Interleukin-34 / CSF1R signaling pathway module

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.

MODULE:il34_signalingDRAFTSignaling Pathwaymodules/il34_signaling.yaml

interleukin-34-mediated signaling pathwayGO:0061514

GO:0061514

interleukin-34-mediated signaling pathway

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.

PMID:18467591

Discovery of a cytokine and its receptor by functional screening of the extracellular proteome.

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).

PMID:22483114

Structural basis for the dual recognition of helical cytokines IL-34 and CSF-1 by CSF-1R.

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.

PMID:26754294

miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis.

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.

PMID:30066957

Interleukin-34, a comprehensive review.

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.

Reactome:R-HSA-6787820

IL34 dimer binds CSF1R

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.

Reactome:R-HSA-8981657

IL34 dimer binds PTPRZ1

Boundary evidence. Reactome reaction documenting IL34 binding to the chondroitin sulfate proteoglycan PTPRZ1, which is primarily expressed on neural progenitor and glial cells.

Reactome:R-HSA-9009558

IL34 dimer binds SDC1

Boundary evidence. Reactome reaction documenting dimeric IL34 binding to chondroitin sulfate chains of syndecan-1 (SDC1), which modulates IL34-induced CSF1R signaling.

file:genes/human/IL34/IL34-ai-review.yaml

Human IL34 gene review

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.

file:genes/human/CSF1R/CSF1R-ai-review.yaml

Human CSF1R gene review

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.

file:interpro/panther/PTHR28606/PTHR28606-review.yaml

PANTHER PTHR28606 (INTERLEUKIN-34) family review

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.

PANTHER:PTN002823014

PAINT node PTN002823014 for IL34

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).

PANTHER:PTN001230349

PAINT node PTN001230349 for CSF1R

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.

PANTHER:PTN002814394

PAINT node PTN002814394 for CSF1R

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.

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.

3Nodes

2Parts

0Variant Sets

0Variants

2Annotons

1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:il34_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

2 gene-function check(s) reflected in core functions · 0 conflict(s) · 1 evidence or coverage gap(s) (4 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

Annoton	Participant	Function	Assessment
il34_cytokine_ligand	IL34 UniProtKB:Q6ZMJ4 Family Representative	cytokine activity GO:0005125	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
csf1r_receptor_kinase	CSF1R UniProtKB:P07333 Family Representative	macrophage colony-stimulating factor receptor activity GO:0005011	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
il34_cytokine_ligand	Interleukin-34 cytokine family PANTHER:PTHR28606 Family	cytokine activity GO:0005125	Family Supported Family review supports GO:0005125 FAMILY_WIDE. All members of PTHR28606 are secreted four-helix-bundle cytokines that act as extracellular receptor ligands to activate CSF1R. Adding GO:0005125 at PTN002823014 resolves the Category C receptor-ligand gap for IL34 across vertebrates.
csf1r_receptor_kinase	Macrophage colony-stimulating factor 1 receptor subfamily PANTHER:PTHR24416:SF47 Family	macrophage colony-stimulating factor receptor activity GO:0005011	Family Scope Restricted GO:0004714 requires member-level assessment of residue site kinase_catalytic_triad; a family identifier does not establish that condition. Within the DDR clade the activity follows the kinase catalytic triad, which is kept everywhere except the dipteran Ddr node PTN002400510: Drosophila Ddr (Ala789, Ser897, Ser910) and Anopheles DDR fail the site and are predicted pseudokinases (not assayed). The PTN001230349 node assessment records the matching IKR recommendation. RESIDUE_DETERMINED means the term is true wherever the triad is intact; it is not the most specific term for vertebrate DDR1 and DDR2, whose reviews refine it to GO:0038062.

