STAT5B

UniProt ID: P51692
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

STAT5B is a latent cytoplasmic signal transducer and sequence-specific transcription factor of the STAT family. It is composed of an N-terminal domain, a coiled-coil domain, a DNA-binding domain, a linker, an SH2 domain, and a C-terminal transactivation domain. STAT5B is activated downstream of numerous cytokine and hormone receptors: it is the principal signal transducer for growth hormone (via JAK2), is activated by the common gamma-chain cytokines IL-2, IL-7, IL-9, IL-15 and IL-21 (via JAK1/JAK3), and is also activated by prolactin, erythropoietin and thrombopoietin (via JAK2), GM-CSF/IL-3/IL-5, G-CSF, and oncostatin-M. Receptor-associated JAK kinases phosphorylate STAT5B on Tyr-699; phosphorylated STAT5B dimerizes through reciprocal SH2-phosphotyrosine interactions (and can form heterodimers with STAT5A or STAT3), translocates to the nucleus, and binds gamma-activated sequence (GAS) DNA elements to activate transcription of target genes. STAT5B drives transcriptional programs controlling postnatal growth (induction of IGF1 downstream of growth hormone), lymphocyte development and immune homeostasis (including regulatory T cells and NK cells), and erythroid/hematopoietic differentiation. Loss-of-function variants cause growth hormone insensitivity syndrome with immune dysregulation (short stature with low IGF1 and normal/elevated growth hormone), while somatic activating mutations such as the SH2-domain N642H substitution drive T-cell and NK-cell leukemias and lymphomas. STAT5B is highly similar to and largely functionally overlapping with, but non-redundant from, its paralog STAT5A.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005634 nucleus
IBA
GO_REF:0000033 		ACCEPT
Summary: STAT5B is active in the nucleus, where activated dimers bind GAS DNA elements and regulate transcription. Strongly supported phylogenetically and by direct experimental evidence.
Reason: Core localization for STAT5B's transcription factor activity; consistent with IDA evidence (PMID:29844444) and the entire STAT mechanism.
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		ACCEPT
Summary: STAT5B is a latent cytoplasmic factor prior to phosphorylation, where it docks to activated receptors and is phosphorylated by JAKs before nuclear translocation.
Reason: Core dual localization (cytoplasm/nucleus) of STAT proteins; supported by IDA (PMID:29844444).
GO:0006357 regulation of transcription by RNA polymerase II
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: STAT5B regulates RNA Pol II transcription of GAS-element target genes. Correct but general; the activator-specific terms (GO:0045944) and MF terms capture the function more precisely.
Reason: Accurate but a general parent of the more specific positive-regulation and DNA-binding TF activity annotations that represent the core function.
GO:0006952 defense response
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Reflects STAT5B's role in immunity downstream of gamma-chain cytokines. This is a very general process term inferred phylogenetically across the family.
Reason: Captures the immune role at too high a level; lymphocyte differentiation / cytokine signaling terms are more informative.
GO:0019221 cytokine-mediated signaling pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: STAT5B is a central transducer of cytokine signaling (IL-2/7/9/15/21, EPO, GM-CSF, etc.). Core process annotation, well supported by experiment and phylogeny.
Reason: Core biological process for STAT5B as a cytokine signal transducer.
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
IBA
GO_REF:0000033 		ACCEPT
Summary: STAT5B binds GAS elements in cis-regulatory regions of Pol II target genes. Supported experimentally by EMSA against the GHRE/GAS probe (PMID:29844444).
Reason: Core sequence-specific DNA-binding molecular function of STAT5B.
GO:0042127 regulation of cell population proliferation
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: STAT5B promotes proliferation/survival of hematopoietic and lymphoid cells downstream of cytokines, and constitutive activation is oncogenic. General downstream process.
Reason: A downstream consequence of STAT5B target-gene programs rather than its direct molecular function.
GO:0007259 cell surface receptor signaling pathway via JAK-STAT
IBA
GO_REF:0000033 		ACCEPT
Summary: STAT5B is a defining component of JAK-STAT signaling downstream of cell surface cytokine/hormone receptors. Core process, strongly supported.
Reason: Core biological process; STAT5B is by definition a JAK-STAT pathway effector.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific
IBA
GO_REF:0000033 		ACCEPT
Summary: STAT5B is a sequence-specific RNA Pol II transcription factor. This is the core molecular function, also supported by ISA (TFClass) and IDA for the activator-specific child term (PMID:29844444).
Reason: Core molecular function of STAT5B.
GO:0090575 RNA polymerase II transcription regulator complex
IBA
GO_REF:0000033 		ACCEPT
Summary: Activated STAT5B dimers act within Pol II transcription regulator complexes at GAS-element promoters/enhancers, recruiting coactivators (e.g. CBP/p300 via NMI; NCOA1/SRC-1).
Reason: Consistent with STAT5B function as part of a transcription regulator complex; also supported by NAS (PMID:24058793).
GO:0043434 response to peptide hormone
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: STAT5B mediates responses to peptide hormones including growth hormone and prolactin. General parent of the more specific GH receptor signaling term.
Reason: Accurate but subsumed by the more specific GH receptor signaling pathway annotation.
GO:0060397 growth hormone receptor signaling pathway via JAK-STAT
IBA
GO_REF:0000033 		ACCEPT
Summary: STAT5B is the principal signal transducer for growth hormone; GH-GHR-JAK2 signaling activates STAT5B to induce IGF1. Core process, also supported by IDA (PMID:12552091) and disease genetics (PMID:29844444).
Reason: Core, signature biological process for STAT5B (GH/IGF1 axis).
GO:0003677 DNA binding
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: STAT5B binds DNA. General parent of the sequence-specific GAS-binding MF; InterPro-based electronic inference is consistent with experimental evidence.
Reason: Correct but a general parent of the specific RNA Pol II cis-regulatory DNA binding annotation.
GO:0003700 DNA-binding transcription factor activity
IEA
GO_REF:0000120 		MODIFY
Summary: STAT5B is a DNA-binding transcription factor. Correct but general; the RNA Pol II-specific child term (GO:0000981) is the precise core MF.
Reason: General term; the RNA Pol II-specific transcription factor activity term (GO:0000981, already annotated) should be used.
GO:0005634 nucleus
IEA
GO_REF:0000120 		ACCEPT
Summary: Nuclear localization of activated STAT5B. Consistent with IDA evidence (PMID:29844444).
Reason: Core localization, redundant with the IBA/IDA nucleus annotations.
GO:0005737 cytoplasm
IEA
GO_REF:0000120 		ACCEPT
Summary: Cytoplasmic localization of latent STAT5B. Consistent with IDA evidence (PMID:29844444).
Reason: Core localization, redundant with IBA/IDA cytoplasm annotations.
GO:0006355 regulation of DNA-templated transcription
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: STAT5B regulates transcription. Very general InterPro-derived process term; subsumed by the Pol II-specific regulation/activation terms.
Reason: General parent term; more specific Pol II transcription terms are present.
GO:0007165 signal transduction
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: STAT5B is part of signal transduction. Very general; the JAK-STAT and cytokine-mediated signaling terms are the specific descendants.
Reason: Root-level process term subsumed by specific JAK-STAT signaling annotations.
GO:0019221 cytokine-mediated signaling pathway
IEA
GO_REF:0000117 		ACCEPT
Summary: Duplicate (ARBA electronic) of the cytokine-mediated signaling pathway annotation; core process for STAT5B.
Reason: Core process; redundant with the IBA annotation to the same term.
GO:1903706 regulation of hemopoiesis
IEA
GO_REF:0000117 		ACCEPT
Summary: STAT5B regulates hematopoiesis, including erythroid differentiation (PMID:20702587) and lymphoid development. Accurate process annotation.
Reason: Supported by experimental erythroid-differentiation evidence and broad hematopoietic role.
GO:0005515 protein binding
IPI
PMID:21106534
The tumor suppressor hTid1 inhibits STAT5b activity via func... 		MARK AS OVER ANNOTATED
Summary: Interaction with the DnaJ tumor suppressor hTid1/DNAJA3, a negative regulator that binds the STAT5B transactivation domain (PMID:21106534). The bare 'protein binding' term is uninformative about function.
Reason: GO:0005515 'protein binding' is uninformative; per guidelines a specific MF should be used. The interaction itself is real but does not define STAT5B's core function.
GO:0005515 protein binding
IPI
PMID:31175292
Structural and functional consequences of the STAT5B(N642H) ... 		MARK AS OVER ANNOTATED
Summary: Interaction with ABL1 (P00519) reported in the STAT5B(N642H) study. Bare 'protein binding' term is uninformative.
Reason: GO:0005515 'protein binding' is uninformative; a specific MF is preferred.
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		MARK AS OVER ANNOTATED
Summary: High-throughput binary interactome (HuRI) interactions. Bare 'protein binding' is uninformative and these HT partners do not inform core function.
Reason: GO:0005515 'protein binding' is uninformative; high-throughput partners add no functional resolution.
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: Affinity-capture interactome (BioPlex) interaction. Bare 'protein binding' is uninformative.
Reason: GO:0005515 'protein binding' is uninformative; high-throughput partner.
GO:0005515 protein binding
IPI
PMID:9989503
Functional association of Nmi with Stat5 and Stat1 in IL-2- ... 		MARK AS OVER ANNOTATED
Summary: Interaction with NMI (Q13287), identified via yeast two-hybrid using the STAT5b coiled-coil region; NMI enhances CBP/p300 recruitment to STAT5 (PMID:9989503). Real and functionally relevant, but 'protein binding' is uninformative.
Reason: GO:0005515 'protein binding' is uninformative; the coactivator-recruitment role is captured by transcription regulator complex membership.
GO:0042802 identical protein binding
IPI
PMID:31175292
Structural and functional consequences of the STAT5B(N642H) ... 		KEEP AS NON CORE
Summary: STAT5B self-association (homodimerization), consistent with the activated STAT5B homodimer. The IDA-supported GO:0042803 protein homodimerization activity (PMID:29844444) captures this more precisely.
Reason: Reflects the functionally important homodimer but is captured more specifically by GO:0042803 (homodimerization activity).
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
IEA
GO_REF:0000107 		ACCEPT
Summary: GAS-element binding inferred from mouse ortholog. Core MF, duplicate of the IBA annotation to the same term.
Reason: Core DNA-binding MF; redundant with IBA annotation.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific
IEA
GO_REF:0000107 		ACCEPT
Summary: STAT5B is a transcriptional activator at GAS elements. Core MF, also supported by IDA (PMID:29844444; luciferase reporter transactivation).
Reason: Core molecular function; STAT5B is a sequence-specific transcriptional activator.
GO:0040014 regulation of multicellular organism growth
IEA
GO_REF:0000107 		ACCEPT
Summary: STAT5B regulates organismal growth via the GH/IGF1 axis; loss of function causes short stature (PMID:29844444). Core organism-level outcome.
Reason: Well-supported by human disease genetics (GH insensitivity / short stature).
GO:0046983 protein dimerization activity
IEA
GO_REF:0000107 		MODIFY
Summary: Activated STAT5B dimerizes. General dimerization term; the IDA-supported homodimerization activity (GO:0042803) is more specific.
Reason: General term; the specific homodimerization activity (GO:0042803, IDA from PMID:29844444) better represents the function.
GO:0060397 growth hormone receptor signaling pathway via JAK-STAT
IEA
GO_REF:0000107 		ACCEPT
Summary: GH receptor signaling via JAK-STAT, inferred from mouse ortholog. Duplicate of the IBA/IDA annotations; core process.
Reason: Core process, redundant with IBA and IDA (PMID:12552091) annotations.
GO:0071363 cellular response to growth factor stimulus
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: STAT5B mediates cellular responses to growth factors/cytokines. General term subsumed by specific JAK-STAT and GH receptor signaling annotations.
Reason: General process term; specific cytokine/GH signaling terms are present.
GO:0007259 cell surface receptor signaling pathway via JAK-STAT
NAS
PMID:24058793
STAT heterodimers in immunity: A mixed message or a unique s... 		ACCEPT
Summary: STAT5B operates in JAK-STAT signaling, including as part of STAT heterodimers in immunity (PMID:24058793 review). Core process.
Reason: Core JAK-STAT process; redundant with IBA/TAS annotations to the same term.
GO:0045944 positive regulation of transcription by RNA polymerase II
NAS
PMID:24058793
STAT heterodimers in immunity: A mixed message or a unique s... 		ACCEPT
Summary: STAT5B positively regulates transcription of GAS-element target genes. Core process; also supported by ISS and the IDA activator MF.
Reason: Core process for STAT5B as a transcriptional activator.
GO:0090575 RNA polymerase II transcription regulator complex
NAS
PMID:24058793
STAT heterodimers in immunity: A mixed message or a unique s... 		ACCEPT
Summary: Activated STAT5B acts within Pol II transcription regulator complexes (including STAT5A/STAT5B and STAT3/STAT5B complexes; ComplexPortal CPX-6044/6045).
Reason: Consistent with STAT5B function in transcription regulator complexes; redundant with IBA annotation.
GO:0038162 erythropoietin-mediated signaling pathway
