id: MODULE:il21_signaling title: Interleukin-21 signaling pathway module description: >- Secreted Interleukin-21 (IL21) binds the private alpha receptor subunit IL21R and recruits the shared common gamma chain (IL2RG) to assemble a heterodimeric class I cytokine receptor complex on B cells, T cells, and natural killer (NK) cells. Receptor assembly juxtaposes and activates receptor-associated Janus kinases JAK1 (on IL21R) and JAK3 (on IL2RG), which phosphorylate IL21R cytoplasmic tyrosines (notably Y519) to recruit and phosphorylate STAT3 (and contextually STAT1 and STAT5), driving germinal center B cell differentiation, immunoglobulin class-switch recombination, T follicular helper (Tfh) cell differentiation, and NK/CD8+ T cell effector maturation. status: DRAFT evidence: - source_id: GO:0038114 title: interleukin-21-mediated signaling pathway statement: >- Grounded in the GO biological process term for interleukin-21-mediated signaling pathway, defined as the series of molecular signals initiated by interleukin-21 binding to its receptor complex (IL21R/IL2RG) on the surface of a target cell. - source_id: PMID:11081504 title: Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. statement: >- Identified human IL21 and IL21R as a novel class I four-helix-bundle cytokine-receptor pair that promotes NK cell expansion and regulates B and T lymphocyte proliferation. - source_id: PMID:12244150 title: IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. statement: >- Demonstrated that IL21 induces STAT3 DNA binding and STAT3 tyrosine phosphorylation in human NK and T cells and the NK-92 line (abstract; STAT1 activation by IL21 is documented in Reactome:R-HSA-9006870). - source_id: PMID:12504082 title: Human IL-21 and IL-4 bind to partially overlapping epitopes of common gamma-chain. statement: >- Established that human IL21 engages the shared cytokine receptor common gamma chain (IL2RG) alongside IL21R to form a functional signaling complex. - source_id: PMID:15546387 title: Biology of IL-21 and the IL-21 receptor. statement: >- Review of IL21 as a common gamma-chain family cytokine whose private receptor IL21R activates the JAK-STAT pathway upon ligand binding, with pleiotropic effects on B, T, NK, and dendritic cells (abstract only). - source_id: PMID:37339051 title: A structural blueprint for interleukin-21 signal modulation. statement: >- Resolves the structural architecture of the ternary IL21:IL21R:IL2RG signaling complex and defines how ligand geometry controls JAK1/JAK3 juxtaposition and STAT3 vs STAT1 activation amplitude. - source_id: Reactome:R-HSA-9005980 title: IL21 binds IL21R:JAK1 statement: >- Reactome reaction documenting initial high-affinity binding of secreted IL21 to the IL21R:JAK1 complex at the plasma membrane. - source_id: Reactome:R-HSA-9006844 title: IL21:IL21R:JAK1 binds IL2RG:JAK3 statement: >- Reactome reaction documenting recruitment of the IL2RG:JAK3 subunit to form the active ternary IL21:IL21R:IL2RG receptor complex. - source_id: Reactome:R-HSA-9006850 title: IL21 receptor JAK phosphorylation statement: >- Reactome reaction documenting reciprocal phosphorylation of JAK1 and JAK3 at the activated IL21 receptor complex. - source_id: Reactome:R-HSA-9006870 title: IL21 receptor STAT phosphorylation statement: >- Reactome reaction documenting JAK1/JAK3-mediated phosphorylation of STAT3 and STAT1 docked at phosphorylated IL21R. - source_id: file:genes/human/IL21/IL21-ai-review.yaml title: Human IL21 gene review statement: >- Curates human IL21 (UniProtKB:Q9HBE4) with GO:0005125 (cytokine activity) and GO:0038114 (interleukin-21-mediated signaling pathway), upgrading GO:0005126 (cytokine receptor binding) and GO:0005134 (interleukin-2 receptor binding). - source_id: file:interpro/panther/PTHR14356/PTHR14356-review.yaml title: PANTHER PTHR14356 (INTERLEUKIN-15-RELATED) family review statement: >- Documents subfamily partitioning of PTHR14356 into PTHR14356:SF2 (IL21) and