SLIT2

Summary

SLIT2 (slit guidance ligand 2, HGNC:11086) is a protein-coding gene on chromosome 4p15.31, encoding Slit homolog 2 protein (O94813). Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors.

This gene encodes a member of the slit family of secreted glycoproteins, which are ligands for the Robo family of immunoglobulin receptors. Slit proteins play highly conserved roles in axon guidance and neuronal migration and may also have functions during other cell migration processes including leukocyte migration. Members of the slit family are characterized by an N-terminal signal peptide, four leucine-rich repeats, nine epidermal growth factor repeats, and a C-terminal cysteine knot. Proteolytic processing of this protein gives rise to an N-terminal fragment that contains the four leucine-rich repeats and five epidermal growth factor repeats and a C-terminal fragment that contains four epidermal growth factor repeats and the cysteine knot. Both full length and cleaved proteins are secreted extracellularly and can function in axon repulsion as well as other specific processes. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 9353 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital anomaly of kidney and urinary tract (Moderate, GenCC)
• Clinical variants (ClinVar): 477 total — 2 pathogenic
• MANE Select transcript: NM_004787

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11086
Approved symbol	SLIT2
Name	slit guidance ligand 2
Location	4p15.31
Locus type	gene with protein product
Status	Approved
Aliases	Slit-2
Ensembl gene	ENSG00000145147
Ensembl biotype	protein_coding
OMIM	603746
Entrez	9353

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000273739, ENST00000503823, ENST00000503837, ENST00000504154, ENST00000508541, ENST00000508824, ENST00000509099, ENST00000509394, ENST00000509941, ENST00000511508, ENST00000512993, ENST00000622093, ENST00000883938

RefSeq mRNA: 3 — MANE Select: NM_004787 NM_001289135, NM_001289136, NM_004787

CCDS: CCDS3426, CCDS75110, CCDS75111

Canonical transcript exons

ENST00000504154 — 37 exons

Exon	Start	End
ENSE00000998130	20519382	20519453
ENSE00000998131	20589644	20589737
ENSE00000998132	20510495	20510566
ENSE00000998133	20616910	20617198
ENSE00000998135	20596415	20596655
ENSE00000998136	20524014	20524177
ENSE00000998137	20531984	20532058
ENSE00000998139	20467752	20467823
ENSE00000998140	20568865	20569004
ENSE00000998141	20553805	20553968
ENSE00000998143	20488819	20488982
ENSE00000998147	20533572	20533715
ENSE00000998148	20595697	20595834
ENSE00000998149	20491761	20491899
ENSE00000998150	20567518	20567615
ENSE00000998151	20541453	20541619
ENSE00000998153	20567262	20567386
ENSE00000998154	20486200	20486271
ENSE00000998156	20525149	20525172
ENSE00000998157	20523760	20523903
ENSE00000998158	20528949	20529099
ENSE00000998159	20539441	20539584
ENSE00000998160	20511066	20511137
ENSE00000998161	20598265	20598395
ENSE00000998162	20480716	20480787
ENSE00001071965	20268810	20268881
ENSE00001316493	20610013	20610167
ENSE00001722579	20256672	20256743
ENSE00001795924	20257868	20257939
ENSE00002031800	20618768	20620561
ENSE00002066916	20251905	20253994
ENSE00003491609	20542494	20542626
ENSE00003547381	20546031	20546099
ENSE00003561586	20548488	20548559
ENSE00003573338	20550827	20550898
ENSE00003578988	20549057	20549128
ENSE00003618372	20617439	20617650

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 97.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.7271 / max 406.2272, expressed in 1280 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47054	13.5037	1271
47056	1.8630	577
47059	0.1757	98
47057	0.1085	56
47058	0.0444	15
47055	0.0319	5