IDA
PMID:9657743
Erythropoietin induces tyrosine phosphorylation of Jak2, STA... 		ACCEPT
Summary: EPO induces tyrosine phosphorylation of JAK2, STAT5A and STAT5B in primary human erythroid precursors, with nuclear translocation of activated STAT5 (PMID:9657743). Direct experimental support.
Reason: Well-supported core process; EPO/JAK2/STAT5B signaling drives erythropoiesis.
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific
IDA
PMID:29844444
Dominant-negative STAT5B mutations cause growth hormone inse... 		ACCEPT
Summary: WT STAT5B bound the STAT5B-specific GHRE DNA probe under GH stimulation and drove luciferase reporter transactivation; DBD variants abolished both (PMID:29844444). Direct evidence for sequence-specific transcriptional activator activity.
Reason: Core molecular function with strong direct experimental support.
GO:0005634 nucleus
IDA
PMID:29844444
Dominant-negative STAT5B mutations cause growth hormone inse... 		ACCEPT
Summary: GH-stimulated WT STAT5B translocates to the nucleus (immunofluorescence; the Q177P variant fails to enter the nucleus) (PMID:29844444). Direct support.
Reason: Core localization with direct experimental evidence.
GO:0005737 cytoplasm
IDA
PMID:29844444
Dominant-negative STAT5B mutations cause growth hormone inse... 		ACCEPT
Summary: Latent and Q177P-mutant STAT5B localize to the cytoplasm/nuclear membrane (PMID:29844444). Direct support.
Reason: Core localization with direct experimental evidence.
GO:0042803 protein homodimerization activity
IDA
PMID:29844444
Dominant-negative STAT5B mutations cause growth hormone inse... 		ACCEPT
Summary: Co-IP experiments showed STAT5B homodimerization (and heterodimerization with WT) upon activation (PMID:29844444). Activated STAT5B functions as a homodimer.
Reason: Core, mechanistically essential molecular function (dimerization precedes nuclear import and DNA binding).
GO:0000785 chromatin
ISA
GO_REF:0000113 		ACCEPT
Summary: As a sequence-specific TF, STAT5B associates with chromatin at target loci. TFClass-based inference, consistent with function.
Reason: Consistent with DNA-binding TF activity and nuclear localization.
GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific
ISA
GO_REF:0000113 		ACCEPT
Summary: TFClass-based assignment of sequence-specific Pol II TF activity. Duplicate of the IBA annotation; core MF.
Reason: Core molecular function; redundant with IBA annotation.
GO:0019530 taurine metabolic process
ISS
GO_REF:0000024 		MARK AS OVER ANNOTATED
Summary: Narrow annotation transferred by sequence similarity from mouse Stat5b (acts upstream of taurine metabolism, likely via regulation of a metabolic target gene). Indirect, organism/context-specific and far from the core function.
Reason: Highly indirect, narrowly-scoped ISS transfer; not representative of STAT5B's core transcription-factor function.
GO:0040014 regulation of multicellular organism growth
ISS
GO_REF:0000024 		ACCEPT
Summary: Growth regulation via the GH/IGF1 axis; duplicate of the Ensembl IEA annotation. Supported by human disease genetics (PMID:29844444).
Reason: Core organism-level outcome of GH/STAT5B signaling.
GO:0045648 positive regulation of erythrocyte differentiation
IDA
PMID:20702587
ZFP36L1 negatively regulates erythroid differentiation of CD... 		ACCEPT
Summary: STAT5B promotes erythroid differentiation; ZFP36L1-mediated down-regulation of Stat5b mRNA drastically decreases erythroid colony formation in human hematopoietic progenitors (PMID:20702587).
Reason: Supported by direct experimental (loss-of-function) evidence in human erythroid progenitors.
GO:0003682 chromatin binding
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: STAT5B binds chromatin at target loci. General MF transferred by similarity; the sequence-specific GAS-binding terms are more precise.
Reason: General DNA/chromatin-binding term subsumed by the specific cis-regulatory DNA binding annotation.
GO:0005634 nucleus
ISS
GO_REF:0000024 		ACCEPT
Summary: Nuclear localization, transferred by similarity. Core localization, redundant with IDA/IBA/IEA annotations.
Reason: Core localization; redundant.
GO:0005737 cytoplasm
ISS
GO_REF:0000024 		ACCEPT
Summary: Cytoplasmic localization, transferred by similarity. Core localization, redundant with IDA/IBA/IEA annotations.
Reason: Core localization; redundant.
GO:0046983 protein dimerization activity
ISS
GO_REF:0000024 		MODIFY
Summary: Dimerization activity transferred by similarity. General; the specific homodimerization activity (GO:0042803, IDA) is preferred.
Reason: General term; replace with the specific homodimerization activity supported by IDA.
GO:0071363 cellular response to growth factor stimulus
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: General response-to-growth-factor process, transferred by similarity. Subsumed by specific cytokine/GH signaling terms.
Reason: General process term; specific signaling annotations are present.
GO:0071364 cellular response to epidermal growth factor stimulus
ISS
GO_REF:0000024 		MARK AS OVER ANNOTATED
Summary: EGF-response annotation transferred from STAT5A (P52632). STAT5 can be activated downstream of EGFR in some contexts, but this is a narrow, similarity-based, non-core annotation for STAT5B.
Reason: Narrow ISS transfer from the paralog; EGF response is not a core, well-established STAT5B function.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-1470012 		KEEP AS NON CORE
Summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone signaling pathways. Consistent with the IDA nucleus annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core nucleus annotation.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-8983379 		KEEP AS NON CORE
Summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone signaling pathways. Consistent with the IDA nucleus annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core nucleus annotation.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9012671 		KEEP AS NON CORE
Summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone signaling pathways. Consistent with the IDA nucleus annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core nucleus annotation.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9670426 		KEEP AS NON CORE
Summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone signaling pathways. Consistent with the IDA nucleus annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core nucleus annotation.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9698016 		KEEP AS NON CORE
Summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone signaling pathways. Consistent with the IDA nucleus annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core nucleus annotation.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9698021 		KEEP AS NON CORE
Summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone signaling pathways. Consistent with the IDA nucleus annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core nucleus annotation.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9698033 		KEEP AS NON CORE
Summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone signaling pathways. Consistent with the IDA nucleus annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core nucleus annotation.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9698041 		KEEP AS NON CORE
Summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone signaling pathways. Consistent with the IDA nucleus annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core nucleus annotation.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9698754 		KEEP AS NON CORE
Summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone signaling pathways. Consistent with the IDA nucleus annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core nucleus annotation.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-9978250 		KEEP AS NON CORE
Summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone signaling pathways. Consistent with the IDA nucleus annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core nucleus annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-1168894 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-1295540 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-1470009 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-1470010 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-1470012 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-1839112 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-452097 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-6785165 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-879909 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-919404 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-921155 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9670412 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9670417 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9670426 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9698005 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9698013 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9698016 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9698029 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9698033 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9703432 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9703435 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0045944 positive regulation of transcription by RNA polymerase II
ISS
GO_REF:0000024 		ACCEPT
Summary: Positive regulation of Pol II transcription, transferred by similarity. Core process; duplicate of the NAS annotation to the same term.
Reason: Core process for STAT5B as a transcriptional activator; redundant.
GO:0005829 cytosol
TAS
Reactome:R-HSA-1433456 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-380782 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-452108 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-879930 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8985929 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-8985988 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9025969 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0005829 cytosol
TAS
Reactome:R-HSA-9670416 		KEEP AS NON CORE
Summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone signaling pathway. Consistent with the IDA cytoplasm annotation; one of many pathway-specific Reactome localization records.
Reason: Correct localization but a pathway-specific Reactome duplicate of the core cytoplasm/cytosol annotation.
GO:0060397 growth hormone receptor signaling pathway via JAK-STAT
IDA
PMID:12552091
Estrogen inhibits GH signaling by suppressing GH-induced JAK... 		ACCEPT
Summary: GH stimulated STAT5-dependent reporter activity in 293GHR/HuH7/T-47D cells, with GH-induced JAK2 phosphorylation (PMID:12552091). Supports STAT5B in GH receptor JAK-STAT signaling. Core process, redundant with the IBA/IEA annotations.
Reason: Core process with direct experimental support; defer to curator (BHF-UCL) full-text reading.
GO:0032355 response to estradiol
IDA
PMID:12552091
Estrogen inhibits GH signaling by suppressing GH-induced JAK... 		KEEP AS NON CORE
Summary: Estradiol (via ER-alpha and SOCS-2) suppresses GH-induced JAK2/STAT5 signaling (PMID:12552091). Captures STAT5B's modulation by estrogen rather than a core function; a context-specific crosstalk process.
Reason: Reflects upstream regulation of STAT5B signaling by estradiol, not a core STAT5B function. Defer to curator who read the full text.
GO:0032870 cellular response to hormone stimulus
IDA
PMID:12552091
Estrogen inhibits GH signaling by suppressing GH-induced JAK... 		KEEP AS NON CORE
Summary: STAT5B mediates cellular responses to hormones (GH, estradiol context; PMID:12552091). Very general process term subsumed by the specific GH receptor signaling annotation.
Reason: General hormone-response term; specific GH receptor signaling annotation is more informative.
GO:0035259 nuclear glucocorticoid receptor binding
IPI
PMID:12552091
Estrogen inhibits GH signaling by suppressing GH-induced JAK... 		UNDECIDED
Summary: Annotation of STAT5B binding the glucocorticoid receptor (NR3C1, P04150), consistent with UniProt SUBUNIT 'Binds NR3C1 (By similarity)'. The cached abstract of PMID:12552091 is an estrogen/SOCS-2 GH-signaling study and does not itself describe GR binding; this is curator (BHF-UCL) judgment from full text (not cached). Cannot independently verify the supporting evidence.
Reason: Per guidelines, cannot verify an experimental IPI annotation whose full text is not in the cache and whose cached abstract does not mention GR binding; do not overrule the curator.
GO:0003700 DNA-binding transcription factor activity
TAS
PMID:8631883
Cloning of human Stat5B. Reconstitution of interleukin-2-ind... 		MODIFY
Summary: STAT5B is a DNA-binding transcription factor (cloning/characterization paper, PMID:8631883). General; the RNA Pol II-specific child term is the precise core MF.
Reason: General term; the RNA Pol II-specific transcription factor activity term (GO:0000981) is preferred.
GO:0006357 regulation of transcription by RNA polymerase II
TAS
PMID:8631883
Cloning of human Stat5B. Reconstitution of interleukin-2-ind... 		KEEP AS NON CORE
Summary: STAT5B regulates Pol II transcription of target genes (PMID:8631883). Correct but general; duplicate of the IBA annotation.
Reason: General process subsumed by the specific positive-regulation annotation.
GO:0007259 cell surface receptor signaling pathway via JAK-STAT
TAS
PMID:8631883
Cloning of human Stat5B. Reconstitution of interleukin-2-ind... 		ACCEPT
Summary: STAT5B was shown to be activated by IL-2 via JAK1/JAK3 and the IL-2R beta/gamma chains, requiring Tyr-699 for dimerization (PMID:8631883). Core JAK-STAT process with direct support.
Reason: Core process; supported by the original IL-2/JAK-STAT reconstitution study.

