id: MODULE:il34_signaling title: Interleukin-34 / CSF1R signaling pathway module description: >- Secreted homodimeric Interleukin-34 (IL34) binds the N-terminal immunoglobulin-like domains of the class III receptor tyrosine kinase CSF1R (macrophage colony-stimulating factor 1 receptor), which it shares with the structurally homologous but sequence-unrelated cytokine CSF1. Ligand binding dimerizes the receptor and activates its intracellular tyrosine kinase, initiating signaling that supports monocyte viability, macrophage differentiation, and the tissue-specific maintenance of Langerhans cells and microglia. status: DRAFT evidence: - source_id: GO:0061514 title: interleukin-34-mediated signaling pathway statement: >- Grounded in the GO biological process term for interleukin-34-mediated signaling pathway (a child of GO:0019221 cytokine-mediated signaling pathway), defined as the series of molecular signals initiated by interleukin-34 binding to its receptor on the surface of a target cell. - source_id: PMID:18467591 title: Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. statement: >- Identified human IL34 in a functional screen of secreted proteins as a highly selective ligand that stimulates monocyte viability, and identified its receptor as the known cytokine receptor CSF1R (abstract only; the ERK1/2 phosphorylation result from this paper is summarized by Reactome:R-HSA-6787820). - source_id: PMID:22483114 title: Structural basis for the dual recognition of helical cytokines IL-34 and CSF-1 by CSF-1R. statement: >- Crystal structures show that dimeric IL34 adopts a helical cytokine fold homologous to CSF1 and binds the N-terminal immunoglobulin domains of CSF1R in an assembly similar to CSF1:CSF1R; IL34 and CSF1 signal through the common receptor CSF1R. - source_id: PMID:26754294 title: miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. statement: >- Reference behind the IDA annotation of human IL34 to GO:0061514 (interleukin-34-mediated signaling pathway); the abstract reports that the effects of miR-28-5p deficiency depend on IL34-mediated tumor-associated macrophage infiltration. - source_id: PMID:30066957 title: Interleukin-34, a comprehensive review. statement: >- Review (abstract only) describing IL34 as a secreted homodimeric glycoprotein that binds the extracellular domains of CSF1R and receptor-type protein-tyrosine phosphatase zeta (PTPRZ1) and the chondroitin sulfate chains of syndecan-1, and as required in a tissue-specific manner for Langerhans cells and microglia. - source_id: Reactome:R-HSA-6787820 title: IL34 dimer binds CSF1R statement: >- Reactome reaction documenting dimeric IL34 binding to CSF1R, ligand- induced receptor dimerization, and ERK1/2 phosphorylation in human monocytes (citing Lin et al. 2008); its summary also lists the generic CSF1R effectors (STAT3, PIK3R1, PLCG2, GRB2, MAPK1/3), which are outside this module's boundary. - source_id: Reactome:R-HSA-8981657 title: IL34 dimer binds PTPRZ1 statement: >- Boundary evidence. Reactome reaction documenting IL34 binding to the chondroitin sulfate proteoglycan PTPRZ1, which is primarily expressed on neural progenitor and glial cells. - source_id: Reactome:R-HSA-9009558 title: IL34 dimer binds SDC1 statement: >- Boundary evidence. Reactome reaction documenting dimeric IL34 binding to chondroitin sulfate chains of syndecan-1 (SDC1), which modulates IL34-induced CSF1R signaling. - source_id: file:genes/human/IL34/IL34-ai-review.yaml title: Human IL34 gene review statement: >- Curates human IL34 (UniProtKB:Q6ZMJ4) with GO:0005125 (cytokine activity) and GO:0061514 (interleukin-34-mediated signaling pathway), modifying GO:0005157 (macrophage colony-stimulating factor receptor binding) to GO:0005125 and GO:0038145 (macrophage colony-stimulating factor signaling pathway) to GO:0061514. - source_id: file:genes/human/CSF1R/CSF1R-ai-review.yaml title: Human CSF1R gene review statement: >- Curates human CSF1R (UniProtKB:P07333) with core molecular function GO:0005011 (macrophage colony-stimulating factor receptor activity), directly involved in GO:0038145 and GO:0061514. - source_id: file:interpro/panther/PTHR28606/PTHR28606-review.yaml title: PANTHER PTHR28606 (INTERLEUKIN-34) family review statement: >- Assesses PAINT node PTN002823014 and recommends GO:0005125 (cytokine activity) and GO:0061514 (interleukin-34-mediated signaling pathway), neither asserted there by PAINT, as family-wide terms for PTHR28606. - source_id: PANTHER:PTN002823014 title: PAINT node