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
lower lobe of lung	UBERON:0008949	97.22	gold quality
olfactory bulb	UBERON:0002264	95.97	gold quality
vena cava	UBERON:0004087	95.87	gold quality
trigeminal ganglion	UBERON:0001675	95.15	gold quality
right lung	UBERON:0002167	94.86	gold quality
dorsal root ganglion	UBERON:0000044	94.15	gold quality
urethra	UBERON:0000057	93.38	gold quality
pericardium	UBERON:0002407	93.23	gold quality
lung	UBERON:0002048	92.72	gold quality
parietal pleura	UBERON:0002400	92.07	gold quality
middle temporal gyrus	UBERON:0002771	92.00	gold quality
nipple	UBERON:0002030	91.70	gold quality
skin of hip	UBERON:0001554	91.69	gold quality
sural nerve	UBERON:0015488	91.69	gold quality
adult organism	UBERON:0007023	91.44	gold quality
periodontal ligament	UBERON:0008266	91.44	gold quality
calcaneal tendon	UBERON:0003701	90.80	gold quality
mammalian vulva	UBERON:0000997	90.76	gold quality
upper lobe of lung	UBERON:0008948	90.70	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.62	gold quality
trachea	UBERON:0003126	90.51	gold quality
upper lobe of left lung	UBERON:0008952	90.50	gold quality
frontal pole	UBERON:0002795	90.27	gold quality
pleura	UBERON:0000977	90.13	gold quality
germinal epithelium of ovary	UBERON:0001304	89.61	gold quality
Brodmann (1909) area 10	UBERON:0013541	89.54	gold quality
visceral pleura	UBERON:0002401	89.45	gold quality
caput epididymis	UBERON:0004358	89.36	gold quality
tibia	UBERON:0000979	89.25	gold quality
smooth muscle tissue	UBERON:0001135	89.07	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	6828.75
E-ANND-2	yes	5967.02
E-CURD-119	yes	5936.38
E-HCAD-56	yes	2704.89
E-CURD-112	yes	519.47
E-MTAB-9154	yes	433.36
E-ANND-3	yes	32.31
E-GEOD-93593	yes	18.96
E-GEOD-81547	yes	8.45
E-MTAB-9388	yes	7.07
E-GEOD-109979	no	313.21
E-MTAB-10290	no	236.63
E-CURD-11	no	72.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

170 targeting SLIT2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-590-3P	99.96	74.34	6478
HSA-LET-7C-3P	99.95	73.42	2862

Literature-anchored findings (GeneRIF, showing 40)