Core Functions

STAT5B is a sequence-specific RNA polymerase II transcription factor that, once activated, binds gamma-activated sequence (GAS) elements in cis-regulatory regions of target genes and activates their transcription, recruiting coactivators such as CBP/p300 (via NMI) and NCOA1/SRC-1. DNA binding and transactivation are directly demonstrated by EMSA against the GHRE/GAS probe and luciferase reporter assays; DNA-binding-domain disease variants abolish both activities.

Molecular Function:
DNA-binding transcription factor activity, RNA polymerase II-specific
Directly Involved In:
positive regulation of transcription by RNA polymerase II
Cellular Locations:
nucleus chromatin
Supporting Evidence:
  • PMID:29844444
    WT STAT5B readily bound and gel-shifted the STAT5B-specific DNA probe (GHRE) only under GH-stimulated conditions
  • PMID:9989503
    Nmi enhances the association of CBP/p300 coactivator proteins with Stat1 and Stat5

STAT5B is a latent cytoplasmic signal transducer for cytokine and hormone receptors that signal through the JAK-STAT pathway. Receptor-associated JAK kinases (JAK1/JAK2/JAK3) phosphorylate STAT5B on Tyr-699, which is required for its activation; this couples upstream signals (common gamma-chain cytokines IL-2/7/9/15/21, growth hormone, prolactin, erythropoietin, thrombopoietin, GM-CSF/IL-3/IL-5) to transcriptional output. This includes the growth hormone receptor signaling pathway that drives IGF1 induction, and erythropoietin-mediated signaling in erythroid precursors.

Molecular Function:
DNA-binding transcription factor activity, RNA polymerase II-specific
Directly Involved In:
cell surface receptor signaling pathway via JAK-STAT cytokine-mediated signaling pathway growth hormone receptor signaling pathway via JAK-STAT erythropoietin-mediated signaling pathway
Cellular Locations:
cytoplasm nucleus
Supporting Evidence:
  • PMID:8631883
    human Stat5 activation is also dependent on Tyr-694 in Stat5A and Tyr-699 in Stat5B, indicating that these tyrosines are required for dimerization
  • PMID:9657743
    erythropoietin induces tyrosine phosphorylation of Jak2, STAT5A, and STAT5B

Upon tyrosine phosphorylation, STAT5B dimerizes through reciprocal SH2-phosphotyrosine interactions (forming homodimers, and also heterodimers with STAT5A or STAT3). Dimerization is a prerequisite for nuclear translocation and DNA binding, and is the basis for the dominant-negative action of disease variants that retain dimerization but lose nuclear import or DNA binding.