PTN002823014 for IL34 statement: >- Local PAINT IBD node in PTHR28606 (node taxon NCBITaxon:117571 Euteleostomi) asserting C:GO:0005576 (20260529), F:GO:0005157 (20190222), P:GO:0008284 (20200809), P:GO:0045651 (20230406), and P:GO:0045657 (20190222); every term is seeded only by human IL34 (UniProtKB:Q6ZMJ4). - source_id: PANTHER:PTN001230349 title: PAINT node PTN001230349 for CSF1R statement: >- Local PAINT IBD node in PTHR24416 (node taxon not recorded in paint.tsv) asserting C:GO:0005886, C:GO:0043235, F:GO:0004714, and P:GO:0007169 (all dated 20260828); human CSF1R (UniProtKB:P07333) seeds the three C and F terms but not P:GO:0007169. - source_id: PANTHER:PTN002814394 title: PAINT node PTN002814394 for CSF1R statement: >- Local PAINT IBD node in PTHR24416 (node taxon NCBITaxon:117571 Euteleostomi) asserting C:GO:1990682, F:GO:0005011, P:GO:0030316, P:GO:0030335, and P:GO:0043408; human CSF1R (UniProtKB:P07333) seeds C:GO:1990682, F:GO:0005011, and P:GO:0030335. notes: >- Two-step ligand-receptor module for Interleukin-34 (IL34, family PTHR28606) signaling through the class III RTK CSF1R (PTHR24416:SF47). Per ligand-in-signaling conventions (projects/LIGANDS_IN_SIGNALING.md), the IL34 ligand annoton uses GO:0005125 (cytokine activity, an is_a child of GO:0048018 receptor ligand activity) rather than the receptor-binding term GO:0005157 (macrophage colony-stimulating factor receptor binding) that PAINT asserts at PTN002823014; that mismatch is recorded in the PTHR28606 family review. Boundary decisions. (1) Downstream effectors are excluded: the phosphotyrosine-recruited adaptors and enzymes (GRB2, PIK3R1, PLCG2, the PI3K catalytic subunit PIK3CA), the ERK1/2 kinases MAPK1/MAPK3, and STAT3 are shared by CSF1 and IL34 and are generic CSF1R effectors, so they belong in a CSF1R receptor-signaling module, which does not exist yet; Reactome:R-HSA-6787820 summarizes them. An earlier draft of this module split the PI3K holoenzyme across two steps and typed ERK1/2 with the generic GO:0004674 rather than GO:0004707 (MAP kinase activity); both problems should be avoided when that CSF1R module is built. (2) PTPRZ1 is not modelled as an alternative receptor. IL34 binds PTPRZ1 (PMID:30066957, Reactome:R-HSA-8981657), but the only cached signaling evidence is a single study in a CSF1R-deficient glioblastoma line summarized by Reactome, which is too thin to define a PTPRZ1 receptor step with a molecular function. (3) SDC1 binds IL34 and modulates CSF1R signaling (Reactome:R-HSA-9009558); it is a co-receptor modulator, not a pathway step. (4) GO:0038145 (macrophage colony-stimulating factor signaling pathway) is not a module concept because it is defined by CSF1 binding, not IL34 binding; CSF1R carries both GO:0038145 and GO:0061514. module: id: il34_signaling label: Interleukin-34 / CSF1R signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: interleukin-34-mediated signaling pathway term: id: GO:0061514 label: interleukin-34-mediated signaling pathway description: >- Series of molecular signals initiated by secreted homodimeric IL34 binding to CSF1R on target myeloid or microglial cells, driving receptor dimerization and activation of the receptor tyrosine kinase. 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 parts: - order: 1 role: il34 ligand node: id: il34_ligand label: Secreted IL34 homodimer acts as a CSF1R ligand module_type: REGULATORY_STEP description: >- Secreted IL34 forms a noncovalent homodimer that binds the N-terminal immunoglobulin-like domains of CSF1R. annotons: - id: il34_cytokine_ligand label: IL34 cytokine ligand participant: selector_type: FAMILY family: preferred_term: Interleukin-34 cytokine family term: id: PANTHER:PTHR28606 label: INTERLEUKIN-34 representative_members: - preferred_term: IL34 term: id: UniProtKB:Q6ZMJ4 label: Interleukin-34 ancestral_nodes: - preferred_term: PAINT node PTN002823014 in PTHR28606 term: id: PANTHER:PTN002823014 label: PTN002823014 description: >- PAINT node in PTHR28606 (node taxon NCBITaxon:117571, Euteleostomi) asserting C:GO:0005576, F:GO:0005157, P:GO:0008284, P:GO:0045651, and P:GO:0045657, each seeded only by human IL34 (UniProtKB:Q6ZMJ4). It does not assert the GO:0005125 used on this step; GO:0005157 is a receptor-binding term, not a receptor ligand activity. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN002823014 in PTHR28606, recorded in interpro/panther/PTHR28606/PTHR28606-paint.tsv. function: preferred_term: cytokine activity term: id: GO:0005125 label: cytokine activity processes: - preferred_term: interleukin-34-mediated signaling pathway term: id: GO:0061514 label: interleukin-34-mediated signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Secreted homodimeric helical cytokine ligand that binds and dimerizes the CSF1R ectodomain to initiate receptor tyrosine kinase signaling. evidence: - source_id: PMID:18467591 statement: >- Discovered human IL34 as a previously undescribed ligand that stimulates monocyte viability, and identified CSF1R as its receptor. - source_id: PMID:22483114 statement: >- Crystal structure of dimeric IL34 bound to the N-terminal immunoglobulin domains of CSF1R. - source_id: Reactome:R-HSA-6787820 statement: >- Dimeric IL34 binds CSF1R and ligand binding leads to receptor dimerisation. - source_id: file:genes/human/IL34/IL34-ai-review.yaml statement: >- Human IL34 review curates GO:0005125 (cytokine activity) and GO:0061514 (interleukin-34-mediated signaling pathway) as core functions. - source_id: file:interpro/panther/PTHR28606/PTHR28606-review.yaml statement: >- PANTHER PTHR28606 family review recommends GO:0005125 and GO:0061514 as family-wide terms at PTN002823014. - order: 2 role: csf1r receptor activation node: id: csf1r_receptor_activation label: IL34-bound CSF1R dimerizes and activates its tyrosine kinase module_type: REGULATORY_STEP description: >- IL34 binding dimerizes CSF1R at the plasma membrane, activating the intracellular receptor tyrosine kinase domain. annotons: - id: csf1r_receptor_kinase label: CSF1R receptor tyrosine kinase participant: selector_type: FAMILY family: preferred_term: Macrophage colony-stimulating factor 1 receptor subfamily term: id: PANTHER:PTHR24416:SF47 label: MACROPHAGE COLONY-STIMULATING FACTOR 1 RECEPTOR representative_members: - preferred_term: CSF1R term: id: UniProtKB:P07333 label: Macrophage colony-stimulating factor 1 receptor ancestral_nodes: - preferred_term: PAINT node PTN001230349 in PTHR24416 term: id: PANTHER:PTN001230349 label: PTN001230349 description: >- PAINT node in PTHR24416 (node taxon not recorded in paint.tsv) asserting C:GO:0005886, C:GO:0043235, F:GO:0004714, and P:GO:0007169. Human CSF1R (UniProtKB:P07333) seeds the C and F terms but not P:GO:0007169. F:GO:0004714 is the parent of the GO:0005011 used on this step. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN001230349 in PTHR24416, recorded in interpro/panther/PTHR24416/PTHR24416-paint.tsv. - preferred_term: PAINT node PTN002814394 in PTHR24416 term: id: PANTHER:PTN002814394 label: PTN002814394 description: >- PAINT node in PTHR24416 (node taxon NCBITaxon:117571, Euteleostomi) asserting C:GO:1990682, F:GO:0005011, P:GO:0030316, P:GO:0030335, and P:GO:0043408. Human CSF1R (UniProtKB:P07333) seeds C:GO:1990682, F:GO:0005011, and P:GO:0030335. evidence: - source_id: GO_REF:0000033 statement: >- IBD propagation from PAINT node PTN002814394 in PTHR24416, recorded in interpro/panther/PTHR24416/PTHR24416-paint.tsv. function: preferred_term: macrophage colony-stimulating factor receptor activity term: id: GO:0005011 label: macrophage colony-stimulating factor receptor activity processes: - preferred_term: interleukin-34-mediated signaling pathway term: id: GO:0061514 label: interleukin-34-mediated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Transmembrane class III receptor tyrosine kinase shared by IL34 and CSF1 that binds extracellular IL34, dimerizes, and activates its intracellular kinase domain. evidence: - source_id: PMID:18467591 statement: >- Identified CSF1R as the receptor for IL34 in a functional screen of transmembrane protein extracellular domains. - source_id: PMID:22483114 statement: >- IL34 and CSF1 signal through the common receptor CSF1R on cells of the mononuclear phagocyte lineage. - source_id: file:genes/human/CSF1R/CSF1R-ai-review.yaml statement: >- Human CSF1R gene review curates GO:0005011 as the core molecular function, directly involved in GO:0061514. connections: - source: il34_ligand target: csf1r_receptor_activation connection_type: CAUSES description: >- Binding of the IL34 homodimer to the CSF1R ectodomain dimerizes the receptor and activates CSF1R signaling. evidence: - source_id: Reactome:R-HSA-6787820 statement: >- Dimeric IL34 binds CSF1R, ligand binding leads to receptor dimerisation, and IL34 stimulation of CSF1R leads to ERK1/2 phosphorylation in human monocytes. - source_id: PMID:22483114 statement: >- The IL34:CSF1R complex architecture is similar to the CSF1:CSF1R assembly, and both cytokines signal through CSF1R.