• Analysis of alternative splicing and conserved domains in human and mouse slit genes (PMID:12141424)
• SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers. (PMID:12384551)
• SLIT2 is an excellent candidate tumor suppressor gene for colorectal cancer. (PMID:12615722)
• Our data indicate that SLIT2 is frequently inactivated by promoter region CpG island hypermethylation in gliomas and may be a good candidate for a glioma tumour suppressor gene (TSG) located at 4p15.2. (PMID:12881718)
• effect of Slit (=Slit-2) on the metastatic properties of breast cancer cells (PMID:14645233)
• evidence showing that Slit1 and Slit2 proteins are selective inhibitors and repellents for dorsally projecting, but not for ventrally projecting, cranial motor axons (PMID:16162649)
• Slit2 inhibits vascular smooth muscle cell migration by suppressing small GTPase Rac1 activation. (PMID:16439689)
• Both medulloblastoma and glioma tumors express Robo1 and Slit2, but only medulloblastoma invasion is inhibited by recombinant Slit2 protein. (PMID:16636676)
• Slit-2 inhibited neurite outgrowth in stem cell cultures. (PMID:16840550)
• Slit2 induces targeted migration and may play a role in brain metastasis of breast cancer cells. (PMID:17268810)
• long-range Ca(2+) signaling coordinates the Slit-2-induced changes in motility at two distant parts of migrating neurons by regulating RhoA distribution (PMID:17448996)
• SLIT2 mRNA decreases with vascular function decline in pulmonary fibrosis. (PMID:17496152)
• Inactivation of SLIT2-ROBO1 signaling pathway may have an important role in uterine cervical carcinoma development. (PMID:17609981)
• the crystal structures of the second LRR domain of human Slit2 and the minimal complex between these proteins (Slit2 D2-Robo1 Ig1). (PMID:17848514)
• a chemorepulsive effect mediated by interaction of Slit2 and Robo1 participates in glioma cell guidance in the brain. (PMID:17968499)
• Slit-2-overexpressing breast cancer cells exhibit tumor suppressor capabilities through the novel mechanism of beta-catenin modulation. (PMID:18611862)
• Slits are negative regulators of Sdf1 and Cxcr4 in breast cancer cells. (PMID:18829537)
• Slit2 plays a role in regulating in vitro osteoblast differentiation. (PMID:19033678)
• Slit2 inhibits tumor growth and metastasis of fibrosarcoma and squamous cell carcinoma and its effect on cell cycle and apoptosis signal pathways is an important mechanism for Slit2-mediated tumor suppression (PMID:19048120)
• These results suggest that epigenetic inactivation of SLIT2 in hepatocellular carcinomas (HCC) may be important in the development and progression of HCC. (PMID:19100240)
• gene variants in SLIT2 are rare causes of VUR in humans. Our results provide further evidence for the genetic heterogeneity of this disorder (PMID:19350278)
• HDAC5 represses angiogenic genes, such as FGF2 and Slit2, which causally contribute to capillary-like sprouting of endothelial cells. (PMID:19351956)
• Fourth Slit2 domain heparan sulphate binding contributes to a Slit-Robo signalling mechanism more intricate than previously thought. (PMID:19498462)
• The SLIT2 5’ CpG island is methylated in chronic and acute lymphocytic leukemia. (PMID:19550140)
• Data uncover a previously unknown function of USP33 and reveal a new player in Slit-Robo signaling in cancer cell migration. (PMID:19706539)
• Slit2 potently inhibits chemotaxis but not random motion of circulating neutrophils (PMID:19759280)
• data reveal that a Slit2-Robo4-paxillin-GIT1 network inhibits the cellular protrusive activity underlying neovascularization and vascular leak, and identify a new therapeutic target for ameliorating diseases involving the vascular system (PMID:19855388)
• Downregulation of Slit2 expression is associated with gliomas. (PMID:20008733)
• This study suggested that the importance of axonal guidance genes(SLIT2) in shaping an individual’s vulnerability to suicidality, likely in the direction of the aggression/impulsivity endophenotype. (PMID:20029409)
• Findings indicate that SLIT2 suppresses lung cancer progression, defining it as a novel “theranostic” factor with potential as a therapeutic target and prognostic predictor in lung cancer. (PMID:20068157)
• These results suggest that Slit2 may play an important role in the pathogenesis of temporal lobe epilepsy (PMID:20153733)
• Activating with the soluble ligand Slit an endothelium-specific, Robo4-dependent signaling pathway that strengthens the vascular barrier, diminishing deleterious aspects of the host’s response to the pathogen-induced cytokine storm. (PMID:20375003)
• these findings reveal that through interacting with Robo1, Slit2 is a novel and potent lymphangiogenic factor and contributes to tumor lymphatic metastasis. (PMID:20438712)
• the newly identified Slit2 gradient at the bronchus-alveoli axis induces attractive PI3K signaling in eosinophils and repulsive srGAP1 signaling in neutrophils through differential srGAP1 expression during lung inflammation. (PMID:20944010)
• Because slit2-DeltaE15 splice variant is present in low invasive cancer cells and nontumor lung tissues, loss of this splice variant is an important event in tumor progression and invasion (PMID:21264840)
• Colorectal carcinoma cells secrete Slit2 for signaling through Robo1 expressed on these same cells. (PMID:21283129)
• Findings establish the critical role of the neuronal differentiation factor NeuroD1 in neuroblastoma as well as its functional relationship with the neuronal repellent factor Slit2. (PMID:21349947)
• Data show that epigenetic silencing of SLIT2 promoter was discovered as an underlying mechanism by which miR-218 is suppressed in NPC. (PMID:21385904)
• three major members (Slit2/3 and Robo1) of Slit/Robo family are widely expressed in the human normal and malignant ovarian tissues; but Slit/Robo signaling may not play an important role in regulating human ovarian cancer cell proliferation and migration (PMID:21465248)
• SLIT2 is epigenetically silenced in ovarian cancers. (PMID:21627385)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slit2	ENSDARG00000004246
mus_musculus	Slit2	ENSMUSG00000031558
rattus_norvegicus	Slit2	ENSRNOG00000003840