PTHR14356:SF3 (IL15), scopes GO:0038114 to subfamily PTHR14356:SF2 (node PTN007637558), and recommends family-wide placement of GO:0005125 (cytokine activity, currently asserted by PAINT only at the IL15 node PTN002682897) at PTN002682898, the node whose seeds span both subfamilies. - source_id: PANTHER:PTN002682898 title: PAINT node PTN002682898 for IL21 statement: >- Local PAINT IBD node in PTHR14356 (node taxon not recorded in paint.tsv; seeds include IL21 and IL15 orthologs) asserting only biological process terms P:GO:0001819 and P:GO:0050778; PAINT date 20240321. - source_id: PANTHER:PTN007637558 title: PAINT node PTN007637558 for IL21 statement: >- Local PAINT IBD node in PTHR14356 (node taxon NCBITaxon:117571; seeds are IL21 orthologs only) asserting the single biological process term P:GO:0045954; PAINT date 20240321. - source_id: PANTHER:PTN000547990 title: PAINT node PTN000547990 for IL21R statement: >- Local PAINT IBD node in PTHR23037 (node taxon not recorded) asserting C:GO:0009897 (20210917), F:GO:0004896 (20260828), and P:GO:0019221 (20251220); human IL21R (UniProtKB:Q9HBE5) seeds only F:GO:0004896. - source_id: PANTHER:PTN002745476 title: PAINT node PTN002745476 for IL2RG statement: >- Local PAINT IBD node in PTHR23037 (node taxon recorded as taxon:2759) asserting C:GO:0005886, C:GO:0043235, F:GO:0004896, F:GO:0019955, and P:GO:0019221 (dates 20230406 to 20260828); human IL2RG (UniProtKB:P31785) seeds all but F:GO:0019955. - source_id: PANTHER:PTN008588077 title: PAINT node PTN008588077 for IL2RG statement: >- Local PAINT IBD node in PTHR23037 (node taxon NCBITaxon:117571) asserting C:GO:0005893, F:GO:0015026, P:GO:0030098, P:GO:0035723, P:GO:0038110, P:GO:0038111, and P:GO:0038113 (dates 20250903 to 20260728); human IL2RG (UniProtKB:P31785) seeds all but P:GO:0030098. - source_id: PANTHER:PTN001562978 title: PAINT node PTN001562978 for JAK1 and JAK3 statement: >- Local PAINT IBD node in PTHR45807 (node taxon NCBITaxon:33213) asserting C:GO:0005829, F:GO:0004715, F:GO:0005126, P:GO:0007259, P:GO:0019221, P:GO:0030154, and P:GO:0035556 (dates 20230112 to 20260828). Human JAK1 (UniProtKB:P23458) seeds F:GO:0004715, P:GO:0007259, and P:GO:0019221; human JAK3 (UniProtKB:P52333) seeds only P:GO:0019221. - source_id: PANTHER:PTN000210448 title: PAINT node PTN000210448 for STAT3 and STAT1 statement: >- Local PAINT IBD node in PTHR11801 (node taxon NCBITaxon:2759) asserting C:GO:0005634, C:GO:0005737 (20260528), F:GO:0000978 (20251218), F:GO:0000981 (20240729), and P:GO:0006357 (20260828); human STAT3 (UniProtKB:P40763) and STAT1 (UniProtKB:P42224) are seeds for all five. notes: >- Three-step JAK-STAT cytokine signaling module modeling Interleukin-21 (subfamily PTHR14356:SF2) signaling through the heterodimeric IL21R (PTHR23037:SF7) and common gamma chain IL2RG (PTHR23037:SF47) receptor complex. Per ligand-in-signaling conventions (projects/LIGANDS_IN_SIGNALING.md), the IL21 ligand annoton uses the subfamily selector PANTHER:PTHR14356:SF2 (because parent family PTHR14356 also contains IL15 in PTHR14356:SF3) and molecular function GO:0005125 (cytokine activity, an is_a child of GO:0048018 receptor ligand activity) rather than receptor-binding terms GO:0005126 or GO:0005134, resolving the Category A gap where GO:0038114 was annotated to IL21R and IL2RG in human GOA but omitted on human IL21. Neither IL21 ligand PAINT node attests a molecular function: PTN002682898 asserts only GO:0001819 and GO:0050778, and PTN007637558 only GO:0045954, all biological process terms; GO:0005125 on the ligand step rests on the IL21 gene review and literature. The IL21R annoton uses the specific GO:0001532 (interleukin-21 receptor activity, an is_a child of GO:0004896); its PAINT node PTN000547990 asserts the parent GO:0004896, a recorded mismatch of specificity. The shared IL2RG chain keeps GO:0004896. module: id: il21_signaling label: Interleukin-21 signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: interleukin-21-mediated signaling pathway term: id: GO:0038114 label: interleukin-21-mediated signaling pathway description: >- Series of molecular signals initiated by secreted IL21 binding to its heterodimeric receptor complex (IL21R and IL2RG) on target lymphocytes, activating receptor-associated JAK1 and JAK3 kinases and downstream STAT3/STAT1 transcriptional programs. context: taxa: - preferred_term: bony vertebrates term: id: NCBITaxon:117571 label: Euteleostomi cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus parts: - order: 1 role: il21 receptor complex assembly node: id: il21_engages_receptor_complex label: IL21 engages the heterodimeric IL21R/IL2RG receptor complex module_type: REGULATORY_STEP description: >- Secreted four-helix-bundle cytokine IL21 binds with high affinity to the private alpha chain IL21R and recruits the shared common gamma chain (IL2RG) into a ternary signaling complex at the lymphocyte plasma membrane. annotons: - id: il21_cytokine_ligand label: IL21 cytokine ligand participant: selector_type: FAMILY family: preferred_term: Interleukin-21 cytokine subfamily term: id: PANTHER:PTHR14356:SF2 label: INTERLEUKIN-21 representative_members: - preferred_term: IL21 term: id: UniProtKB:Q9HBE4 label: Interleukin-21 ancestral_nodes: - preferred_term: PAINT node PTN002682898 in PTHR14356 term: id: PANTHER:PTN002682898 label: PTN002682898 description: >- PAINT node in PTHR14356 (node taxon not recorded in paint.tsv) whose IBD seeds include both IL21 and IL15 orthologs, so it is ancestral to both subfamilies. It asserts only biological process terms: P:GO:0001819 (seeds MGI:MGI:1890474, UniProtKB:P40933 IL15, UniProtKB:Q9HBE4 IL21) and P:GO:0050778 (seeds MGI:MGI:103014, MGI:MGI:1890474, UniProtKB:Q9HBE4). It asserts no molecular function and no cellular component term. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN002682898 in PTHR14356, recorded in interpro/panther/PTHR14356/PTHR14356-paint.tsv. - preferred_term: PAINT node PTN007637558 in PTHR14356 term: id: PANTHER:PTN007637558 label: PTN007637558 description: >- PAINT node in PTHR14356 (node taxon NCBITaxon:117571, Euteleostomi) whose only IBD seeds are IL21 orthologs (MGI:MGI:1890474, UniProtKB:Q9HBE4). It asserts a single biological process term, P:GO:0045954, and no molecular function, so the ligand step's GO:0005125 is not attested by either IL21 ligand node. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN007637558 in PTHR14356, recorded in interpro/panther/PTHR14356/PTHR14356-paint.tsv. function: preferred_term: cytokine activity term: id: GO:0005125 label: cytokine activity processes: - preferred_term: interleukin-21-mediated signaling pathway term: id: GO:0038114 label: interleukin-21-mediated signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Secreted four-helix-bundle cytokine ligand that binds IL21R and recruits IL2RG to initiate the interleukin-21-mediated JAK1/JAK3 signaling cascade. evidence: - source_id: PMID:11081504 statement: >- Discovered human IL21 as the secreted cytokine agonist for IL21R on NK, B, and T lymphocytes. - source_id: PMID:37339051 statement: >- Structural blueprint of the ternary IL21:IL21R:IL2RG complex showing how IL21 bridges IL21R and IL2RG. - source_id: file:genes/human/IL21/IL21-ai-review.yaml statement: >- Human IL21 review curates GO:0005125 (cytokine activity) and GO:0038114 (interleukin-21-mediated signaling pathway) as core functions. - source_id: file:interpro/panther/PTHR14356/PTHR14356-review.yaml statement: >- PTHR14356 family review scopes GO:0038114 to subfamily PTHR14356:SF2 (PTN007637558) and recommends placing GO:0005125 at PTN002682898, whose seeds span both subfamilies (PAINT currently asserts it only at the IL15 node PTN002682897). - id: il21r_receptor_alpha label: IL21R receptor alpha subunit participant: selector_type: FAMILY family: preferred_term: Interleukin-21 receptor subfamily term: id: PANTHER:PTHR23037:SF7 label: INTERLEUKIN-21 RECEPTOR representative_members: - preferred_term: IL21R term: id: UniProtKB:Q9HBE5 label: Interleukin-21 receptor ancestral_nodes: - preferred_term: PAINT node PTN000547990 in PTHR23037 term: id: PANTHER:PTN000547990 label: PTN000547990 description: >- PAINT node in PTHR23037 (node taxon not recorded in paint.tsv) asserting C:GO:0009897, F:GO:0004896, and P:GO:0019221. Human IL21R (UniProtKB:Q9HBE5) seeds only F:GO:0004896, the parent of the GO:0001532 used on this step. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN000547990 in PTHR23037, recorded in interpro/panther/PTHR23037/PTHR23037-paint.tsv. function: preferred_term: interleukin-21 receptor activity term: id: GO:0001532 label: interleukin-21 receptor activity processes: - preferred_term: interleukin-21-mediated signaling pathway term: id: GO:0038114 label: interleukin-21-mediated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Private ligand-specific alpha subunit of the IL21 receptor complex that binds IL21, constitutively associates with JAK1 via its intracellular Box1/Box2 motifs, and provides phosphorylated Y519 docking sites for STAT3 and STAT1. evidence: - source_id: PMID:11081504 statement: >- Identified IL21R as a lymphoid class I cytokine receptor capable of signal transduction and used it to clone its ligand IL21, supporting interleukin-21 receptor activity (GO:0001532). - source_id: PMID:12504082 statement: >- Biosensor analysis of recombinant ectodomains showed high-affinity IL21 binding to IL21R (KD 70 pM) and ternary complex formation with the common gamma chain. - source_id: PMID:15546387 statement: >- Review stating that IL21R activates the JAK-STAT pathway upon ligand binding. - id: il2rg_common_gamma_chain label: IL2RG common gamma chain participant: selector_type: FAMILY family: preferred_term: Cytokine receptor common subunit gamma subfamily term: id: PANTHER:PTHR23037:SF47 label: INTERLEUKIN 2 RECEPTOR SUBUNIT GAMMA representative_members: - preferred_term: IL2RG term: id: UniProtKB:P31785 label: Cytokine receptor common subunit gamma ancestral_nodes: - preferred_term: PAINT node PTN002745476 in PTHR23037 term: id: PANTHER:PTN002745476 label: PTN002745476 description: >- PAINT node in PTHR23037 (node taxon recorded as taxon:2759) asserting C:GO:0005886, C:GO:0043235, F:GO:0004896, F:GO:0019955, and P:GO:0019221. Human IL2RG (UniProtKB:P31785) seeds C:GO:0005886, C:GO:0043235, F:GO:0004896, and P:GO:0019221, but not F:GO:0019955. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN002745476 in PTHR23037, recorded in interpro/panther/PTHR23037/PTHR23037-paint.tsv. - preferred_term: PAINT node PTN008588077 in PTHR23037 term: id: PANTHER:PTN008588077 label: PTN008588077 description: >- PAINT node in PTHR23037 (node taxon NCBITaxon:117571, Euteleostomi) asserting C:GO:0005893, F:GO:0015026, P:GO:0030098, P:GO:0035723, P:GO:0038110, P:GO:0038111, and P:GO:0038113. Human IL2RG (UniProtKB:P31785) seeds all except P:GO:0030098, which is seeded by a zebrafish gene (ZFIN:ZDB-GENE-080402-1). evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN008588077 in PTHR23037, recorded in interpro/panther/PTHR23037/PTHR23037-paint.tsv. function: preferred_term: cytokine receptor activity term: id: GO:0004896 label: cytokine receptor activity processes: - preferred_term: interleukin-21-mediated signaling pathway term: id: GO:0038114 label: interleukin-21-mediated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Shared signaling receptor subunit (gamma-c) recruited to the IL21:IL21R complex that brings associated JAK3 into proximity with IL21R-bound JAK1. evidence: - source_id: PMID:12504082 statement: >- Demonstrated direct binding of IL21 to IL2RG and requirement of IL2RG for IL21 signal transduction. - order: 2 role: jak1 and jak3 kinase activation node: id: il21_jak_activation label: JAK1 and JAK3 trans-phosphorylation and receptor phosphorylation module_type: REGULATORY_STEP description: >- Juxtaposed JAK1 (on IL21R) and JAK3 (on