Molecular Function:
protein homodimerization activity
Directly Involved In:
cell surface receptor signaling pathway via JAK-STAT
Cellular Locations:
cytoplasm nucleus
Supporting Evidence:
  • PMID:29844444
    each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000113
Gene Ontology annotation of human sequence-specific DNA binding transcription factors (DbTFs) based on the TFClass database
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:12552091
Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2.
PMID:20702587
ZFP36L1 negatively regulates erythroid differentiation of CD34+ hematopoietic stem cells by interfering with the Stat5b pathway.
PMID:21106534
The tumor suppressor hTid1 inhibits STAT5b activity via functional interaction.
PMID:24058793
STAT heterodimers in immunity: A mixed message or a unique signal?
PMID:29844444
Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation.
PMID:31175292
Structural and functional consequences of the STAT5B(N642H) driver mutation.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:8631883
Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells.
PMID:9657743
Erythropoietin induces tyrosine phosphorylation of Jak2, STAT5A, and STAT5B in primary cultured human erythroid precursors.
PMID:9989503
Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling.
Reactome:R-HSA-1168894
p-STAT5A/B dissociates from the Growth Hormone receptor
Reactome:R-HSA-1295540
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:STAT5A,STAT5B phosphorylates STAT5
Reactome:R-HSA-1433456
Recruitment of STATs
Reactome:R-HSA-1470009
Phosphorylation of STATs
Reactome:R-HSA-1470010
Dimerization of STATs
Reactome:R-HSA-1470012
Disassociation and translocation of STATs to the nucleus
Reactome:R-HSA-1839112
Phosphorylation of STAT5 by cytosolic FGFR1 fusions
Reactome:R-HSA-380782
STAT binds to the active receptor
Reactome:R-HSA-452097
Recruited STAT5 is phosphorylated
Reactome:R-HSA-452108
Phosphorylation of IL2RB Y338, Y392 or Y510 enables STAT recruitment
Reactome:R-HSA-6785165
p-STAT5A, p-STAT5B dissociate from IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:p-STAT5A,p-STAT5B
Reactome:R-HSA-879909
Activation of STAT5a/b by JAK2
Reactome:R-HSA-879930
STAT5 is recruited by JAK2
Reactome:R-HSA-8983379
p-Y-STAT3:p-STAT5 translocates to the nucleus
Reactome:R-HSA-8985929
IL9:p-Y407-IL9R:JAK1:IL2RG:p-904,939-JAK3 binds STAT1, STAT3, STAT5A or STAT5B
Reactome:R-HSA-8985988
IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:STAT3 phosphorylates STAT1, STAT3 or STAT5
Reactome:R-HSA-9012671
p-STAT5 binds CISH, SOCS1 and SOCS2 gene
Reactome:R-HSA-9025969
IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3 binds STAT5
Reactome:R-HSA-919404
Phosphorylated STAT5 is released
Reactome:R-HSA-921155
p-STAT5 dissociates from the receptor complex
Reactome:R-HSA-9670412
Phosphorylation of STATs downstream of KIT mutants
Reactome:R-HSA-9670416
Recruitment of STATs by KIT mutants
Reactome:R-HSA-9670417
Dimerization of STATs downstream of KIT mutants
Reactome:R-HSA-9670426
Disassociation and translocation of STATs to the nucleus downstream of KIT mutants
Reactome:R-HSA-9698005
FLT3 ITD mutants phosphorylate STAT5
Reactome:R-HSA-9698013
PTPN11:p-STAT5 dissociates from mutant FLT3
Reactome:R-HSA-9698016
PTPN11:p-STAT5 translocates to nucleus downstream of mutant FLT3
Reactome:R-HSA-9698021
PTPN11:p-STAT5 binds BCL2L1 promoter
Reactome:R-HSA-9698029
p-STAT5 dissociates from mutant FLT3
Reactome:R-HSA-9698033
p-STAT5 translocates to nucleus downstream of mutant FLT3
Reactome:R-HSA-9698041
p-STAT5 binds the CDKN1A gene
Reactome:R-HSA-9698754
p-STAT5 binds the NOX4 promoter
Reactome:R-HSA-9703432
p-STAT5 dissociates from FLT3 fusion proteinsp-
Reactome:R-HSA-9703435
FLT3 fusions activate STAT5
Reactome:R-HSA-9978250
Phosphorylated STAT5 dimer binds the IL4R gene

Suggested Questions for Experts

Q: Which target-gene programs are uniquely dependent on STAT5B versus STAT5A in human cells, given their high sequence identity and largely overlapping but non-redundant functions?

Q: How do STAT5B heterodimers (e.g. STAT5A/STAT5B, STAT3/STAT5B) differ from homodimers in DNA-element preference and target-gene output in lymphocytes?

Q: What distinguishes the transcriptional consequences of germline loss-of-function STAT5B variants (growth/immune phenotypes) from somatic gain-of-function variants (e.g. N642H) in leukemia?

Suggested Experiments

Experiment: ChIP-seq for endogenous STAT5B (with STAT5A-specific controls) in cytokine- or GH-stimulated primary human T cells and erythroid progenitors to define the STAT5B-specific GAS-element cistrome and target genes.

Experiment: Paired RNA-seq after STAT5B-specific versus STAT5A-specific degron/knockdown to quantify non-redundant target-gene programs downstream of IL-2, GH and EPO.

Experiment: Structure-function and EMSA/reporter assays of additional CCD, DBD and SH2 variants to map how each domain contributes to dimerization, nuclear import and DNA binding, extending the dominant-negative analyses of PMID:29844444.

📚 Additional Documentation

Notes

(STAT5B-notes.md)

STAT5B (P51692) — Gene Review Notes

Journal of research and provenance for the AI review of human STAT5B (HGNC:11367).

Overview / identity

  • UniProt P51692, "Signal transducer and activator of transcription 5B" (STA5B_HUMAN), 787 aa, chr17q21.2.
  • Member of the STAT family of transcription factors. Domain architecture (from UniProt + PMID:29844444): N-terminal domain (ND), 4-alpha-helix coiled-coil domain (CCD), DNA-binding domain (DBD), linker, SH2 domain (aa 589–686), C-terminal transactivation domain (TAD).
  • Paralog: STAT5A (P42229), ~90% identical, differing mainly in the C-terminal TAD. Largely overlapping but non-redundant functions.

Core mechanism (latent cytoplasmic TF → activated nuclear TF)

STAT5B is a latent cytoplasmic transcription factor. Cytokine/hormone receptor engagement activates receptor-associated JAK kinases, which phosphorylate STAT5B on Tyr-699; phospho-STAT5B dimerizes (via reciprocal SH2–pTyr interactions), translocates to the nucleus, binds GAS (gamma-activated sequence) DNA elements, and activates transcription of target genes.

  • Activating tyrosine: Tyr-699. [UniProt P51692 FT MOD_RES 699 "Phosphotyrosine; by HCK, JAK and PTK6"]; PMID:8631883.
  • Subcellular location: Cytoplasm and Nucleus; "Translocated into the nucleus in response to phosphorylation." [UniProt P51692 SUBCELLULAR LOCATION, ECO:0000269|PubMed:29844444].
  • Homodimerization on activation: PMID:29844444; UniProt SUBUNIT "Upon activation, forms homodimers (PubMed:29844444)".
  • DNA binding to canonical STAT5B response element (GHRE/GAS): PMID:29844444 and luciferase reporter transactivation PMID:29844444.

Upstream activators (cytokines/hormones → JAKs)

STAT5B is activated downstream of many cytokine and hormone receptors:
- Common gamma-chain cytokines: IL-2, IL-7, IL-9, IL-15, IL-21 (via JAK1/JAK3). IL-2: PMID:8631883; reconstitution required "coexpression of Jak3 along with the IL-2 receptor beta chain and the common cytokine receptor gamma-chain" PMID:8631883.
- Growth hormone (GH): the "key signal transducer for GH" PMID:29844444; GH → JAK2 → STAT5B → IGF1 induction. GHISID1/2 phenotypes (below).
- Prolactin (PRL): UniProt FUNCTION "Binds to the GAS element and activates PRL-induced transcription."
- Erythropoietin (EPO) via JAK2: [PMID:9657743 "erythropoietin induces tyrosine phosphorylation of Jak2, STAT5A, and STAT5B"; "Tyrosine phosphorylation of STAT5 is accompanied by the translocation of activated STAT5 to the nucleus"].
- Oncostatin-M via type II OSM receptor (OSMR/IL6ST): UniProt FUNCTION (PubMed:9188471).
- Also GM-CSF/IL-3/IL-5, thrombopoietin, G-CSF, KIT (SCF), FLT3, FGFR1 fusions (Reactome pathways in UniProt DR lines; many in oncogenic context).

Biological roles

  • Growth / IGF1 axis: STAT5B loss-of-function causes growth hormone insensitivity syndrome with immune dysregulation (GHISID1, AR; GHISID2, AD). PMID:29844444. Dominant-negative missense variants in CCD (Q177P, abrogated nuclear import) and DBD (Q474R, A478V, loss of DNA binding) disrupt WT STAT5B by heterodimerizing with it PMID:29844444.
  • Lymphocyte development / immunity: gamma-chain cytokine signaling drives T-cell (esp. Treg via Foxp3) and NK development; STAT5B deficiency → immune dysregulation, T-lymphopenia. General "defense response" / immunity role (IBA). Note STAT5B can form STAT heterodimers (e.g., STAT3/STAT5B, STAT5A/STAT5B) [PMID:24058793 review of STAT heterodimers in immunity].
  • Hematopoiesis / erythropoiesis: positively regulates erythroid differentiation; STAT5B level controlled post-transcriptionally by ZFP36L1 [PMID:20702587 "ZFP36L1 negatively regulates erythroid differentiation ... by directly binding the 3' untranslated region of Stat5b encoding mRNA"; "Stat5b down-regulation ... results ... in a drastic decrease of erythroid colonies formation"].
  • Oncogenesis: recurrent somatic activating mutations (e.g., SH2-domain N642H) in T/NK leukemias and lymphomas. PMID:29844444; structural/functional study of N642H driver mutation PMID:31175292.

Protein interactions (GO:0005515 IPI sources)

  • NMI (Q13287): identified via yeast two-hybrid with the STAT5b coiled-coil region; augments STAT5/STAT1 transcription by enhancing CBP/p300 recruitment [PMID:9989503 "Using the coiled-coil region of Stat5b as the bait in a yeast two-hybrid screen, we identified the association of Nmi"; "Nmi enhances the association of CBP/p300 coactivator proteins with Stat1 and Stat5"].
  • hTid1 / DNAJA3 (Q96EY1): DnaJ tumor suppressor binding the STAT5b TAD; negative regulator [PMID:21106534 "hTid1 interacts specifically with STAT5b but not with STAT5a"; "hTid1 negatively regulates the expression and transcriptional activity of STAT5b"].
  • ABL1 (P00519): IntAct (PMID:31175292), UniProt INTERACTION block.
  • High-throughput binary/affinity interactome partners (PMID:32296183 HuRI; PMID:33961781 BioPlex): HNRNPA2B1, USP2, CDKN1A, PIK3R3, RBBP4, CHAF1A, LMO4, MED25, MRPS6, STAC, SUOX, TSSK3, ZNF410, LGALS14 — mostly generic/HT, not core function.
  • NR3C1 / glucocorticoid receptor (P04150): GO:0035259 nuclear glucocorticoid receptor binding (IPI, PMID:12552091). Note: PMID:12552091 itself is an estrogen/SOCS-2/GH-signaling paper (see caveat below).

