deficient mice with phospho-specific Western blotting; siRNA knockdown of MSC/PPP2R2B with PP2A and phospho-Ser-193 readouts in human Th17 cells

    PMID:28100634 PMID:28612433

    Open questions at the time
    • Molecular link between CRY and Tyr-699 phosphorylation not defined
    • Each mechanism from a single lab
  12. 2018 High

    Defined the pathomechanism of dominant-negative STAT5B growth hormone insensitivity, showing mutants poison wild-type function by impairing nuclear localization or DNA binding while still dimerizing.

    Evidence Patient-derived cells with GH-stimulation, localization imaging, EMSA, and co-IP for heterodimerization

    PMID:29844444

    Open questions at the time
    • Genotype-phenotype correlation for clinical severity not fully mapped
    • Quantitative dominant-negative threshold not established
  13. 2019 High

    Provided the structural and oncogenic mechanism of STAT5B activation, showing N642H increases pTyr-SH2 affinity, stabilizes the dimer, and confers dephosphorylation resistance, and that STAT5B drives leukemia by suppressing IFN responses.

    Evidence SPR, X-ray crystallography, MD simulations, and transgenic/syngeneic mouse models; STAT5A/B-specific knockouts with RNA-seq and IFN-inhibition rescue in BCR/ABL models

    PMID:25586472 PMID:30679796 PMID:31175292

    Open questions at the time
    • Full set of leukemic target genes downstream of stabilized STAT5B not enumerated
    • How dephosphorylation resistance integrates with PTP1B in vivo unresolved
  14. 2022 High

    Defined a B-cell intrinsic brake function for STAT5B, showing it restrains IL-21-driven plasmablast differentiation via SOCS3 and BCL6.

    Evidence CRISPR STAT5B deletion in B-cell lines with phospho-flow and RNA-seq, plus STAT5B-null patient PBMC studies

    PMID:35469842

    Open questions at the time
    • Direct STAT5B occupancy at SOCS3/BCL6 loci in primary B cells not detailed
    • Interplay with other STAT5B immune phenotypes not integrated
  15. 2024 High

    Established in vivo that C-terminal tyrosine phosphorylation of STAT5B is required for maximal IL-2-driven CD8+ T-cell proliferation through cell-cycle and receptor-expression programs.

    Evidence Tyr-to-Phe knockin mice with flow cytometry, RNA-seq, proteomics, and cell-cycle analysis

    PMID:39191751

    Open questions at the time
    • Separation of STAT5A vs STAT5B contributions to the phenotype incomplete
    • Direct cell-cycle gene targets not individually validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The kinases responsible for Ser-193 phosphorylation and the labile feedback protein governing GH-signal termination remain molecularly unidentified, and the structural basis for paralog-specific target selection in vivo is unresolved.
  • Ser-193 kinase identity unknown
  • Feedback inhibitor protein not cloned
  • In vivo determinants of STAT5A/STAT5B target divergence beyond Gly-433 unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 4 GO:0140110 transcription regulator activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005829 cytosol 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
CRKLEGFRGRJAK2PTP1BSTAT5A

