Slit-Robo signaling pathway module

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.

MODULE:slit_robo_signalingDRAFTABSTRACTSignaling Pathwaymodules/slit_robo_signaling.yaml
Roundabout signaling pathwayGO:0035385
GO:0035385
Roundabout signaling pathway
The module is grounded in the GO biological process term for Roundabout signaling.
PMID:27578174
Slit-Robo signaling.
Review of Slit-Robo signaling, used for the module boundary.
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.
PMID:10102268
Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance.
Drosophila Slit and mammalian Slit2 bind Robo receptors with high affinity, and Slits act as conserved repulsive ligands for Robo.
These results support the hypothesis that Slit proteins have an evolutionarily conserved role in axon guidance as repulsive ligands for Robo receptors.

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.

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:slit_robo_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

0 gene-function check(s) reflected in core functions · 0 conflict(s) · 11 evidence or coverage gap(s) (11 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.

AnnotonParticipantFunctionAssessment
slit_ligand_family SLIT1
UniProtKB:O75093
Family Representative 		chemorepellent activity
GO:0045499 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
slit_ligand_family SLIT2
UniProtKB:O94813
Family Representative 		chemorepellent activity
GO:0045499 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
slit_ligand_family SLIT3
UniProtKB:O75094
Family Representative 		chemorepellent activity
GO:0045499 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
slit_ligand_family sli
UniProtKB:P24014
Family Representative 		chemorepellent activity
GO:0045499 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
robo_receptor_family ROBO1
UniProtKB:Q9Y6N7
Family Representative 		axon guidance receptor activity
GO:0008046 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
robo_receptor_family ROBO2
UniProtKB:Q9HCK4
Family Representative 		axon guidance receptor activity
GO:0008046 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
robo_receptor_family robo1
UniProtKB:Q9W213
Family Representative 		axon guidance receptor activity
GO:0008046 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
robo_receptor_family robo2
UniProtKB:Q9VQ08
Family Representative 		axon guidance receptor activity
GO:0008046 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
robo_receptor_family robo3
UniProtKB:Q9VPZ7
Family Representative 		axon guidance receptor activity
GO:0008046 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
slit_ligand_family Slit proteins
PANTHER:PTHR45836
Family 		chemorepellent activity
GO:0045499 		Family Scope Restricted
GO:0045499 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope. Slit proteins are repulsive ligands of Robo receptors; this is the ligand-activity form of the Roundabout binding role and applies to the Slit subfamilies only, not to the LRR receptors or Notch receptors in the family.
robo_receptor_family Roundabout (Robo) receptors
Family 		axon guidance receptor activity
GO:0008046 		Family Id Missing
The family has no identifier linking it to a curated family review.

Gene-review completeness (0/9 grounded genes reviewed)

0 complete review(s) · 0 with deep research · 9 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
SLIT1 O75093 ✗ — —
SLIT3 O75094 ✗ — —
SLIT2 O94813 ✗ — —
sli P24014 ✗ — —
ROBO2 Q9HCK4 ✗ — —
robo3 Q9VPZ7 ✗ — —
robo2 Q9VQ08 ✗ — —
robo1 Q9W213 ✗ — —
ROBO1 Q9Y6N7 ✗ — —

Details

Context
BilateriaNCBITaxon:33213
Slit-Robo signaling pathwaySignaling Pathwayslit_robo_signaling

A secreted Slit binds a Robo receptor on a growth cone or migrating cell and repels it from the Slit source.

Roundabout signaling pathwayGO:0035385
Context
BilateriaNCBITaxon:33213

Connections

slit_ligand -> robo_receptor Positively Regulates
Slit binding activates the Robo receptor.
Part 1: secreted ligand
Slit ligandSignaling Pathwayslit_ligand

A secreted Slit presented by the signal-sending tissue, such as midline glia.

Annotons

Slit ligand
slit_ligand_family
Participant: Family: Slit proteins
Family:
Slit proteinsPANTHER:PTHR45836 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: SLIT1UniProtKB:O75093 SLIT2UniProtKB:O94813 SLIT3UniProtKB:O75094 sliUniProtKB:P24014

Function

chemorepellent activityGO:0045499

Processes

Roundabout signaling pathwayGO:0035385

Locations

extracellular regionGO:0005576

Secreted Slit that binds Robo receptors and acts as a repellent.

PMID:10102268
Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance.
Drosophila Slit and mammalian Slit2 bind Robo proteins with high affinity.
show specific, high-affinity binding to Robo proteins
Part 2: receptor
Robo receptorSignaling Pathwayrobo_receptor

Transmembrane Robo receptor on the responding growth cone or cell. Different Robo paralogs and their combinations set midline crossing and lateral position.

Annotons

Robo receptor
robo_receptor_family
Participant: Family: Roundabout (Robo) receptors
Family:
Roundabout (Robo) receptors No PANTHER id is asserted because Robo receptors are split across PTHR12231, PTHR44170 and PTHR10075.
Representative Members: ROBO1UniProtKB:Q9Y6N7 ROBO2UniProtKB:Q9HCK4 robo1UniProtKB:Q9W213 robo2UniProtKB:Q9VQ08 robo3UniProtKB:Q9VPZ7

Function

axon guidance receptor activityGO:0008046

Processes

Roundabout signaling pathwayGO:0035385

Locations

plasma membraneGO:0005886

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).

PMID:11163264
Short-range and long-range guidance by slit and its Robo receptors. Robo and Robo2 play distinct roles in midline guidance.
Drosophila has three Robo receptors; loss of robo and robo2 together phenocopies slit.
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.
PMID:11163179
Short-range and long-range guidance by Slit and its Robo receptors: a combinatorial code of Robo receptors controls lateral position.
A combinatorial code of Robo, Robo2 and Robo3 sets lateral axon position.
Here we show that a combinatorial code of Robo receptors controls lateral position in the CNS by responding to this presumptive Slit gradient.