id: MODULE:slit_robo_signaling title: Slit-Robo signaling pathway module description: >- Slits are secreted leucine-rich-repeat glycoproteins that bind Roundabout (Robo) receptors on migrating cells and axons. Slit-Robo signaling is best known as the repulsive cue that keeps axons from crossing, or recrossing, the CNS midline, and it also patterns the lateral position of longitudinal axon pathways. status: DRAFT scope: ABSTRACT evidence: - source_id: GO:0035385 title: Roundabout signaling pathway statement: The module is grounded in the GO biological process term for Roundabout signaling. - source_id: PMID:27578174 title: Slit-Robo signaling. statement: Review of Slit-Robo signaling, used for the module boundary. supporting_text: >- Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. - source_id: PMID:10102268 title: Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. statement: Drosophila Slit and mammalian Slit2 bind Robo receptors with high affinity, and Slits act as conserved repulsive ligands for Robo. supporting_text: >- These results support the hypothesis that Slit proteins have an evolutionarily conserved role in axon guidance as repulsive ligands for Robo receptors. notes: >- Boundary. The module has two steps: a secreted Slit ligand and a Robo receptor on the responding cell. Intracellular effectors (for example Abelson kinase, Enabled, Son of sevenless and the srGAP Rho GTPase-activating proteins), the Robo regulator Commissureless and its vertebrate counterparts, and heparan sulfate proteoglycan co-receptors are not modelled as parts. The module is species-neutral; the representative members (human SLIT1-3, ROBO1 and ROBO2; Drosophila sli, robo1, robo2 and robo3) are examples, not a species scope. Human ROBO3 and ROBO4 are omitted because they diverge from the canonical Slit-receptor role. The taxon scope Bilateria (NCBITaxon:33213) tracks the taxon placement of the PAINT Slit clade node PTN002911633 (whereas the netrin module uses Eumetazoa, NCBITaxon:6072, matching its PAINT node PTN008501429). Ligand function term. The ligand step uses GO:0045499 chemorepellent activity, a child of receptor ligand activity, following the GO-CAM signaling receptor guideline that a ligand enables receptor ligand activity or a child. The receptor-specific GO:0048495 Roundabout binding records binding only and is not under receptor ligand activity. The Slit PAINT node PTN002911633 asserts Roundabout binding; the PTHR45836 family review records that its IBD should use the ligand-activity term, restricted to the Slit subfamilies. Human SLIT2 already carries chemorepellent activity in GOA; Drosophila sli has only Roundabout binding. Receptor family and function term. Robo receptors are split across PANTHER families: human ROBO1-3 and Drosophila robo2 are in PTHR12231, ROBO4 and Drosophila robo1 in PTHR44170, and Drosophila robo3 in PTHR10075 (UniProt PANTHER cross-references). No family id is asserted for the receptor step. The receptor step uses GO:0008046 axon guidance receptor activity (the specific receptor MF carried by human ROBO1/ROBO2 and Drosophila robo1 in GOA); GO lacks a pathway-specific Roundabout receptor activity term, so GO:0008046 represents the canonical axon-guidance instance of the broader growth-cone and cell-migration receptor role described in the module. Annotation state (GOA GAFs dated 2026-05-21). Human: SLIT2, SLIT3 and ROBO1 are annotated to GO:0035385; SLIT1 and ROBO2 are not. Drosophila: sli and robo1 are annotated to GO:0035385; robo2 and robo3 are not, and neither has a receptor MF. module: id: slit_robo_signaling label: Slit-Robo signaling pathway module_type: SIGNALING_PATHWAY description: >- A secreted Slit binds a Robo receptor on a growth cone or migrating cell and repels it from the Slit source. concepts: - preferred_term: Roundabout signaling pathway term: id: GO:0035385 label: Roundabout signaling pathway context: taxa: - preferred_term: Bilateria term: id: NCBITaxon:33213 label: Bilateria parts: - order: 1 role: secreted ligand node: id: slit_ligand label: Slit ligand module_type: SIGNALING_PATHWAY description: A secreted Slit presented by the signal-sending tissue, such as midline glia. annotons: - id: slit_ligand_family label: Slit ligand participant: selector_type: FAMILY family: preferred_term: Slit proteins term: id: PANTHER:PTHR45836 label: SLIT HOMOLOG description: >- PTHR45836 also contains non-Slit proteins such as Crumbs. The role is restricted to the Slit subfamilies PTHR45836:SF2 (SLIT2), SF3 (SLIT1), SF9 (SLIT3) and SF4 (Drosophila sli), matching the SUBFAMILY_ONLY scope of chemorepellent activity in interpro/panther/PTHR45836/PTHR45836-review.yaml. representative_members: - preferred_term: SLIT1 term: id: UniProtKB:O75093 label: Slit homolog 1 protein - preferred_term: SLIT2 term: id: UniProtKB:O94813 label: Slit homolog 2 protein - preferred_term: SLIT3 term: id: UniProtKB:O75094 label: Slit homolog 3 protein - preferred_term: sli term: id: UniProtKB:P24014 label: Protein slit ancestral_nodes: - preferred_term: PAINT node PTN002911633 (Slit Roundabout binding) term: id: PANTHER:PTN002911633 label: PTN002911633 description: >- Local PAINT IBD node in PTHR45836 (taxon:33213) seeded by Drosophila sli (FB:FBgn0264089), human SLIT1, SLIT2 and SLIT3, and mouse MGI:1315203. The node marks the origin of the Slit Robo-ligand role. PAINT records that role as F:GO:0048495 Roundabout binding; the PTHR45836 family review assesses the ligand-activity form, chemorepellent activity, for the Slit subfamilies. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002911633 in PTHR45836. function: preferred_term: chemorepellent activity term: id: GO:0045499 label: chemorepellent activity processes: - preferred_term: Roundabout signaling pathway term: id: GO:0035385 label: Roundabout signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Secreted Slit that binds Robo receptors and acts as a repellent. evidence: - source_id: PMID:10102268 title: Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. statement: Drosophila Slit and mammalian Slit2 bind Robo proteins with high affinity. supporting_text: >- show specific, high-affinity binding to Robo proteins - order: 2 role: receptor node: id: robo_receptor label: Robo receptor module_type: SIGNALING_PATHWAY description: Transmembrane Robo receptor on the responding growth cone or cell. Different Robo paralogs and their combinations set midline crossing and lateral position. annotons: - id: robo_receptor_family label: Robo receptor participant: selector_type: FAMILY family: preferred_term: Roundabout (Robo) receptors description: >- No PANTHER id is asserted because Robo receptors are split across PTHR12231, PTHR44170 and PTHR10075. representative_members: - preferred_term: ROBO1 term: id: UniProtKB:Q9Y6N7 label: Roundabout homolog 1 - preferred_term: ROBO2 term: id: UniProtKB:Q9HCK4 label: Roundabout homolog 2 - preferred_term: robo1 term: id: UniProtKB:Q9W213 label: Roundabout 1, isoform A - preferred_term: robo2 term: id: UniProtKB:Q9VQ08 label: Roundabout 2, isoform A - preferred_term: robo3 term: id: UniProtKB:Q9VPZ7 label: Roundabout 3, isoform A function: preferred_term: axon guidance receptor activity term: id: GO:0008046 label: axon guidance receptor activity processes: - preferred_term: Roundabout signaling pathway term: id: GO:0035385 label: Roundabout signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Slit-binding transmembrane receptor that mediates repulsion from the Slit source (typed with GO:0008046 axon guidance receptor activity, the axon-guidance instance of the receptor role, because GO lacks a broader Roundabout receptor activity term). evidence: - source_id: PMID:11163264 title: Short-range and long-range guidance by slit and its Robo receptors. Robo and Robo2 play distinct roles in midline guidance. statement: Drosophila has three Robo receptors; loss of robo and robo2 together phenocopies slit. supporting_text: >- Here we show that the Drosophila genome encodes three Robo receptors and that Robo and Robo2 have distinct functions, which together control repulsive axon guidance at the midline. The robo,robo2 double mutant is largely identical to slit. - source_id: PMID:11163179 title: 'Short-range and long-range guidance by Slit and its Robo receptors: a combinatorial code of Robo receptors controls lateral position.' statement: A combinatorial code of Robo, Robo2 and Robo3 sets lateral axon position. supporting_text: >- Here we show that a combinatorial code of Robo receptors controls lateral position in the CNS by responding to this presumptive Slit gradient. connections: - source: slit_ligand target: robo_receptor connection_type: POSITIVELY_REGULATES description: Slit binding activates the Robo receptor.