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 STAT5B (then called Stat5b) was cloned from mouse mammary tissue and shown to recognize GAS sites (TTCNNNGAA) in vitro and mediate prolactin-induced transcription in COS cells co-transfected with the prolactin receptor, establishing its role as a transcriptional activator downstream of prolactin/JAK2 signaling. cDNA cloning, in vitro DNA-binding assays, COS cell transfection with PRL receptor and reporter genes Proceedings of the National Academy of Sciences of the United States of America High 7568026
1996 STAT5B is activated by IL-2 in peripheral blood lymphocytes and NK-like cells. IL-2-induced STAT5B DNA-binding activity in COS-7 cells requires JAK3, the IL-2Rβ chain, the common γ-chain, and either Tyr-392 or Tyr-510 of IL-2Rβ as docking sites. Tyr-699 of STAT5B is required for dimerization. COS-7 reconstitution with specific antisera, dominant-negative constructs, site-directed tyrosine mutants of IL-2Rβ and STAT5B The Journal of biological chemistry High 8631883
1996 Upon prolactin-induced tyrosine phosphorylation, STAT5A and STAT5B form homo- and heterodimers and translocate to the nucleus, where both isoforms contribute to the DNA-binding activity detected during lactation. Stat5b homodimers are less abundant than Stat5a homodimers in mammary cells. Isoform-specific antibodies, EMSA, supershift analysis, immunodepletion, co-immunoprecipitation in mammary tissue/cells Molecular endocrinology (Baltimore, Md.) High 8961260
1997 Growth hormone induces tyrosyl phosphorylation of both STAT5A and STAT5B, and JAK2 kinase is required for GH-dependent tyrosyl phosphorylation of STAT5B. The GH receptor's C-terminal cytoplasmic domain and Tyr-333/338 are required for maximal STAT5B activation. COS cell expression with GHR truncation/mutation constructs, JAK2-deficient cell lines (gamma2A-GHR vs. 2C4-GHR), Western blotting, EMSA Endocrinology High 9231797
1998 STAT5A and STAT5B homodimers have distinct DNA-binding specificities determined by a single amino acid: Gly-433 in STAT5B (vs. Glu at the equivalent position in STAT5A) in the DNA-binding domain determines their differential DNA-binding preference. Chimeric STAT5 molecules, site-directed mutagenesis, EMSA with different GAS-site oligonucleotides The Journal of biological chemistry High 9852045
1998 In mammary cells, STAT5A, STAT5B, and the glucocorticoid receptor (GR) are physically associated in vivo independently of lactogenic hormone treatment. Upon lactogenic hormone treatment, Stat5a-Stat5b heterodimers form and translocate to the nucleus. The GR does not bind the Stat5 DNA-binding site directly but is detectable in the Stat5-DNA complex, suggesting GR acts as a cofactor for milk protein gene transcription. Co-immunoprecipitation, immunodepletion, EMSA, HC11 mammary cell experiments at different developmental stages Molecular and cellular biology High 9528750
1998 STAT5B is essential for IL-2- and IL-15-mediated NK cell proliferation and cytolytic activity. Stat5b-/- mice show greatly diminished NK cell numbers and responsiveness, and diminished IL-2Rβ chain expression, establishing STAT5B as a non-redundant regulator of NK cell function via IL-2Rβ expression. Stat5b-knockout mice, anti-CD3 proliferation assays, NK cytolytic activity assays, flow cytometry The Journal of experimental medicine High 9841920
1998 Stat5a and Stat5b have essential and often redundant roles in cytokine responses. Stat5a is specifically required for prolactin-induced mammary gland development, while Stat5b is specifically required for growth hormone-mediated pubertal growth and sex-specific liver gene expression. Deletion of both leads to more severe phenotypes than single knockouts. Individual and double Stat5a/Stat5b gene-targeted knockout mice; phenotypic analysis of mammary, hepatic, and hematopoietic responses Cell High 9630227