Caveats / citation notes

  • PMID:12552091 (Leung et al., PNAS 2003) is titled/abstracted as "Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2." The abstract reports GH-stimulated STAT5 reporter activity in 293GHR/HuH7/T-47D cells. It is the original_reference for four annotations: GO:0060397 (GH receptor signaling via JAK-STAT, IDA), GO:0032355 (response to estradiol, IDA), GO:0032870 (cellular response to hormone stimulus, IDA), and GO:0035259 (nuclear glucocorticoid receptor binding, IPI). The GR-binding annotation is curator (BHF-UCL) judgment from full text; abstract is consistent with GH/STAT5 + estradiol but does not itself mention GR binding in the cached abstract. Full text not cached (full_text_available: false) — defer to curator where evidence is experimental (do not REMOVE).
  • PMID:8631883, PMID:9657743, PMID:9989503, PMID:12552091 are abstract-only in cache.
  • PMID:11773439 (TC-PTP/PTPN2 regulation of STAT5) was RETRACTED (PMID:24319783). Not in GOA annotation set here; noted for completeness.
  • GO:0019530 taurine metabolic process (ISS, acts_upstream_of_positive_effect, from mouse P42232) is a narrow, indirectly-transferred annotation; flagged as over-annotation / non-core.

Core function summary

  1. Sequence-specific RNA Pol II DNA-binding transcription (activator) factor binding GAS elements (GO:0000981 / GO:0001228).
  2. Cytokine/JAK-STAT signal transducer (GO:0007259 / GO:0019221), including GH receptor signaling (GO:0060397) and EPO signaling (GO:0038162).
  3. Activation-dependent homo/heterodimerization (GO:0042803).
    Outputs: regulation of growth (IGF1 axis), lymphocyte/Treg/NK development & immunity, and erythroid/hematopoietic differentiation.