IL2RG) trans-phosphorylate and phosphorylate cytoplasmic tyrosine residues on IL21R (principally Y519), creating SH2 docking sites for STAT3 and STAT1. annotons: - id: jak1_tyrosine_kinase label: JAK1 non-receptor tyrosine kinase participant: selector_type: FAMILY family: preferred_term: Tyrosine-protein kinase JAK1 subfamily term: id: PANTHER:PTHR45807:SF5 label: TYROSINE-PROTEIN KINASE JAK1 representative_members: - preferred_term: JAK1 term: id: UniProtKB:P23458 label: Tyrosine-protein kinase JAK1 ancestral_nodes: - preferred_term: PAINT node PTN001562978 in PTHR45807 term: id: PANTHER:PTN001562978 label: PTN001562978 description: >- PAINT node in PTHR45807 (node taxon NCBITaxon:33213, Bilateria) asserting C:GO:0005829, F:GO:0004715, F:GO:0005126, P:GO:0007259, P:GO:0019221, P:GO:0030154, and P:GO:0035556. Human JAK1 (UniProtKB:P23458) seeds F:GO:0004715, P:GO:0007259, and P:GO:0019221. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN001562978 in PTHR45807, recorded in interpro/panther/PTHR45807/PTHR45807-paint.tsv. function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- IL21R-associated Janus kinase activated upon ternary complex assembly to phosphorylate IL21R cytoplasmic tyrosines and docked STAT3/STAT1 transcription factors. evidence: - source_id: PMID:15546387 statement: >- Review stating that the private receptor IL21R activates the JAK-STAT pathway upon ligand binding (abstract; JAK1 activation specifically is documented in Reactome:R-HSA-9006850). - source_id: Reactome:R-HSA-9006870 statement: >- Reactome reaction for JAK1/JAK3-mediated STAT phosphorylation at the activated IL21 receptor complex. - id: jak3_tyrosine_kinase label: JAK3 non-receptor tyrosine kinase participant: selector_type: FAMILY family: preferred_term: Tyrosine-protein kinase JAK3 subfamily term: id: PANTHER:PTHR45807:SF3 label: TYROSINE-PROTEIN KINASE JAK3 representative_members: - preferred_term: JAK3 term: id: UniProtKB:P52333 label: Tyrosine-protein kinase JAK3 ancestral_nodes: - preferred_term: PAINT node PTN001562978 in PTHR45807 term: id: PANTHER:PTN001562978 label: PTN001562978 description: >- PAINT node in PTHR45807 (node taxon NCBITaxon:33213, Bilateria) asserting C:GO:0005829, F:GO:0004715, F:GO:0005126, P:GO:0007259, P:GO:0019221, P:GO:0030154, and P:GO:0035556. Human JAK3 (UniProtKB:P52333) seeds only P:GO:0019221. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN001562978 in PTHR45807, recorded in interpro/panther/PTHR45807/PTHR45807-paint.tsv. function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- IL2RG-associated Janus kinase that trans-activates with JAK1 upon IL21-induced receptor heterodimerization to drive STAT3 and STAT1 phosphorylation. evidence: - source_id: PMID:15546387 statement: >- Review placing IL21 in the common gamma-chain cytokine family whose private receptor IL21R activates JAK-STAT signaling (abstract; JAK3 activation by the IL21 receptor complex is documented in Reactome:R-HSA-9006850). - source_id: Reactome:R-HSA-9006850 statement: >- Reactome reaction documenting reciprocal phosphorylation of JAK1 and JAK3 in the IL21 receptor complex. - order: 3 role: stat3 and stat1 transcriptional output node: id: il21_stat_transcriptional_output label: STAT3 and STAT1 nuclear translocation and transcriptional output module_type: REGULATORY_STEP description: >- Tyrosine-phosphorylated STAT3 (the dominant effector) and STAT1 dimerize, translocate to the nucleus, and activate target genes (including BCL6, PRDM1/BLIMP1, IFNG, and GZMB) that govern germinal center B cell differentiation, immunoglobulin production, Tfh differentiation, and lymphocyte cytotoxicity. annotons: - id: stat3_transcription_factor label: STAT3 transcription factor participant: selector_type: FAMILY family: preferred_term: Signal transducer and activator of transcription 3 subfamily term: id: PANTHER:PTHR11801:SF2 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 representative_members: - preferred_term: STAT3 term: id: UniProtKB:P40763 label: Signal transducer and activator of transcription 3 ancestral_nodes: - preferred_term: PAINT node PTN000210448 in PTHR11801 term: id: PANTHER:PTN000210448 label: PTN000210448 description: >- PAINT node in PTHR11801 (node taxon NCBITaxon:2759, Eukaryota) asserting C:GO:0005634, C:GO:0005737, F:GO:0000978, F:GO:0000981, and P:GO:0006357. Human STAT3 (UniProtKB:P40763) is a seed for all five. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN000210448 in PTHR11801, recorded in interpro/panther/PTHR11801/PTHR11801-paint.tsv. function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Primary transcriptional effector of IL21 signaling that docks at phosphorylated IL21R Y519, is phosphorylated on Y705 by JAK1/JAK3, and drives B cell plasma cell differentiation, Tfh generation, and humoral immunity. evidence: - source_id: PMID:12244150 statement: >- Demonstrated IL21-induced STAT3 DNA binding and STAT3 tyrosine phosphorylation in human NK and T cells. - source_id: PMID:37339051 statement: >- Demonstrated that STAT3 is the most potent and sustained signaling output of the IL21:IL21R:IL2RG receptor complex. - id: stat1_transcription_factor label: STAT1 transcription factor participant: selector_type: FAMILY family: preferred_term: Signal transducer and activator of transcription 1 subfamily term: id: PANTHER:PTHR11801:SF18 label: SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1-ALPHA_BETA representative_members: - preferred_term: STAT1 term: id: UniProtKB:P42224 label: Signal transducer and activator of transcription 1-alpha/beta ancestral_nodes: - preferred_term: PAINT node PTN000210448 in PTHR11801 term: id: PANTHER:PTN000210448 label: PTN000210448 description: >- PAINT node in PTHR11801 (node taxon NCBITaxon:2759, Eukaryota) asserting C:GO:0005634, C:GO:0005737, F:GO:0000978, F:GO:0000981, and P:GO:0006357. Human STAT1 (UniProtKB:P42224) is a seed for all five. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN000210448 in PTHR11801, recorded in interpro/panther/PTHR11801/PTHR11801-paint.tsv. function: preferred_term: DNA-binding transcription factor activity, RNA polymerase II-specific term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Secondary transcriptional effector activated by IL21/IL21R/IL2RG that promotes IFNG and T-bet (TBX21) expression in T and NK cells and balances STAT3-driven transcriptional programs. evidence: - source_id: PMID:12244150 statement: >- IL21 up-regulates IFNG and other innate immunity and Th1 genes in human T and NK cells (abstract reports STAT3, not STAT1; STAT1 activation is documented in Reactome:R-HSA-9006870). - source_id: PMID:37339051 statement: >- Engineered IL21 variants reveal differential tuning of STAT1 versus STAT3 phosphorylation downstream of IL21R/IL2RG. connections: - source: il21_engages_receptor_complex target: il21_jak_activation connection_type: CAUSES description: >- IL21-induced heterodimerization of IL21R and IL2RG juxtaposes IL21R-associated JAK1 and IL2RG-associated JAK3 for reciprocal trans-phosphorylation and IL21R Y519 phosphorylation. evidence: - source_id: PMID:15546387 statement: >- Review stating that IL21R activates the JAK-STAT pathway upon ligand binding. - source_id: Reactome:R-HSA-9006850 statement: >- Reactome reaction documenting reciprocal JAK1/JAK3 phosphorylation in the ternary IL21 receptor complex. - source: il21_jak_activation target: il21_stat_transcriptional_output connection_type: CAUSES description: >- Activated JAK1 and JAK3 phosphorylate STAT3 (on Y705) and STAT1 (on Y701) docked at phosphorylated IL21R, triggering STAT dimerization and nuclear transcriptional activation. evidence: - source_id: PMID:12244150 statement: >- IL21 stimulation induces STAT3 tyrosine phosphorylation and DNA binding in human NK and T cells. - source_id: Reactome:R-HSA-9006870 statement: >- Reactome reaction documenting STAT3 and STAT1 phosphorylation at the activated IL21 receptor complex.