1999 STAT5B is required for GH pulse-induced SOCS-2 and SOCS-3 expression in liver but not in mammary gland, demonstrating tissue-specific STAT5B-dependent regulation of negative feedback inhibitors of cytokine signaling. Comparison of GH-induced SOCS mRNA expression in wild-type vs. STAT5b-deficient mice by Northern/RT-PCR Molecular and cellular endocrinology High 10630411
1999 STAT5B is required for GH pulse responsiveness in liver. STAT5b-deficient mice fail to respond to pulsatile GH replacement with normal body weight gain, male-specific CYP2D9 expression, or suppression of female-specific CYP2B enzymes, establishing STAT5B as an essential mediator of pulsatile GH-driven sex-specific liver gene expression. Hypophysectomized wild-type vs. STAT5b-deficient mice with pulsatile GH replacement; liver P450 enzyme measurements The Journal of biological chemistry High 10585399
1999 Termination of GH pulse-induced STAT5B signaling involves: (1) synthesis of a labile protein factor (blocked by cycloheximide), (2) proteasome-dependent degradation (blocked by MG132), and (3) dephosphorylation by a phosphotyrosine phosphatase (blocked by pervanadate). A serine kinase (H7-sensitive) is required for down-regulation of JAK2 signaling to STAT5B. Rat liver cell line CWSV-1 with pharmacological inhibitors (cycloheximide, MG132, pervanadate, H7), kinetic Western blotting Molecular endocrinology (Baltimore, Md.) High 9892011
1999 Continuous (female-pattern) GH exposure down-regulates STAT5B activity in liver cells via enhanced dephosphorylation of both STAT5B and GHR-JAK2, with the latter step leading to increased internalization/degradation of the receptor-kinase complex. Pervanadate treatment reverses the down-regulation, confirming phosphotyrosine phosphatase involvement. CWSV-1 rat liver cell line, continuous vs. pulsatile GH treatment, pervanadate/proteasome inhibitors, EMSA for STAT5B DNA-binding activity Molecular endocrinology (Baltimore, Md.) High 9973252
1999 PRL-activated STAT5B selectively translocates to the nucleus upon src kinase activation, but src activation (unlike prolactin) does not activate a beta-casein reporter, suggesting src and JAK2 activate STAT5B via distinct mechanisms resulting in differential nuclear function. The C-terminal sequences of STAT5B mediate its selective nuclear translocation by src. Indirect immunofluorescence microscopy, dominant-negative JAK2 overexpression, co-transfection assays with beta-casein-luciferase reporter The Journal of biological chemistry Medium 10428824
1999 PRL-activated STAT5B inhibits NF-κB-mediated transcription by competing for limiting coactivators (p300/CBP) in the nucleus. This inhibitory effect requires the C-terminus of STAT5B and STAT5B nuclear translocation, but is independent of STAT5B-DNA interactions. Co-transfection assays with NF-κB reporters, dominant-negative STAT5B, p300/CBP co-expression titration experiments Molecular endocrinology (Baltimore, Md.) Medium 10628751
2000 PTP1B specifically dephosphorylates and deactivates prolactin-activated STAT5A and STAT5B in COS7 cells and in vitro. Overexpression of PTP1B inhibits nuclear translocation of both STAT5 isoforms and PRL-induced beta-casein gene transcription. Substrate-trapping PTP1B mutants co-precipitate tyrosine-phosphorylated STAT5. In vitro phosphatase assays, co-precipitation with substrate-trapping PTP1B mutants, retrovirus-mediated overexpression in mammary epithelial cells, reporter gene assay The Journal of biological chemistry High 10993888