📄 View Raw YAML

 
id: P51692
gene_symbol: STAT5B
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  STAT5B is a latent cytoplasmic signal transducer and sequence-specific transcription
  factor of the STAT family. It is composed of an N-terminal domain, a coiled-coil
  domain, a DNA-binding domain, a linker, an SH2 domain, and a C-terminal transactivation
  domain. STAT5B is activated downstream of numerous cytokine and hormone receptors: it
  is the principal signal transducer for growth hormone (via JAK2), is activated by the
  common gamma-chain cytokines IL-2, IL-7, IL-9, IL-15 and IL-21 (via JAK1/JAK3), and is
  also activated by prolactin, erythropoietin and thrombopoietin (via JAK2), GM-CSF/IL-3/IL-5,
  G-CSF, and oncostatin-M. Receptor-associated JAK kinases phosphorylate STAT5B on Tyr-699;
  phosphorylated STAT5B dimerizes through reciprocal SH2-phosphotyrosine interactions
  (and can form heterodimers with STAT5A or STAT3), translocates to the nucleus, and binds
  gamma-activated sequence (GAS) DNA elements to activate transcription of target genes.
  STAT5B drives transcriptional programs controlling postnatal growth (induction of IGF1
  downstream of growth hormone), lymphocyte development and immune homeostasis (including
  regulatory T cells and NK cells), and erythroid/hematopoietic differentiation. Loss-of-function
  variants cause growth hormone insensitivity syndrome with immune dysregulation (short
  stature with low IGF1 and normal/elevated growth hormone), while somatic activating
  mutations such as the SH2-domain N642H substitution drive T-cell and NK-cell leukemias
  and lymphomas. STAT5B is highly similar to and largely functionally overlapping with,
  but non-redundant from, its paralog STAT5A.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: STAT5B is active in the nucleus, where activated dimers bind GAS DNA
      elements and regulate transcription. Strongly supported phylogenetically and
      by direct experimental evidence.
    action: ACCEPT
    reason: Core localization for STAT5B's transcription factor activity; consistent
      with IDA evidence (PMID:29844444) and the entire STAT mechanism.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: STAT5B is a latent cytoplasmic factor prior to phosphorylation, where it
      docks to activated receptors and is phosphorylated by JAKs before nuclear
      translocation.
    action: ACCEPT
    reason: Core dual localization (cytoplasm/nucleus) of STAT proteins; supported by
      IDA (PMID:29844444).
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: STAT5B regulates RNA Pol II transcription of GAS-element target genes.
      Correct but general; the activator-specific terms (GO:0045944) and MF terms
      capture the function more precisely.
    action: KEEP_AS_NON_CORE
    reason: Accurate but a general parent of the more specific positive-regulation
      and DNA-binding TF activity annotations that represent the core function.
- term:
    id: GO:0006952
    label: defense response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Reflects STAT5B's role in immunity downstream of gamma-chain cytokines.
      This is a very general process term inferred phylogenetically across the family.
    action: KEEP_AS_NON_CORE
    reason: Captures the immune role at too high a level; lymphocyte differentiation /
      cytokine signaling terms are more informative.
- term:
    id: GO:0019221
    label: cytokine-mediated signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: STAT5B is a central transducer of cytokine signaling (IL-2/7/9/15/21,
      EPO, GM-CSF, etc.). Core process annotation, well supported by experiment and
      phylogeny.
    action: ACCEPT
    reason: Core biological process for STAT5B as a cytokine signal transducer.
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: STAT5B binds GAS elements in cis-regulatory regions of Pol II target
      genes. Supported experimentally by EMSA against the GHRE/GAS probe (PMID:29844444).
    action: ACCEPT
    reason: Core sequence-specific DNA-binding molecular function of STAT5B.
- term:
    id: GO:0042127
    label: regulation of cell population proliferation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: STAT5B promotes proliferation/survival of hematopoietic and lymphoid
      cells downstream of cytokines, and constitutive activation is oncogenic. General
      downstream process.
    action: KEEP_AS_NON_CORE
    reason: A downstream consequence of STAT5B target-gene programs rather than its
      direct molecular function.
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: STAT5B is a defining component of JAK-STAT signaling downstream of cell
      surface cytokine/hormone receptors. Core process, strongly supported.
    action: ACCEPT
    reason: Core biological process; STAT5B is by definition a JAK-STAT pathway effector.
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: STAT5B is a sequence-specific RNA Pol II transcription factor. This is
      the core molecular function, also supported by ISA (TFClass) and IDA for the
      activator-specific child term (PMID:29844444).
    action: ACCEPT
    reason: Core molecular function of STAT5B.
- term:
    id: GO:0090575
    label: RNA polymerase II transcription regulator complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Activated STAT5B dimers act within Pol II transcription regulator
      complexes at GAS-element promoters/enhancers, recruiting coactivators (e.g.
      CBP/p300 via NMI; NCOA1/SRC-1).
    action: ACCEPT
    reason: Consistent with STAT5B function as part of a transcription regulator
      complex; also supported by NAS (PMID:24058793).
- term:
    id: GO:0043434
    label: response to peptide hormone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: STAT5B mediates responses to peptide hormones including growth hormone
      and prolactin. General parent of the more specific GH receptor signaling term.
    action: KEEP_AS_NON_CORE
    reason: Accurate but subsumed by the more specific GH receptor signaling pathway
      annotation.
- term:
    id: GO:0060397
    label: growth hormone receptor signaling pathway via JAK-STAT
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: STAT5B is the principal signal transducer for growth hormone; GH-GHR-JAK2
      signaling activates STAT5B to induce IGF1. Core process, also supported by IDA
      (PMID:12552091) and disease genetics (PMID:29844444).
    action: ACCEPT
    reason: Core, signature biological process for STAT5B (GH/IGF1 axis).
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: STAT5B binds DNA. General parent of the sequence-specific GAS-binding MF;
      InterPro-based electronic inference is consistent with experimental evidence.
    action: KEEP_AS_NON_CORE
    reason: Correct but a general parent of the specific RNA Pol II cis-regulatory DNA
      binding annotation.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: STAT5B is a DNA-binding transcription factor. Correct but general; the
      RNA Pol II-specific child term (GO:0000981) is the precise core MF.
    action: MODIFY
    reason: General term; the RNA Pol II-specific transcription factor activity term
      (GO:0000981, already annotated) should be used.
    proposed_replacement_terms:
    - id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Nuclear localization of activated STAT5B. Consistent with IDA evidence
      (PMID:29844444).
    action: ACCEPT
    reason: Core localization, redundant with the IBA/IDA nucleus annotations.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Cytoplasmic localization of latent STAT5B. Consistent with IDA evidence
      (PMID:29844444).
    action: ACCEPT
    reason: Core localization, redundant with IBA/IDA cytoplasm annotations.
- term:
    id: GO:0006355
    label: regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: STAT5B regulates transcription. Very general InterPro-derived process
      term; subsumed by the Pol II-specific regulation/activation terms.
    action: KEEP_AS_NON_CORE
    reason: General parent term; more specific Pol II transcription terms are present.
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: STAT5B is part of signal transduction. Very general; the JAK-STAT and
      cytokine-mediated signaling terms are the specific descendants.
    action: KEEP_AS_NON_CORE
    reason: Root-level process term subsumed by specific JAK-STAT signaling annotations.
- term:
    id: GO:0019221
    label: cytokine-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Duplicate (ARBA electronic) of the cytokine-mediated signaling pathway
      annotation; core process for STAT5B.
    action: ACCEPT
    reason: Core process; redundant with the IBA annotation to the same term.
- term:
    id: GO:1903706
    label: regulation of hemopoiesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: STAT5B regulates hematopoiesis, including erythroid differentiation
      (PMID:20702587) and lymphoid development. Accurate process annotation.
    action: ACCEPT
    reason: Supported by experimental erythroid-differentiation evidence and broad
      hematopoietic role.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21106534
  qualifier: enables
  review:
    summary: Interaction with the DnaJ tumor suppressor hTid1/DNAJA3, a negative
      regulator that binds the STAT5B transactivation domain (PMID:21106534). The
      bare 'protein binding' term is uninformative about function.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 'protein binding' is uninformative; per guidelines a specific
      MF should be used. The interaction itself is real but does not define STAT5B's
      core function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31175292
  qualifier: enables
  review:
    summary: Interaction with ABL1 (P00519) reported in the STAT5B(N642H) study. Bare
      'protein binding' term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 'protein binding' is uninformative; a specific MF is preferred.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary interactome (HuRI) interactions. Bare 'protein
      binding' is uninformative and these HT partners do not inform core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 'protein binding' is uninformative; high-throughput partners
      add no functional resolution.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Affinity-capture interactome (BioPlex) interaction. Bare 'protein binding'
      is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 'protein binding' is uninformative; high-throughput partner.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:9989503
  qualifier: enables
  review:
    summary: Interaction with NMI (Q13287), identified via yeast two-hybrid using the
      STAT5b coiled-coil region; NMI enhances CBP/p300 recruitment to STAT5
      (PMID:9989503). Real and functionally relevant, but 'protein binding' is
      uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 'protein binding' is uninformative; the coactivator-recruitment
      role is captured by transcription regulator complex membership.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31175292
  qualifier: enables
  review:
    summary: STAT5B self-association (homodimerization), consistent with the activated
      STAT5B homodimer. The IDA-supported GO:0042803 protein homodimerization activity
      (PMID:29844444) captures this more precisely.
    action: KEEP_AS_NON_CORE
    reason: Reflects the functionally important homodimer but is captured more
      specifically by GO:0042803 (homodimerization activity).
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: GAS-element binding inferred from mouse ortholog. Core MF, duplicate of
      the IBA annotation to the same term.
    action: ACCEPT
    reason: Core DNA-binding MF; redundant with IBA annotation.
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: STAT5B is a transcriptional activator at GAS elements. Core MF, also
      supported by IDA (PMID:29844444; luciferase reporter transactivation).
    action: ACCEPT
    reason: Core molecular function; STAT5B is a sequence-specific transcriptional
      activator.
- term:
    id: GO:0040014
    label: regulation of multicellular organism growth
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: STAT5B regulates organismal growth via the GH/IGF1 axis; loss of function
      causes short stature (PMID:29844444). Core organism-level outcome.
    action: ACCEPT
    reason: Well-supported by human disease genetics (GH insensitivity / short stature).
- term:
    id: GO:0046983
    label: protein dimerization activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Activated STAT5B dimerizes. General dimerization term; the IDA-supported
      homodimerization activity (GO:0042803) is more specific.
    action: MODIFY
    reason: General term; the specific homodimerization activity (GO:0042803, IDA from
      PMID:29844444) better represents the function.
    proposed_replacement_terms:
    - id: GO:0042803
      label: protein homodimerization activity
- term:
    id: GO:0060397
    label: growth hormone receptor signaling pathway via JAK-STAT
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: GH receptor signaling via JAK-STAT, inferred from mouse ortholog.
      Duplicate of the IBA/IDA annotations; core process.
    action: ACCEPT
    reason: Core process, redundant with IBA and IDA (PMID:12552091) annotations.
- term:
    id: GO:0071363
    label: cellular response to growth factor stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: STAT5B mediates cellular responses to growth factors/cytokines. General
      term subsumed by specific JAK-STAT and GH receptor signaling annotations.
    action: KEEP_AS_NON_CORE
    reason: General process term; specific cytokine/GH signaling terms are present.
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: NAS
  original_reference_id: PMID:24058793
  qualifier: involved_in
  review:
    summary: STAT5B operates in JAK-STAT signaling, including as part of STAT
      heterodimers in immunity (PMID:24058793 review). Core process.
    action: ACCEPT
    reason: Core JAK-STAT process; redundant with IBA/TAS annotations to the same term.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: NAS
  original_reference_id: PMID:24058793