Paralogs (25): SLITRK3 (ENSG00000121871), LRFN3 (ENSG00000126243), LRFN1 (ENSG00000128011), LRFN2 (ENSG00000156564), LRRC38 (ENSG00000162494), SLITRK5 (ENSG00000165300), LRFN5 (ENSG00000165379), LRTM2 (ENSG00000166159), LINGO1 (ENSG00000169783), LRRN2 (ENSG00000170382), LRRN3 (ENSG00000173114), LRFN4 (ENSG00000173621), LINGO2 (ENSG00000174482), LRRN1 (ENSG00000175928), SLITRK1 (ENSG00000178235), GP5 (ENSG00000178732), SLITRK4 (ENSG00000179542), LRRC55 (ENSG00000183908), SLIT3 (ENSG00000184347), SLITRK6 (ENSG00000184564), SLITRK2 (ENSG00000185985), LRRC70 (ENSG00000186105), SLIT1 (ENSG00000187122), TLR9 (ENSG00000239732), TPBGL (ENSG00000261594)

Protein

Protein identifiers

Slit homolog 2 protein — O94813 (reviewed: O94813)

All UniProt accessions (7): A0A087WYV5, E9PCX4, O94813, F5H0U4, H0Y968, H0Y9Z6, X6R3P0

UniProt curated annotations — full annotation on UniProt →

Function. Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors. During neural development involved in axonal navigation at the ventral midline of the neural tube and projection of axons to different regions. SLIT1 and SLIT2 seem to be essential for midline guidance in the forebrain by acting as repulsive signal preventing inappropriate midline crossing by axons projecting from the olfactory bulb. In spinal cord development may play a role in guiding commissural axons once they reached the floor plate by modulating the response to netrin. In vitro, silences the attractive effect of NTN1 but not its growth-stimulatory effect and silencing requires the formation of a ROBO1-DCC complex. May be implicated in spinal cord midline post-crossing axon repulsion. In vitro, only commissural axons that crossed the midline responded to SLIT2. In the developing visual system appears to function as repellent for retinal ganglion axons by providing a repulsion that directs these axons along their appropriate paths prior to, and after passage through, the optic chiasm. In vitro, collapses and repels retinal ganglion cell growth cones. Seems to play a role in branching and arborization of CNS sensory axons, and in neuronal cell migration. In vitro, Slit homolog 2 protein N-product, but not Slit homolog 2 protein C-product, repels olfactory bulb (OB) but not dorsal root ganglia (DRG) axons, induces OB growth cones collapse and induces branching of DRG axons. Seems to be involved in regulating leukocyte migration.

Subunit / interactions. Interacts with GREM1. Homodimer. Binds ROBO1 and ROBO2 with high affinity.

Subcellular location. Secreted.

Tissue specificity. Fetal lung and kidney, and adult spinal cord. Weak expression in adult adrenal gland, thyroid, trachea and other tissues examined.

Domain organisation. The leucine-rich repeat domain is sufficient for guiding both axon projection and neuronal migration, in vitro.