2000 In platelets stimulated with thrombopoietin (TPO), CrkL adapter protein is present in DNA-bound STAT5 complexes and binds predominantly to STAT5B, identifying CrkL as a STAT5B-associated protein in TPO signaling. EMSA, immunoprecipitation, Western blotting in TPO-stimulated human platelets Experimental hematology Medium 10720694
2002 STAT5B shuttles constitutively between nucleus and cytoplasm as a monomer (independent of cytokine stimulation), via a CRM1-dependent nuclear export mechanism. Cytokine-dependent nuclear import uses a different mechanism requiring Tyr-699 phosphorylation and dimerization, and the coiled-coil domain. The nuclear export is sensitive to leptomycin B. Leptomycin B treatment, Tyr-699 mutant STAT5B, deletion mutants, nuclear/cytoplasmic fractionation, immunofluorescence in Ba/F3 cells Journal of immunology (Baltimore, Md. : 1950) High 11971004
2002 STAT5B mediates EGF-induced DNA synthesis downstream of EGFR overexpression and c-Src co-overexpression. EGF-induced phosphorylation of STAT5B requires Tyr-845 of the EGFR (phosphorylated by c-Src). STAT5B phosphorylation involves Tyr-699 (required for transcriptional activation) and Tyr-725/740/743 in the C-terminus. Site-specific EGFR tyrosine mutants, dominant-negative STAT5B, kinase-defective c-Src, breast tumor cell lines and C3H10T1/2 fibroblasts, [3H]-thymidine incorporation The Journal of biological chemistry High 12429742
2002 STAT5b-RARα fusion protein (APL) binds retinoic acid response elements (RAREs) as homodimer and as heterodimer with RXRα, inhibiting wild-type RARα/RXRα transactivation. The coiled-coil domain of STAT5b is required for homodimerization, inhibition of RARα/RXRα activity, and stability of the STAT5b-RARα/SMRT complex. STAT5b-RARα also enhances STAT3-dependent transcription via a distinct mechanism. RARE reporter assays, SMRT/TRAM-1 co-IP, domain deletion/mutation analysis in transfected cells Blood Medium 11929748
2003 Ligand-activated PPARα and PPARγ inhibit GH-induced, STAT5B-dependent transcription by up to ~80% without blocking STAT5B tyrosine phosphorylation or DNA binding. The inhibition requires the AF-1 (N-terminal) domain of PPARα and occurs downstream of STAT5B activation, suggesting competition for nuclear cofactors. Conversely, GH-activated STAT5B also inhibits PPAR-regulated transcription, demonstrating bidirectional cross-inhibition. COS-1 cell co-transfection with PPAR and STAT5B reporters, PPAR domain mutants, constitutively active STAT5B, Western blotting for phosphorylation status Molecular pharmacology Medium 12869640
2003 IFN-γ preferentially activates STAT5B (not STAT5A) in primary human dermal fibroblasts, and this activation is required for IFN-γ-induced upregulation of IGF-I mRNA. In fibroblasts with non-functional STAT5B, only STAT5A is activated and IGF-I induction is severely blunted, demonstrating that STAT5A cannot substitute for STAT5B in IGF-I transcriptional regulation. Primary human fibroblasts with functional vs. non-functional STAT5B, IFN-γ stimulation, nuclear translocation assays, IGF-I mRNA quantification The Journal of biological chemistry Medium 14570891
2003 A NOD mouse mutation (L327M) in the DNA-binding domain of Stat5b results in weaker DNA binding, confirmed by DNA-protein binding assays and correlated with decreased mRNA and protein levels of Stat5b target genes IL-2Rβ and Pim1. Sequencing, homology modeling, DNA-protein binding assays (EMSA), Western blotting comparing NOD vs. B6 mice The Journal of biological chemistry Medium 14701862