  qualifier: involved_in
  review:
    summary: STAT5B positively regulates transcription of GAS-element target genes.
      Core process; also supported by ISS and the IDA activator MF.
    action: ACCEPT
    reason: Core process for STAT5B as a transcriptional activator.
- term:
    id: GO:0090575
    label: RNA polymerase II transcription regulator complex
  evidence_type: NAS
  original_reference_id: PMID:24058793
  qualifier: part_of
  review:
    summary: Activated STAT5B acts within Pol II transcription regulator complexes
      (including STAT5A/STAT5B and STAT3/STAT5B complexes; ComplexPortal CPX-6044/6045).
    action: ACCEPT
    reason: Consistent with STAT5B function in transcription regulator complexes;
      redundant with IBA annotation.
- term:
    id: GO:0038162
    label: erythropoietin-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:9657743
  qualifier: involved_in
  review:
    summary: EPO induces tyrosine phosphorylation of JAK2, STAT5A and STAT5B in
      primary human erythroid precursors, with nuclear translocation of activated
      STAT5 (PMID:9657743). Direct experimental support.
    action: ACCEPT
    reason: Well-supported core process; EPO/JAK2/STAT5B signaling drives erythropoiesis.
- term:
    id: GO:0001228
    label: DNA-binding transcription activator activity, RNA polymerase II-specific
  evidence_type: IDA
  original_reference_id: PMID:29844444
  qualifier: enables
  review:
    summary: WT STAT5B bound the STAT5B-specific GHRE DNA probe under GH stimulation
      and drove luciferase reporter transactivation; DBD variants abolished both
      (PMID:29844444). Direct evidence for sequence-specific transcriptional activator
      activity.
    action: ACCEPT
    reason: Core molecular function with strong direct experimental support.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:29844444
  qualifier: located_in
  review:
    summary: GH-stimulated WT STAT5B translocates to the nucleus (immunofluorescence;
      the Q177P variant fails to enter the nucleus) (PMID:29844444). Direct support.
    action: ACCEPT
    reason: Core localization with direct experimental evidence.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:29844444
  qualifier: located_in
  review:
    summary: Latent and Q177P-mutant STAT5B localize to the cytoplasm/nuclear membrane
      (PMID:29844444). Direct support.
    action: ACCEPT
    reason: Core localization with direct experimental evidence.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:29844444
  qualifier: enables
  review:
    summary: Co-IP experiments showed STAT5B homodimerization (and heterodimerization
      with WT) upon activation (PMID:29844444). Activated STAT5B functions as a
      homodimer.
    action: ACCEPT
    reason: Core, mechanistically essential molecular function (dimerization precedes
      nuclear import and DNA binding).
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  qualifier: located_in
  review:
    summary: As a sequence-specific TF, STAT5B associates with chromatin at target
      loci. TFClass-based inference, consistent with function.
    action: ACCEPT
    reason: Consistent with DNA-binding TF activity and nuclear localization.
- term:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence_type: ISA
  original_reference_id: GO_REF:0000113
  qualifier: enables
  review:
    summary: TFClass-based assignment of sequence-specific Pol II TF activity.
      Duplicate of the IBA annotation; core MF.
    action: ACCEPT
    reason: Core molecular function; redundant with IBA annotation.
- term:
    id: GO:0019530
    label: taurine metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: acts_upstream_of_positive_effect
  review:
    summary: Narrow annotation transferred by sequence similarity from mouse Stat5b
      (acts upstream of taurine metabolism, likely via regulation of a metabolic
      target gene). Indirect, organism/context-specific and far from the core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Highly indirect, narrowly-scoped ISS transfer; not representative of STAT5B's
      core transcription-factor function.
- term:
    id: GO:0040014
    label: regulation of multicellular organism growth
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Growth regulation via the GH/IGF1 axis; duplicate of the Ensembl IEA
      annotation. Supported by human disease genetics (PMID:29844444).
    action: ACCEPT
    reason: Core organism-level outcome of GH/STAT5B signaling.
- term:
    id: GO:0045648
    label: positive regulation of erythrocyte differentiation
  evidence_type: IDA
  original_reference_id: PMID:20702587
  qualifier: involved_in
  review:
    summary: STAT5B promotes erythroid differentiation; ZFP36L1-mediated down-regulation
      of Stat5b mRNA drastically decreases erythroid colony formation in human
      hematopoietic progenitors (PMID:20702587).
    action: ACCEPT
    reason: Supported by direct experimental (loss-of-function) evidence in human
      erythroid progenitors.
- term:
    id: GO:0003682
    label: chromatin binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: STAT5B binds chromatin at target loci. General MF transferred by
      similarity; the sequence-specific GAS-binding terms are more precise.
    action: KEEP_AS_NON_CORE
    reason: General DNA/chromatin-binding term subsumed by the specific cis-regulatory
      DNA binding annotation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Nuclear localization, transferred by similarity. Core localization,
      redundant with IDA/IBA/IEA annotations.
    action: ACCEPT
    reason: Core localization; redundant.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Cytoplasmic localization, transferred by similarity. Core localization,
      redundant with IDA/IBA/IEA annotations.
    action: ACCEPT
    reason: Core localization; redundant.
- term:
    id: GO:0046983
    label: protein dimerization activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Dimerization activity transferred by similarity. General; the specific
      homodimerization activity (GO:0042803, IDA) is preferred.
    action: MODIFY
    reason: General term; replace with the specific homodimerization activity supported
      by IDA.
    proposed_replacement_terms:
    - id: GO:0042803
      label: protein homodimerization activity
- term:
    id: GO:0071363
    label: cellular response to growth factor stimulus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: General response-to-growth-factor process, transferred by similarity.
      Subsumed by specific cytokine/GH signaling terms.
    action: KEEP_AS_NON_CORE
    reason: General process term; specific signaling annotations are present.
- term:
    id: GO:0071364
    label: cellular response to epidermal growth factor stimulus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: EGF-response annotation transferred from STAT5A (P52632). STAT5 can be
      activated downstream of EGFR in some contexts, but this is a narrow,
      similarity-based, non-core annotation for STAT5B.
    action: MARK_AS_OVER_ANNOTATED
    reason: Narrow ISS transfer from the paralog; EGF response is not a core, well-established
      STAT5B function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1470012
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone
      signaling pathways. Consistent with the IDA nucleus annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      nucleus annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8983379
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone
      signaling pathways. Consistent with the IDA nucleus annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      nucleus annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9012671
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone
      signaling pathways. Consistent with the IDA nucleus annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      nucleus annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9670426
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone
      signaling pathways. Consistent with the IDA nucleus annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      nucleus annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9698016
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone
      signaling pathways. Consistent with the IDA nucleus annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      nucleus annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9698021
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone
      signaling pathways. Consistent with the IDA nucleus annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      nucleus annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9698033
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone
      signaling pathways. Consistent with the IDA nucleus annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      nucleus annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9698041
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone
      signaling pathways. Consistent with the IDA nucleus annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      nucleus annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9698754
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone
      signaling pathways. Consistent with the IDA nucleus annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      nucleus annotation.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9978250
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization of activated STAT5B within Reactome cytokine/hormone
      signaling pathways. Consistent with the IDA nucleus annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      nucleus annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1168894
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1295540
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1470009
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1470010
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1470012
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1839112
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-452097
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6785165
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-879909
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-919404
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-921155
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9670412
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9670417
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9670426
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9698005
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9698013
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9698016
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9698029
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9698033
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9703432
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9703435
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Positive regulation of Pol II transcription, transferred by similarity.
      Core process; duplicate of the NAS annotation to the same term.
    action: ACCEPT
    reason: Core process for STAT5B as a transcriptional activator; redundant.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1433456
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-380782
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-452108
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-879930
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8985929
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8985988
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9025969
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9670416
  qualifier: located_in
  review:
    summary: Cytosolic localization of latent STAT5B within a Reactome cytokine/hormone
      signaling pathway. Consistent with the IDA cytoplasm annotation; one of many
      pathway-specific Reactome localization records.
    action: KEEP_AS_NON_CORE
    reason: Correct localization but a pathway-specific Reactome duplicate of the core
      cytoplasm/cytosol annotation.
- term:
    id: GO:0060397
    label: growth hormone receptor signaling pathway via JAK-STAT
  evidence_type: IDA
  original_reference_id: PMID:12552091
  qualifier: involved_in
  review:
    summary: GH stimulated STAT5-dependent reporter activity in 293GHR/HuH7/T-47D
      cells, with GH-induced JAK2 phosphorylation (PMID:12552091). Supports STAT5B in
      GH receptor JAK-STAT signaling. Core process, redundant with the IBA/IEA
      annotations.
    action: ACCEPT
    reason: Core process with direct experimental support; defer to curator (BHF-UCL)
      full-text reading.
- term:
    id: GO:0032355
    label: response to estradiol
  evidence_type: IDA
  original_reference_id: PMID:12552091
  qualifier: involved_in
  review:
    summary: Estradiol (via ER-alpha and SOCS-2) suppresses GH-induced JAK2/STAT5
      signaling (PMID:12552091). Captures STAT5B's modulation by estrogen rather than
      a core function; a context-specific crosstalk process.
    action: KEEP_AS_NON_CORE
    reason: Reflects upstream regulation of STAT5B signaling by estradiol, not a core
      STAT5B function. Defer to curator who read the full text.
- term:
    id: GO:0032870
    label: cellular response to hormone stimulus
  evidence_type: IDA
  original_reference_id: PMID:12552091
  qualifier: involved_in
  review:
    summary: STAT5B mediates cellular responses to hormones (GH, estradiol context;
      PMID:12552091). Very general process term subsumed by the specific GH receptor
      signaling annotation.
    action: KEEP_AS_NON_CORE
    reason: General hormone-response term; specific GH receptor signaling annotation
      is more informative.
- term:
    id: GO:0035259
    label: nuclear glucocorticoid receptor binding
  evidence_type: IPI
  original_reference_id: PMID:12552091
  qualifier: enables
  review:
    summary: Annotation of STAT5B binding the glucocorticoid receptor (NR3C1, P04150),
      consistent with UniProt SUBUNIT 'Binds NR3C1 (By similarity)'. The cached
      abstract of PMID:12552091 is an estrogen/SOCS-2 GH-signaling study and does not
      itself describe GR binding; this is curator (BHF-UCL) judgment from full text