Isoforms (3)

UniProt ID	Names	Canonical?
O94813-1	1	yes
O94813-2	2
O94813-3	3

RefSeq proteins (3): NP_001276064, NP_001276065, NP_004778* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000372	LRRNT	Domain
IPR000483	Cys-rich_flank_reg_C	Domain
IPR000742	EGF	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR001791	Laminin_G	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR003645	Fol_N	Domain
IPR006207	Cys_knot_C	Domain
IPR013032	EGF-like_CS	Conserved_site
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR051355	Notch/Slit_guidance	Family

Pfam: PF00008, PF00054, PF00560, PF01462, PF01463, PF12661, PF13855

UniProt features (158 total): disulfide bond 43, strand 26, repeat 20, domain 17, helix 17, glycosylation site 12, turn 11, chain 3, sequence conflict 3, sequence variant 2, splice variant 2, signal peptide 1, site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2V9T	X-RAY DIFFRACTION	1.7
2WFH	X-RAY DIFFRACTION	1.8
2V9S	X-RAY DIFFRACTION	2
2V70	X-RAY DIFFRACTION	3.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94813-F1	79.98	0.25

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 1121–1122 (cleavage)

Disulfide bonds (43): 277–286, 434–457, 436–478, 506–512, 510–519, 668–691, 670–712, 727–733, 731–740, 863–886, 865–907, 922–933, 927–943, 945–954, 961–972, 966–984, 986–995, 1002–1013, 1007–1022, 1024–1033 …

Glycosylation sites (12): 66, 186, 564, 623, 794, 799, 1009, 1010, 1019, 1183, 1266, 1300

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-373752	Netrin-1 signaling
R-HSA-376176	Signaling by ROBO receptors
R-HSA-428540	Activation of RAC1
R-HSA-428542	Regulation of commissural axon pathfinding by SLIT and ROBO
R-HSA-428543	Inactivation of CDC42 and RAC1
R-HSA-428890	Role of ABL in ROBO-SLIT signaling
R-HSA-8985586	SLIT2:ROBO1 increases RHOA activity
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9830674	Formation of the ureteric bud
R-HSA-1266738	Developmental Biology
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development
R-HSA-9830369	Kidney development

MSigDB gene sets: 486 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_FOREBRAIN_NEURON_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOBP_OLFACTORY_BULB_INTERNEURON_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, BENPORATH_ES_WITH_H3K27ME3

GO Biological Process (52): ureteric bud development (GO:0001657), negative regulation of protein phosphorylation (GO:0001933), cell migration involved in sprouting angiogenesis (GO:0002042), negative regulation of leukocyte chemotaxis (GO:0002689), aortic valve morphogenesis (GO:0003180), pulmonary valve morphogenesis (GO:0003184), axon guidance (GO:0007411), motor neuron axon guidance (GO:0008045), negative regulation of lamellipodium assembly (GO:0010593), negative regulation of endothelial cell migration (GO:0010596), negative regulation of smooth muscle cell migration (GO:0014912), chemorepulsion involved in postnatal olfactory bulb interneuron migration (GO:0021836), corticospinal neuron axon guidance through spinal cord (GO:0021972), negative regulation of cell growth (GO:0030308), negative regulation of cell migration (GO:0030336), negative regulation of actin filament polymerization (GO:0030837), retinal ganglion cell axon guidance (GO:0031290), cellular response to hormone stimulus (GO:0032870), Roundabout signaling pathway (GO:0035385), positive regulation of apoptotic process (GO:0043065), negative regulation of vascular permeability (GO:0043116), branching morphogenesis of an epithelial tube (GO:0048754), axon extension involved in axon guidance (GO:0048846), positive regulation of axonogenesis (GO:0050772), negative chemotaxis (GO:0050919), induction of negative chemotaxis (GO:0050929), negative regulation of small GTPase mediated signal transduction (GO:0051058), response to cortisol (GO:0051414), ventricular septum morphogenesis (GO:0060412), apoptotic process involved in luteolysis (GO:0061364), negative regulation of chemokine-mediated signaling pathway (GO:0070100), cellular response to heparin (GO:0071504), negative regulation of smooth muscle cell chemotaxis (GO:0071672), negative regulation of mononuclear cell migration (GO:0071676), negative regulation of neutrophil chemotaxis (GO:0090024), negative regulation of monocyte chemotaxis (GO:0090027), negative regulation of retinal ganglion cell axon guidance (GO:0090260), negative regulation of cellular response to growth factor stimulus (GO:0090288), kidney development (GO:0001822), chemotaxis (GO:0006935)