2006 HNF4α inhibits GH-activated STAT5B transcriptional activity by blocking GH-stimulated JAK2 tyrosine phosphorylation (upstream mechanism), while STAT5B synergistically enhances HNF4α-driven transcription of ApoCIII. This bidirectional cross-talk is selective (HNF4α does not affect IFN-γ/STAT1 activity). HepG2 cell co-transfection, dominant-negative PTP1B, pervanadate treatment, JAK2 and STAT5B phosphorylation Western blotting, promoter-reporter assays The Biochemical journal Medium 16584384
2006 In T lymphocytes, glucocorticoids recruit STAT5B to the P4 promoter of bcl-X. STAT5B remains bound while GR is released; subsequent co-recruitment of SMRT and HDAC3 leads to histone H3 deacetylation, RNA Pol II departure, and transcriptional repression. Inhibition of STAT5 activity converts glucocorticoid repression to activation. [Note: paper is marked as retracted.] ChIP assays in S49 T cells and primary thymocytes, STAT5 inhibitor, STAT5B co-transfection The Journal of biological chemistry Low 16959781
2006 CrkL adapter protein co-precipitates with Stat5b and is a binding cofactor that enhances Stat5b DNA-binding ability. Recombinant CrkL profection significantly increases Stat5b DNA binding and rescues the binding defect of the NOD mutant Stat5b. Co-immunoprecipitation, recombinant protein profection, EMSA in NOD and congenic mouse backgrounds Diabetes Medium 16505237
2010 STAT5B associates constitutively with the C-terminal tail of the δ-opioid receptor (δ-OR). δ-OR stimulation leads to STAT5B tyrosine phosphorylation in a G protein (Gi/Go) and c-Src kinase-dependent manner. STAT5B, c-Src, and selective Gα and Gβγ subunits form a multi-component signaling complex (signalosome) at the δ-OR C-terminus. Co-immunoprecipitation in HEK293 cells stably expressing δ-OR, pertussis toxin (G protein inhibition), c-Src kinase assays, STAT5B transcriptional reporter assays Neuropharmacology Medium 20433855
2012 STAT5B Ser-193 is a novel cytokine-induced (IL-2, IL-7, IL-9, IL-15) phosphorylation site that occurs in the cytoplasm prior to nuclear translocation. Ser-193 phosphorylation is sensitive to mTOR inhibitors (rapamycin) and enhanced by PP2A inhibition. Ser-193 phosphorylation is required for maximal STAT5B transcriptional activity (confirmed by site-directed mutagenesis). Constitutive Ser-193 phosphorylation is found in primary leukemia/lymphoma cells. Mass spectrometry identification, phospho-specific antibodies, mTOR/PP2A inhibitors, site-directed mutagenesis, HEK293 reconstitution assays, EMSA, reporter assays The Journal of biological chemistry High 22442148
2012 ΔEGFR (EGFRvIII) activates STAT5B at Y699 in a Src family kinase-dependent manner (distinct from full-length EGF-stimulated EGFR). Phosphorylated STAT5B and ΔEGFR form a nuclear complex that binds DNA and occupies promoters (including Bcl-XL and Aurora A). STAT5B knockdown reduces Bcl-XL levels and sensitizes glioblastoma cells to cisplatin. Co-immunoprecipitation, ChIP, siRNA knockdown, cisplatin cytotoxicity assays in glioblastoma cell lines and patient samples International journal of cancer Medium 22729867
2015 Activating mutations of STAT5B (particularly N642H in the SH2 domain) are frequent in γδ-T and NK-cell lymphomas. The N642H mutation markedly increases the binding affinity of phosphotyrosine-Y699 for the SH2 domain (measured by surface plasmon resonance), prolonging phospho-STAT5B persistence and increasing binding to target sites. Next-generation and Sanger sequencing, surface plasmon resonance, molecular modelling, phospho-STAT5B Western blotting, JAK inhibitor growth assays in transduced cell lines and primary NK cells Nature communications High 25586472