Gene-review completeness (2/2 grounded genes reviewed)

1 complete review(s) · 1 with deep research · 0 missing review · 1 reviewed but lacking deep research

Gene	Review	Complete	Deep research
CSF1R P07333	✓	115/116	✓
IL34 Q6ZMJ4	✓	✓	✗

Tree

Interleukin-34 / CSF1R signaling pathwaySignaling Pathwayil34_signaling

Parts
1. 1. il34 ligand
2. Secreted IL34 homodimer acts as a CSF1R ligandRegulatory Stepil34_ligand
  
  Annotons
  - IL34 cytokine ligand Family: Interleukin-34 cytokine family
3. 2. csf1r receptor activation
4. IL34-bound CSF1R dimerizes and activates its tyrosine kinaseRegulatory Stepcsf1r_receptor_activation
  
  Annotons
  - CSF1R receptor tyrosine kinase Family: Macrophage colony-stimulating factor 1 receptor subfamily

Details

Context

bony vertebratesNCBITaxon:117571

extracellular regionGO:0005576 plasma membraneGO:0005886

Interleukin-34 / CSF1R signaling pathwaySignaling Pathwayil34_signaling

interleukin-34-mediated signaling pathwayGO:0061514

Context

bony vertebratesNCBITaxon:117571

extracellular regionGO:0005576 plasma membraneGO:0005886

Connections

il34_ligand -> csf1r_receptor_activation Causes

Binding of the IL34 homodimer to the CSF1R ectodomain dimerizes the receptor and activates CSF1R signaling.

Reactome:R-HSA-6787820

Dimeric IL34 binds CSF1R, ligand binding leads to receptor dimerisation, and IL34 stimulation of CSF1R leads to ERK1/2 phosphorylation in human monocytes.

PMID:22483114

The IL34:CSF1R complex architecture is similar to the CSF1:CSF1R assembly, and both cytokines signal through CSF1R.

Part 1: il34 ligand

Secreted IL34 homodimer acts as a CSF1R ligandRegulatory Stepil34_ligand

Secreted IL34 forms a noncovalent homodimer that binds the N-terminal immunoglobulin-like domains of CSF1R.

Annotons

IL34 cytokine ligand

il34_cytokine_ligand

Participant: Family: Interleukin-34 cytokine family

Family:

Interleukin-34 cytokine familyPANTHER:PTHR28606

Representative Members: IL34UniProtKB:Q6ZMJ4

Function

cytokine activityGO:0005125

Processes

interleukin-34-mediated signaling pathwayGO:0061514

Locations

extracellular regionGO:0005576

Secreted homodimeric helical cytokine ligand that binds and dimerizes the CSF1R ectodomain to initiate receptor tyrosine kinase signaling.

PMID:18467591

Discovered human IL34 as a previously undescribed ligand that stimulates monocyte viability, and identified CSF1R as its receptor.

PMID:22483114

Crystal structure of dimeric IL34 bound to the N-terminal immunoglobulin domains of CSF1R.

Reactome:R-HSA-6787820

Dimeric IL34 binds CSF1R and ligand binding leads to receptor dimerisation.

file:genes/human/IL34/IL34-ai-review.yaml

Human IL34 review curates GO:0005125 (cytokine activity) and GO:0061514 (interleukin-34-mediated signaling pathway) as core functions.

file:interpro/panther/PTHR28606/PTHR28606-review.yaml

PANTHER PTHR28606 family review recommends GO:0005125 and GO:0061514 as family-wide terms at PTN002823014.

Part 2: csf1r receptor activation

IL34-bound CSF1R dimerizes and activates its tyrosine kinaseRegulatory Stepcsf1r_receptor_activation

IL34 binding dimerizes CSF1R at the plasma membrane, activating the intracellular receptor tyrosine kinase domain.

Annotons

CSF1R receptor tyrosine kinase

csf1r_receptor_kinase

Participant: Family: Macrophage colony-stimulating factor 1 receptor subfamily

Family:

Macrophage colony-stimulating factor 1 receptor subfamilyPANTHER:PTHR24416:SF47

Representative Members: CSF1RUniProtKB:P07333

Function

macrophage colony-stimulating factor receptor activityGO:0005011

Processes

interleukin-34-mediated signaling pathwayGO:0061514

Locations

plasma membraneGO:0005886

Transmembrane class III receptor tyrosine kinase shared by IL34 and CSF1 that binds extracellular IL34, dimerizes, and activates its intracellular kinase domain.

PMID:18467591

Identified CSF1R as the receptor for IL34 in a functional screen of transmembrane protein extracellular domains.

PMID:22483114

IL34 and CSF1 signal through the common receptor CSF1R on cells of the mononuclear phagocyte lineage.

file:genes/human/CSF1R/CSF1R-ai-review.yaml

Human CSF1R gene review curates GO:0005011 as the core molecular function, directly involved in GO:0061514.