GO Molecular Function (9): GTPase inhibitor activity (GO:0005095), calcium ion binding (GO:0005509), heparin binding (GO:0008201), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), laminin-1 binding (GO:0043237), proteoglycan binding (GO:0043394), Roundabout binding (GO:0048495), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by ROBO receptors	6
Axon guidance	2
Developmental Biology	2
Kidney development	1
Nervous system development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
axon guidance	3
cellular anatomical structure	3
heart valve morphogenesis	2
negative regulation of cell migration	2
protein binding	2
mesonephric tubule development	1
regulation of protein phosphorylation	1
protein phosphorylation	1
negative regulation of protein modification process	1
negative regulation of phosphorylation	1
sprouting angiogenesis	1
blood vessel endothelial cell migration	1
negative regulation of leukocyte migration	1
regulation of leukocyte chemotaxis	1
leukocyte chemotaxis	1
negative regulation of chemotaxis	1
aortic valve development	1
pulmonary valve development	1
axonogenesis	1
neuron projection guidance	1
regulation of lamellipodium assembly	1
lamellipodium assembly	1
negative regulation of plasma membrane bounded cell projection assembly	1
negative regulation of lamellipodium organization	1
regulation of endothelial cell migration	1
endothelial cell migration	1
smooth muscle cell migration	1
regulation of smooth muscle cell migration	1
postnatal olfactory bulb interneuron migration	1
negative chemotaxis	1
corticospinal neuron axon guidance	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
actin filament polymerization	1
regulation of actin filament polymerization	1

Protein interactions and networks

STRING

2590 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLIT2	ROBO2	Q9HCK4	999
SLIT2	ROBO1	Q9Y6N7	999
SLIT2	ROBO4	Q8WZ75	996
SLIT2	ROBO3	Q96MS0	905
SLIT2	NTN1	O95631	803
SLIT2	SEMA3A	Q14563	712
SLIT2	GPC1	P35052	711
SLIT2	DCC	P43146	708
SLIT2	CXCR4	P30991	699
SLIT2	NKX6-1	P78426	662
SLIT2	NKX6-2	Q9C056	658
SLIT2	SRGAP1	Q7Z6B7	650
SLIT2	GDNF	P39905	614
SLIT2	UNC5C	O95185	610
SLIT2	EFNA5	P52803	591

IntAct

60 interactions, top by confidence:

A	B	Type	Score
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640
SLIT2	ROBO1	psi-mi:“MI:0407”(direct interaction)	0.560
SLIT2	SLIT2	psi-mi:“MI:0407”(direct interaction)	0.560
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
PRG3	ZNF324	psi-mi:“MI:0914”(association)	0.530
PRICKLE3	SIAH2	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
	SLIT2	psi-mi:“MI:0407”(direct interaction)	0.440
SLIT2		psi-mi:“MI:0915”(physical association)	0.370
SLIT2	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
	ZW10	psi-mi:“MI:0914”(association)	0.350
MYC	ILVBL	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
ANKRD12	SLIT2	psi-mi:“MI:0914”(association)	0.350
TP53BP1	BCKDK	psi-mi:“MI:0914”(association)	0.350
N	RBM47	psi-mi:“MI:0914”(association)	0.350
POC5	PDHX	psi-mi:“MI:0914”(association)	0.350