2017 Cryptochromes (CRY1/2) control IGF-1 circadian rhythms by regulating JAK2-dependent phosphorylation of STAT5B at Y699 (JAK2-dependent site). Cry-deficient mice show markedly reduced Y699 STAT5B phosphorylation in liver and skeletal muscle despite normal JAK2 phosphorylation, placing CRY activity downstream of JAK2 in the IGF-1 pathway. Cry-deficient mouse model, phospho-specific STAT5B and JAK2 Western blotting in liver and skeletal muscle, IGF-1 ELISA, Igf-1 mRNA quantification Molecular biology of the cell Medium 28100634
2017 Musculin (MSC), expressed in human Th17 cells in a RORγt-dependent manner, upregulates PP2A regulatory subunit PPP2R2B, which dephosphorylates STAT5B Ser-193, reducing STAT5B DNA binding and transcriptional activity on IL-2 target genes in Th17 cells. siRNA knockdown of MSC and PPP2R2B, PP2A assays, STAT5B Ser-193 phospho-Western blotting, EMSA, reporter assays in primary human Th17 cells European journal of immunology Medium 28612433
2018 Dominant-negative STAT5B missense mutations cause growth hormone insensitivity by two distinct mechanisms: either failure of nuclear localization or failure to bind canonical STAT5B DNA response elements. Despite being robustly tyrosine-phosphorylated, each mutant retains the ability to dimerize with wild-type STAT5B, disrupting wild-type transcriptional functions. Patient-derived cell studies, GH stimulation/phosphorylation assays, nuclear localization imaging, EMSA, co-IP for dimerization with wild-type STAT5B Nature communications High 29844444
2019 Crystal structures of human STAT5B and STAT5B-N642H reveal that the N642H mutation leads to alternative SH2 domain conformations. Biophysical data indicate that STAT5B-N642H can adopt both hyper-activated and hyper-inactivated states with resistance to dephosphorylation. MD simulations show sustained interchain cross-domain interactions in N642H, conferring kinetic stability to the mutant anti-parallel dimer. X-ray crystallography, molecular dynamics simulations, biophysical dephosphorylation assays, transgenic mouse model, syngeneic transplant models Nature communications High 31175292
2019 STAT5B (but not STAT5A) is the major STAT5 isoform driving BCR/ABL+ leukemia. STAT5B-deficient BCR/ABL+ cells have markedly enhanced IFN-α and IFN-γ signaling signatures, and inhibition of IFN responses rescues BCR/ABL+ colony formation of Stat5b-deficient cells, demonstrating that STAT5B enables leukemic transformation by suppressing IFN-α/γ responses. STAT5A/B-specific knockouts in BCR/ABL cell models, RNA-seq profiling, IFN pathway inhibition rescue experiments, leukemia transplant models Leukemia High 30679796
2022 STAT5B restrains IL-21-induced human B-cell differentiation into plasmablasts by inducing SOCS3 (which attenuates IL-21 signaling) and BCL6 (which represses plasma cell formation and class switching). CRISPR-mediated STAT5B deletion in B-cell lines diminishes IL-21-mediated SOCS3 induction; STAT5B-null patients have expanded immunoglobulin class-switched B cells and follicular T helper cells. CRISPR-mediated STAT5B deletion in B-cell lines, phospho-flow cytometry, RNA-seq, patient PBMC studies, in vitro B-cell differentiation assays The Journal of allergy and clinical immunology High 35469842
2024 Tyrosine phosphorylation of both STAT5A and STAT5B (at the C-terminal tyrosine) is essential for maximal IL-2 signaling and CD8+ T-cell proliferation in vivo. Tyrosine-to-phenylalanine knockin mice show reduced CD8+ T cells, impaired IL-2-induced proliferation correlated with reduced Myc, pRB, cyclins, CDKs, and a partial G1→S block, as well as decreased IL-2Rβ and IL-2Rγ expression and reduced pERK and pAKT. Knockin mice with Tyr-to-Phe mutations in STAT5A and STAT5B, flow cytometry, transcriptomics (RNA-seq), proteomics, cell cycle analysis Nature communications High 39191751