      (not cached). Cannot independently verify the supporting evidence.
    action: UNDECIDED
    reason: Per guidelines, cannot verify an experimental IPI annotation whose
      full text is not in the cache and whose cached abstract does not mention GR
      binding; do not overrule the curator.
- term:
    id: GO:0003700
    label: DNA-binding transcription factor activity
  evidence_type: TAS
  original_reference_id: PMID:8631883
  qualifier: enables
  review:
    summary: STAT5B is a DNA-binding transcription factor (cloning/characterization
      paper, PMID:8631883). General; the RNA Pol II-specific child term is the precise
      core MF.
    action: MODIFY
    reason: General term; the RNA Pol II-specific transcription factor activity term
      (GO:0000981) is preferred.
    proposed_replacement_terms:
    - id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
- term:
    id: GO:0006357
    label: regulation of transcription by RNA polymerase II
  evidence_type: TAS
  original_reference_id: PMID:8631883
  qualifier: involved_in
  review:
    summary: STAT5B regulates Pol II transcription of target genes (PMID:8631883).
      Correct but general; duplicate of the IBA annotation.
    action: KEEP_AS_NON_CORE
    reason: General process subsumed by the specific positive-regulation annotation.
- term:
    id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  evidence_type: TAS
  original_reference_id: PMID:8631883
  qualifier: involved_in
  review:
    summary: STAT5B was shown to be activated by IL-2 via JAK1/JAK3 and the IL-2R
      beta/gamma chains, requiring Tyr-699 for dimerization (PMID:8631883). Core
      JAK-STAT process with direct support.
    action: ACCEPT
    reason: Core process; supported by the original IL-2/JAK-STAT reconstitution study.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000113
  title: Gene Ontology annotation of human sequence-specific DNA binding transcription
    factors (DbTFs) based on the TFClass database
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12552091
  title: Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation,
    an effect mediated by SOCS-2.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract verified against PubMed. The paper studies GH/JAK2/STAT5
      signaling and its suppression by estradiol via SOCS-2; supports the GH receptor
      signaling, response to estradiol and cellular response to hormone IDA annotations.
      However the cached abstract does not mention the GO:0035259 glucocorticoid
      receptor binding annotation, which is BHF-UCL curator judgment from full text
      (not cached) - left UNDECIDED rather than removed.
- id: PMID:20702587
  title: ZFP36L1 negatively regulates erythroid differentiation of CD34+ hematopoietic
    stem cells by interfering with the Stat5b pathway.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text cached. Supports the GO:0045648 positive regulation of
      erythrocyte differentiation annotation - ZFP36L1 binds the Stat5b mRNA 3'UTR and
      down-regulation of Stat5b drastically reduces erythroid colony formation in human
      hematopoietic progenitors, demonstrating STAT5B promotes erythroid differentiation.
- id: PMID:21106534
  title: The tumor suppressor hTid1 inhibits STAT5b activity via functional interaction.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text cached. hTid1/DNAJA3 binds specifically to the STAT5b (not
      STAT5a) transactivation domain and negatively regulates STAT5b expression and
      transcriptional activity. Supports a GO:0005515 interaction (marked over-annotated
      as bare protein binding).
- id: PMID:24058793
  title: 'STAT heterodimers in immunity: A mixed message or a unique signal?'
  findings: []
- id: PMID:29844444
  title: Dominant-negative STAT5B mutations cause growth hormone insensitivity with
    short stature and mild immune dysregulation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PMC full text available and read. Directly establishes STAT5B as the
      key GH signal transducer; provides experimental evidence for GH-induced Tyr
      phosphorylation, homo/heterodimerization (co-IP), nuclear translocation (IF),
      GHRE/GAS DNA binding (EMSA) and reporter transactivation, plus dominant-negative
      disease variants. Supports the GO:0001228, GO:0042803, nucleus and cytoplasm
      IDA annotations.
- id: PMID:31175292
  title: Structural and functional consequences of the STAT5B(N642H) driver mutation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text cached. Structural/functional study of the SH2-domain N642H
      oncogenic driver mutation; source of the ABL1 and self-association (GO:0042802)
      IntAct interactions. Informs STAT5B's role in leukemia/lymphoma but not its core
      physiological function.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:8631883
  title: Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and
    Stat5B DNA binding activity in COS-7 cells.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract verified against PubMed. Original cloning/characterization
      of human STAT5B; shows IL-2 activation via JAK1/JAK3 and the IL-2R beta/gamma
      chains and that Tyr-699 is required for dimerization. Supports the TAS JAK-STAT
      and transcription-factor annotations. Cached as abstract-only.
- id: PMID:9657743
  title: Erythropoietin induces tyrosine phosphorylation of Jak2, STAT5A, and STAT5B
    in primary cultured human erythroid precursors.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract verified against PubMed. Directly supports the GO:0038162
      erythropoietin-mediated signaling pathway IDA annotation - EPO induces JAK2,
      STAT5A and STAT5B tyrosine phosphorylation and nuclear translocation in primary
      human erythroid precursors. Cached as abstract-only.
- id: PMID:9989503
  title: Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated
    signaling.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract verified against PubMed. NMI (Q13287) was found via yeast
      two-hybrid using the STAT5b coiled-coil region and augments STAT5/STAT1
      transcription by enhancing CBP/p300 recruitment. Supports the GO:0005515 NMI
      interaction (marked over-annotated as bare protein binding). Cached as
      abstract-only.
- id: Reactome:R-HSA-1168894
  title: p-STAT5A/B dissociates from the Growth Hormone receptor
  findings: []
- id: Reactome:R-HSA-1295540
  title: IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:STAT5A,STAT5B phosphorylates STAT5
  findings: []
- id: Reactome:R-HSA-1433456
  title: Recruitment of STATs
  findings: []
- id: Reactome:R-HSA-1470009
  title: Phosphorylation of STATs
  findings: []
- id: Reactome:R-HSA-1470010
  title: Dimerization of STATs
  findings: []
- id: Reactome:R-HSA-1470012
  title: Disassociation and translocation of STATs to the nucleus
  findings: []
- id: Reactome:R-HSA-1839112
  title: Phosphorylation of STAT5 by cytosolic FGFR1 fusions
  findings: []
- id: Reactome:R-HSA-380782
  title: STAT binds to the active receptor
  findings: []
- id: Reactome:R-HSA-452097
  title: Recruited STAT5 is phosphorylated
  findings: []
- id: Reactome:R-HSA-452108
  title: Phosphorylation of IL2RB Y338, Y392 or Y510 enables STAT recruitment
  findings: []
- id: Reactome:R-HSA-6785165
  title: p-STAT5A, p-STAT5B dissociate from IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3:p-STAT5A,p-STAT5B
  findings: []
- id: Reactome:R-HSA-879909
  title: Activation of STAT5a/b by JAK2
  findings: []
- id: Reactome:R-HSA-879930
  title: STAT5 is recruited by JAK2
  findings: []
- id: Reactome:R-HSA-8983379
  title: p-Y-STAT3:p-STAT5 translocates to the nucleus
  findings: []
- id: Reactome:R-HSA-8985929
  title: IL9:p-Y407-IL9R:JAK1:IL2RG:p-904,939-JAK3 binds STAT1, STAT3, STAT5A or STAT5B
  findings: []
- id: Reactome:R-HSA-8985988
  title: IL9:p-Y116-IL9R:JAK1:IL2RG:p-904,939-JAK3:STAT3 phosphorylates STAT1, STAT3
    or STAT5
  findings: []
- id: Reactome:R-HSA-9012671
  title: p-STAT5 binds CISH, SOCS1 and SOCS2 gene
  findings: []
- id: Reactome:R-HSA-9025969
  title: IL7:p-Y449-IL7R:JAK1:IL2RG:p-JAK3 binds STAT5
  findings: []
- id: Reactome:R-HSA-919404
  title: Phosphorylated STAT5 is released
  findings: []
- id: Reactome:R-HSA-921155
  title: p-STAT5 dissociates from the receptor complex
  findings: []
- id: Reactome:R-HSA-9670412
  title: Phosphorylation of STATs downstream of KIT mutants
  findings: []
- id: Reactome:R-HSA-9670416
  title: Recruitment of STATs by KIT mutants
  findings: []
- id: Reactome:R-HSA-9670417
  title: Dimerization of STATs downstream of KIT mutants
  findings: []
- id: Reactome:R-HSA-9670426
  title: Disassociation and translocation of STATs to the nucleus downstream of KIT
    mutants
  findings: []
- id: Reactome:R-HSA-9698005
  title: FLT3 ITD mutants phosphorylate STAT5
  findings: []
- id: Reactome:R-HSA-9698013
  title: PTPN11:p-STAT5 dissociates from mutant FLT3
  findings: []
- id: Reactome:R-HSA-9698016
  title: PTPN11:p-STAT5 translocates to nucleus downstream of mutant FLT3
  findings: []
- id: Reactome:R-HSA-9698021
  title: PTPN11:p-STAT5 binds BCL2L1 promoter
  findings: []
- id: Reactome:R-HSA-9698029
  title: p-STAT5 dissociates from mutant FLT3
  findings: []
- id: Reactome:R-HSA-9698033
  title: p-STAT5 translocates to nucleus downstream of mutant FLT3
  findings: []
- id: Reactome:R-HSA-9698041
  title: p-STAT5 binds the CDKN1A gene
  findings: []
- id: Reactome:R-HSA-9698754
  title: p-STAT5 binds the NOX4 promoter
  findings: []
- id: Reactome:R-HSA-9703432
  title: p-STAT5 dissociates from FLT3 fusion proteinsp-
  findings: []
- id: Reactome:R-HSA-9703435
  title: FLT3 fusions activate STAT5
  findings: []
- id: Reactome:R-HSA-9978250
  title: Phosphorylated STAT5 dimer binds the IL4R gene
  findings: []
core_functions:
- description: >-
    STAT5B is a sequence-specific RNA polymerase II transcription factor that, once
    activated, binds gamma-activated sequence (GAS) elements in cis-regulatory regions
    of target genes and activates their transcription, recruiting coactivators such as
    CBP/p300 (via NMI) and NCOA1/SRC-1. DNA binding and transactivation are directly
    demonstrated by EMSA against the GHRE/GAS probe and luciferase reporter assays;
    DNA-binding-domain disease variants abolish both activities.
  molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  locations:
  - id: GO:0005634
    label: nucleus
  - id: GO:0000785
    label: chromatin
  supported_by:
  - reference_id: PMID:29844444
    supporting_text: "WT STAT5B readily bound and gel-shifted the STAT5B-specific DNA probe (GHRE) only under GH-stimulated conditions"
  - reference_id: PMID:9989503
    supporting_text: "Nmi enhances the association of CBP/p300 coactivator proteins with Stat1 and Stat5"
- description: >-
    STAT5B is a latent cytoplasmic signal transducer for cytokine and hormone receptors
    that signal through the JAK-STAT pathway. Receptor-associated JAK kinases (JAK1/JAK2/JAK3)
    phosphorylate STAT5B on Tyr-699, which is required for its activation; this couples
    upstream signals (common gamma-chain cytokines IL-2/7/9/15/21, growth hormone,
    prolactin, erythropoietin, thrombopoietin, GM-CSF/IL-3/IL-5) to transcriptional
    output. This includes the growth hormone receptor signaling pathway that drives IGF1
    induction, and erythropoietin-mediated signaling in erythroid precursors.
  molecular_function:
    id: GO:0000981
    label: DNA-binding transcription factor activity, RNA polymerase II-specific
  directly_involved_in:
  - id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  - id: GO:0019221
    label: cytokine-mediated signaling pathway
  - id: GO:0060397
    label: growth hormone receptor signaling pathway via JAK-STAT
  - id: GO:0038162
    label: erythropoietin-mediated signaling pathway
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:8631883
    supporting_text: "human Stat5 activation is also dependent on Tyr-694 in Stat5A and Tyr-699 in Stat5B, indicating that these tyrosines are required for dimerization"
  - reference_id: PMID:9657743
    supporting_text: "erythropoietin induces tyrosine phosphorylation of Jak2, STAT5A, and STAT5B"
- description: >-
    Upon tyrosine phosphorylation, STAT5B dimerizes through reciprocal SH2-phosphotyrosine
    interactions (forming homodimers, and also heterodimers with STAT5A or STAT3). Dimerization
    is a prerequisite for nuclear translocation and DNA binding, and is the basis for the
    dominant-negative action of disease variants that retain dimerization but lose nuclear
    import or DNA binding.
  molecular_function:
    id: GO:0042803
    label: protein homodimerization activity
  directly_involved_in:
  - id: GO:0007259
    label: cell surface receptor signaling pathway via JAK-STAT
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:29844444
    supporting_text: "each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B"
suggested_questions:
- question: >-
    Which target-gene programs are uniquely dependent on STAT5B versus STAT5A in human
    cells, given their high sequence identity and largely overlapping but non-redundant
    functions?
- question: >-
    How do STAT5B heterodimers (e.g. STAT5A/STAT5B, STAT3/STAT5B) differ from homodimers
    in DNA-element preference and target-gene output in lymphocytes?
- question: >-
    What distinguishes the transcriptional consequences of germline loss-of-function
    STAT5B variants (growth/immune phenotypes) from somatic gain-of-function variants
    (e.g. N642H) in leukemia?
suggested_experiments:
- description: >-
    ChIP-seq for endogenous STAT5B (with STAT5A-specific controls) in cytokine- or
    GH-stimulated primary human T cells and erythroid progenitors to define the
    STAT5B-specific GAS-element cistrome and target genes.
- description: >-
    Paired RNA-seq after STAT5B-specific versus STAT5A-specific degron/knockdown to
    quantify non-redundant target-gene programs downstream of IL-2, GH and EPO.
- description: >-
    Structure-function and EMSA/reporter assays of additional CCD, DBD and SH2 variants
    to map how each domain contributes to dimerization, nuclear import and DNA binding,
    extending the dominant-negative analyses of PMID:29844444.