BioGRID (72): SLIT2 (Affinity Capture-MS), SLIT2 (Affinity Capture-MS), SLIT2 (Affinity Capture-MS), SLIT2 (Affinity Capture-MS), SLIT2 (Affinity Capture-MS), SLIT2 (Affinity Capture-MS), SLIT2 (Affinity Capture-MS), LUM (Affinity Capture-MS), RSRC1 (Affinity Capture-MS), EXOSC9 (Affinity Capture-MS), EXOSC7 (Affinity Capture-MS), EXOSC2 (Affinity Capture-MS), EXOSC4 (Affinity Capture-MS), LRRC47 (Affinity Capture-MS), SLIT2 (Affinity Capture-Western)

ESM2 similar proteins: C0STK7, G5EFX6, G5EG78, O15455, O35103, O35367, O42235, O60938, O62702, O73798, O75094, O77742, O88280, O94813, P08953, P24014, P24348, P46023, Q04833, Q0PV50, Q3ZBN5, Q58A48, Q5RI43, Q5TJ59, Q65YW8, Q65Z91, Q6AXL3, Q6R5N8, Q6X0I2, Q8C031, Q8SXT3, Q965M2, Q99983, Q99MB1, Q99MQ4, Q9BXN1, Q9CQ76, Q9DE66, Q9HCJ2, Q9JI18

Diamond homologs: A0A1D5PUP4, A0JP86, A2ASQ1, A3KN33, A5YT95, E9Q7X7, G4V4G1, G5ECE3, O00468, O00634, O09118, O15230, O62650, O75094, O75445, O88280, O94813, O95631, O95633, O95980, P02468, P02469, P07942, P0DKM7, P0DKM8, P0DKM9, P10184, P10669, P11046, P11047, P15215, P15800, P16895, P19883, P21674, P25304, P31514, P31515, P31696, P47931

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
TET1	“up-regulates quantity by expression”	SLIT2	“transcriptional regulation”
SLIT2	up-regulates	GPC1	binding
SLIT2	up-regulates	ROBO4	binding
SLIT2	up-regulates	ROBO	binding
SLIT2	“up-regulates activity”	ROBO2	binding
SLIT2	“up-regulates activity”	ROBO3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

477 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	258
Likely benign	152
Benign	35

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
684623	NM_004787.4(SLIT2):c.292G>A (p.Ala98Thr)	Pathogenic
684624	NM_004787.4(SLIT2):c.2712A>T (p.Lys904Asn)	Pathogenic

SpliceAI

6655 predictions. Top by Δscore:

Variant	Effect	Δscore
4:20253995:G:GG	donor_gain	1.0000
4:20256669:TAGG:T	acceptor_loss	1.0000
4:20256670:A:AG	acceptor_gain	1.0000
4:20256670:AG:A	acceptor_gain	1.0000
4:20256670:AGG:A	acceptor_gain	1.0000
4:20256671:G:A	acceptor_loss	1.0000
4:20256671:G:GG	acceptor_gain	1.0000
4:20256671:GG:G	acceptor_gain	1.0000
4:20256671:GGG:G	acceptor_gain	1.0000
4:20256739:GTTCT:G	donor_gain	1.0000
4:20256740:TTCT:T	donor_gain	1.0000
4:20256741:TCT:T	donor_gain	1.0000
4:20256742:CT:C	donor_gain	1.0000
4:20256743:TGTAA:T	donor_loss	1.0000
4:20256744:G:GA	donor_loss	1.0000
4:20256744:G:GG	donor_gain	1.0000
4:20256745:TAAG:T	donor_loss	1.0000
4:20256746:AAGT:A	donor_loss	1.0000
4:20257866:A:AG	acceptor_gain	1.0000
4:20257867:G:GA	acceptor_gain	1.0000
4:20257867:GTC:G	acceptor_gain	1.0000
4:20257867:GTCA:G	acceptor_gain	1.0000
4:20257935:AGACT:A	donor_gain	1.0000
4:20257936:GACT:G	donor_gain	1.0000
4:20257936:GACTG:G	donor_gain	1.0000
4:20257937:ACT:A	donor_gain	1.0000
4:20257938:CT:C	donor_gain	1.0000
4:20257940:G:GG	donor_gain	1.0000
4:20268878:GGCT:G	donor_gain	1.0000
4:20268879:GCT:G	donor_gain	1.0000