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
1995 Cloning and expression of Stat5 and an additional homologue (Stat5b) involved in prolactin signal transduction in mouse mammary tissue. Proceedings of the National Academy of Sciences of the United States of America 460 7568026
2015 Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells. Nature communications 333 25586472
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
1998 Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. The Journal of experimental medicine 258 9841920
2013 Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia. Blood 251 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 200 10743504
1996 Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells. The Journal of biological chemistry 183 8631883
2000 A cytosolic protein-tyrosine phosphatase PTP1B specifically dephosphorylates and deactivates prolactin-activated STAT5a and STAT5b. The Journal of biological chemistry 139 10993888
1998 Characterization of Stat5a and Stat5b homodimers and heterodimers and their association with the glucocortiocoid receptor in mammary cells. Molecular and cellular biology 131 9528750
2002 STAT5b, a Mediator of Synergism between c-Src and the Epidermal Growth Factor Receptor. The Journal of biological chemistry 128 12429742
2012 The STAT5b Pathway Defect and Autoimmunity. Frontiers in immunology 101 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
2017 HIV-1-mediated insertional activation of STAT5B and BACH2 trigger viral reservoir in T regulatory cells. Nature communications 96 28887441
2012 Mapping the growth hormone--Stat5b--IGF-I transcriptional circuit. Trends in endocrinology and metabolism: TEM 91 22361342
2011 STAT5b deficiency: lessons from STAT5b gene mutations. Best practice & research. Clinical endocrinology & metabolism 90 21396575
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 83 10585399
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 Upregulation of Foxp3 expression in mouse and human Treg is IL-2/STAT5 dependent: implications for the NOD STAT5B mutation in diabetes pathogenesis. Annals of the New York Academy of Sciences 76 17130555
2002 Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways. Blood 76 11929748
2006 Clinical and biochemical characteristics of a male patient with a novel homozygous STAT5b mutation. The Journal of clinical endocrinology and metabolism 75 16787985
2000 Both stat5a and stat5b are required for antigen-induced eosinophil and T-cell recruitment into the tissue. Blood 74 10666213
2018 Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia. Leukemia 71 30573779
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 Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma. Cell death and differentiation 68 24440911
2014 Identification of STAT5A and STAT5B target genes in human T cells. PloS one 68 24497979
2013 Differential contributions of STAT5A and STAT5B to stress protection and tyrosine kinase inhibitor resistance of chronic myeloid leukemia stem/progenitor cells. Cancer research 68 23400594
2008 Inhibition of transcription factor STAT5b suppresses proliferation, induces G1 cell cycle arrest and reduces tumor cell invasion in human glioblastoma multiforme cells. Cancer letters 68 18793823
1999 Insulin inhibits growth hormone signaling via the growth hormone receptor/JAK2/STAT5B pathway. The Journal of biological chemistry 67 10224108
1998 A single amino acid in the DNA binding regions of STAT5A and STAT5B confers distinct DNA binding specificities. The Journal of biological chemistry 66 9852045
1997 Growth hormone-induced tyrosyl phosphorylation and deoxyribonucleic acid binding activity of Stat5A and Stat5B. Endocrinology 65 9231797
2019 Structural and functional consequences of the STAT5BN642H driver mutation. Nature communications 64 31175292
1999 Termination of growth hormone pulse-induced STAT5b signaling. Molecular endocrinology (Baltimore, Md.) 64 9892011
2002 Stat5B shuttles between cytoplasm and nucleus in a cytokine-dependent and -independent manner. Journal of immunology (Baltimore, Md. : 1950) 60 11971004
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
2012 MSM enhances GH signaling via the Jak2/STAT5b pathway in osteoblast-like cells and osteoblast differentiation through the activation of STAT5b in MSCs. PloS one 56 23071812
1999 Down-regulation of liver JAK2-STAT5b signaling by the female plasma pattern of continuous growth hormone stimulation. Molecular endocrinology (Baltimore, Md.) 54 9973252
2017 Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation. Molecular biology of the cell 53 28100634
2020 STAT3 and STAT5B Mutations in T/NK-Cell Chronic Lymphoproliferative Disorders of Large Granular Lymphocytes (LGL): Association with Disease Features. Cancers 49 33255665
2003 Down-regulation of STAT5b transcriptional activity by ligand-activated peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma. Molecular pharmacology 49 12869640
2023 STAT5b: A master regulator of key biological pathways. Frontiers in immunology 48 36755813
2001 Cross-talk between Stat5b and estrogen receptor-alpha and -beta in mammary epithelial cells. Journal of molecular endocrinology 48 11463580
2019 Twins with different personalities: STAT5B-but not STAT5A-has a key role in BCR/ABL-induced leukemia. Leukemia 47 30679796
2009 Signal transducer and activator of transcription (STAT)-5A and STAT5B differentially regulate human mammary carcinoma cell behavior. Endocrinology 47 19966185
2003 Transcriptional regulation of insulin-like growth factor-I by interferon-gamma requires STAT-5b. The Journal of biological chemistry 46 14570891
2016 Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome. PloS one 45 26959237
2013 Differentiating the roles of STAT5B and STAT5A in human CD4+ T cells. Clinical immunology (Orlando, Fla.) 45 23773921
2010 Activation of c-Src/HER1/STAT5b and HER1/ERK1/2 signaling pathways and cell migration by hexachlorobenzene in MDA-MB-231 human breast cancer cell line. Toxicological sciences : an official journal of the Society of Toxicology 45 21205633
2004 Simultaneous, bidirectional inhibitory crosstalk between PPAR and STAT5b. Toxicology and applied pharmacology 45 15364543
2022 Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia. Blood cancer journal 44 35210405
2016 Disruption of STAT5b-Regulated Sexual Dimorphism of the Liver Transcriptome by Diverse Factors Is a Common Event. PloS one 43 26959975
2012 Nuclear EGFRvIII-STAT5b complex contributes to glioblastoma cell survival by direct activation of the Bcl-XL promoter. International journal of cancer 38 22729867
2012 STAT5b as molecular target in pancreatic cancer--inhibition of tumor growth, angiogenesis, and metastases. Neoplasia (New York, N.Y.) 38 23097626
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
2013 JAK2-STAT5B pathway and osteoblast differentiation. JAK-STAT 37 24470975
2012 A novel missense mutation in the SH2 domain of the STAT5B gene results in a transcriptionally inactive STAT5b associated with severe IGF-I deficiency, immune dysfunction, and lack of pulmonary disease. The Journal of clinical endocrinology and metabolism 37 22419735
2007 Endotoxin attenuates growth hormone-induced hepatic insulin-like growth factor I expression by inhibiting JAK2/STAT5 signal transduction and STAT5b DNA binding. American journal of physiology. Endocrinology and metabolism 37 17327369
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
2018 Regulation of human trophoblast cell syncytialization by transcription factors STAT5B and NR4A3. Journal of cellular biochemistry 35 29377304
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 35 10984246
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 33 22442148
2017 STAT5B: A Differential Regulator of the Life and Death of CD4+ Effector Memory T Cells. Journal of immunology (Baltimore, Md. : 1950) 32 29187589
2011 Novel mechanism for Fc{epsilon}RI-mediated signal transducer and activator of transcription 5 (STAT5) tyrosine phosphorylation and the selective influence of STAT5B over mast cell cytokine production. The Journal of biological chemistry 32 22130676
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
2019 Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function. The Journal of allergy and clinical immunology 31 31600547
2007 Hypoxia activates the IGF-1 expression through STAT5b in human HepG2 cells. Biochemical and biophysical research communications 29 17509524
2022 STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis. The Journal of allergy and clinical immunology 27 35469842
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
2014 BCR-ABL affects STAT5A and STAT5B differentially. PloS one 27 24836440
2006 Signalling cross-talk between hepatocyte nuclear factor 4alpha and growth-hormone-activated STAT5b. The Biochemical journal 27 16584384
2021 miR-146a enhances regulatory T-cell differentiation and function in allergic rhinitis by targeting STAT5b. Allergy 26 34716993
2002 Diabetic LDL inhibits cell-cycle progression via STAT5B and p21(waf). The Journal of clinical investigation 23 11781356
2000 Molecular characterization of STAT5A- and STAT5B-encoding genes reveals extended intragenic sequence homogeneity in cattle and mouse and different degrees of divergent evolution of various domains. Journal of molecular evolution 23 10835485
2016 Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion. Oncology reports 22 27035235
2013 Constitutive activation of STAT5A and STAT5B regulates IgM secretion in Waldenstrom's macroglobulinemia. Blood 22 24335105
2000 Constitutively active STAT5A and STAT5B in vitro and in vivo: mutation of STAT5 is not a frequent cause of leukemogenesis. International journal of hematology 22 10729993
2007 Growth hormone secretion and immunological function of a male patient with a homozygous STAT5b mutation. European journal of endocrinology 21 17287404
2025 The histone lactylation of AIM2 influences the suppression of ferroptosis by ACSL4 through STAT5B and promotes the progression of lung cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 39792364
2024 Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R-STAT5B-driven neoplasms. Nature immunology 19 38802512
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
2024 Tyrosine phosphorylation of both STAT5A and STAT5B is necessary for maximal IL-2 signaling and T cell proliferation. Nature communications 18 39191751
2013 δ-opioid receptor activation leads to neurite outgrowth and neuronal differentiation via a STAT5B-Gαi/o pathway. Journal of neurochemistry 18 23906478
2006 Retracted: Glucocorticoids repress bcl-X expression in lymphoid cells by recruiting STAT5B to the P4 promoter. The Journal of biological chemistry 18 16959781
2012 Repression of STAT3, STAT5A, and STAT5B expressions in chronic myelogenous leukemia cell line K-562 with unmodified or chemically modified siRNAs and induction of apoptosis. Annals of hematology 17 23053176
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
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
2019 Epilepsy Associates with Decreased HIF-1α/STAT5b Signaling in Glioblastoma. Cancers 16 30621209
2017 A novel regulatory role of RGS4 in STAT5B activation, neurite outgrowth and neuronal differentiation. Neuropharmacology 16 28219718
2010 Multi-component signaling complexes of the delta-opioid receptor with STAT5B and G proteins. Neuropharmacology 16 20433855
2006 Impaired Crkl expression contributes to the defective DNA binding of Stat5b in nonobese diabetic mice. Diabetes 16 16505237

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