AlphaMissense

10135 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:20257883:T:A	N89K	1.000
4:20257883:T:G	N89K	1.000
4:20257939:T:C	L108P	1.000
4:20268881:T:C	L132P	1.000
4:20467757:T:C	L134P	1.000
4:20467767:C:A	N137K	1.000
4:20467767:C:G	N137K	1.000
4:20480721:T:C	L158P	1.000
4:20480731:C:A	N161K	1.000
4:20480731:C:G	N161K	1.000
4:20480787:T:C	L180P	1.000
4:20486205:T:A	L182H	1.000
4:20486205:T:C	L182P	1.000
4:20486209:C:A	N183K	1.000
4:20486209:C:G	N183K	1.000
4:20486213:A:T	N185Y	1.000
4:20486214:A:T	N185I	1.000
4:20486215:C:A	N185K	1.000
4:20486215:C:G	N185K	1.000
4:20486240:A:C	S194R	1.000
4:20486242:T:A	S194R	1.000
4:20486242:T:G	S194R	1.000
4:20488824:T:C	L206P	1.000
4:20488834:C:A	N209K	1.000
4:20488834:C:G	N209K	1.000
4:20488844:T:C	C213R	1.000
4:20488845:G:A	C213Y	1.000
4:20488846:T:G	C213W	1.000
4:20488864:G:C	W219C	1.000
4:20488864:G:T	W219C	1.000

dbSNP variants (sampled 300 via entrez): RS1000001091 (4:20458393 G>A), RS1000001588 (4:20497647 G>A), RS1000003480 (4:20565964 C>G,T), RS1000005926 (4:20337951 C>T), RS1000013476 (4:20460946 A>G,T), RS1000015592 (4:20255352 C>A,T), RS1000019094 (4:20539370 C>A,T), RS1000020573 (4:20382820 A>G), RS10000297 (4:20390284 T>A,G), RS1000044226 (4:20420134 T>C), RS1000054969 (4:20613467 G>A), RS1000058812 (4:20405405 A>C,G), RS1000067918 (4:20255107 C>G), RS1000069972 (4:20496199 A>C,G), RS1000093389 (4:20335582 G>A)

Disease associations

OMIM: gene MIM:603746 | disease phenotypes: MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital anomaly of kidney and urinary tract	Moderate	Autosomal dominant

Mondo (1): congenital anomaly of kidney and urinary tract (MONDO:0019719)

Orphanet (1): Renal or urinary tract malformation (Orphanet:93545)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566906	Cakut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

72 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression	3
(+)-JQ1 compound	increases expression, affects cotreatment, decreases expression	3
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
Aflatoxin B1	affects expression, affects methylation, decreases methylation	3
aristolochic acid I	decreases expression, decreases reaction, increases activity, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Acetaminophen	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Rotenone	decreases expression	2
Tunicamycin	decreases expression	2
p-Chloromercuribenzoic Acid	increases expression, affects cotreatment	2
OTX015	increases expression	1
mivebresib	increases expression	1
methylmercuric chloride	increases expression	1
methyleugenol	decreases expression	1
bisphenol A	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
afimoxifene	decreases expression, decreases reaction	1
benzo(e)pyrene	decreases methylation	1
N-acetyl-4-benzoquinoneimine	affects response to substance	1
ferrous chloride	increases expression	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
beta-methylcholine	affects expression	1
enniatins	decreases expression	1

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1UH	Abcam U-87MG SLIT2 KO	Cancer cell line	Male
CVCL_E1FT	Abcam HEK293 SLIT2 KO	Transformed cell line	Female
CVCL_TP41	HAP1 SLIT2 (-) 1	Cancer cell line	Male
CVCL_XT50	HAP1 SLIT2 (-) 2	Cancer cell line	Male
CVCL_XT51	HAP1 SLIT2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

4 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)