Affinage

SLITRK5

SLIT and NTRK-like protein 5 · UniProt O94991

Length
958 aa
Mass
107.5 kDa
Annotated
2026-06-10
29 papers in source corpus 7 papers cited in narrative 8 extracted findings
Cross-family judge faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLITRK5 is a single-pass transmembrane protein with extracellular leucine-rich repeat (LRR) domains and a C-terminal TRK-like domain that operates as an adhesion and signaling regulator at corticostriatal synapses (PMID:14557068, PMID:20418887). Loss of Slitrk5 in mice produces deficient corticostriatal neurotransmission, altered striatal anatomy and glutamate receptor composition, and OCD-like behaviors that are alleviated by fluoxetine, establishing it as an essential synaptic molecule (PMID:20418887); rare human OCD-associated SLITRK5 variants disrupt its synaptogenic activity in vitro (PMID:28085938). Mechanistically, SLITRK5 engages in a stimulus-dependent switch of binding partners: under basal conditions it binds the transsynaptic phosphatase PTPδ, and upon BDNF stimulation it shifts to a cis-interaction with TrkB, recruiting the Rab11 effector Rab11-FIP3 to target TrkB to Rab11-positive recycling endosomes and thereby tuning BDNF-dependent signaling (PMID:26004511). Independently of its synaptic role, SLITRK5 acts as a negative regulator of hedgehog signaling: it binds hedgehog ligands through its extracellular domain and PTCH1 through its intracellular domain, localizes to the primary cilium, and restricts SHH-induced SMO ciliary enrichment and downstream target gene expression in osteoblasts (PMID:34326333).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2003 Medium

    Established the basic molecular identity of SLITRK5 as a neural-enriched integral membrane protein combining SLIT-like LRR domains with a TRK-like cytoplasmic region capable of modulating neurite outgrowth, framing it as a candidate synaptic/neuronal adhesion molecule.

    Evidence cDNA cloning, domain/homology analysis, and neurite outgrowth assays in cultured neurons across SLITRK family members

    PMID:14557068

    Open questions at the time
    • SLITRK5-specific function not distinguished from family-level findings
    • No binding partners or signaling mechanism identified
    • No in vivo role established
  2. 2010 High

    Defined SLITRK5 as physiologically essential at corticostriatal synapses by showing that its loss disrupts neurotransmission, striatal morphology, and glutamate receptor composition and produces fluoxetine-reversible OCD-like behavior, linking the molecule to a defined circuit and disease phenotype.

    Evidence Slitrk5 knockout mouse with behavioral, neuroanatomical, electrophysiological, and receptor composition analyses plus pharmacological rescue

    PMID:20418887

    Open questions at the time
    • Molecular binding partners mediating synaptic function not yet identified
    • Direct molecular cause of altered glutamate receptor composition unresolved
    • Cell-autonomous vs circuit-level contributions not dissected
  3. 2015 High

    Resolved a molecular mechanism by demonstrating a BDNF-triggered partner switch (PTPδ to TrkB) and a role in TrkB recycling, explaining how SLITRK5 couples transsynaptic adhesion to neurotrophin signaling and endosomal trafficking.

    Evidence Reciprocal co-immunoprecipitation under basal vs BDNF conditions, structured illumination microscopy, and TrkB trafficking/Rab11-FIP3 recruitment assays in Slitrk5-deficient neurons

    PMID:26004511

    Open questions at the time
    • Structural basis of the cis-TrkB versus trans-PTPδ switch unknown
    • How the partner switch connects to the glutamate receptor and behavioral phenotypes not established
    • Stoichiometry and dynamics of Rab11-FIP3 recruitment not quantified
  4. 2017 Medium

    Connected human genetic variation to mechanism by showing OCD-associated SLITRK5 coding variants impair synaptogenic activity while control variants do not, providing functional support for SLITRK5 as a disease-relevant synaptogenic protein.

    Evidence Resequencing of SLITRK5 in OCD subjects with in vitro synaptogenesis assays using recombinant mutant proteins versus matched controls

    PMID:28085938

    Open questions at the time
    • In vitro synaptogenesis defect not validated in vivo
    • Variant effects on PTPδ/TrkB binding not tested
    • Causal link between specific variants and human OCD remains correlational
  5. 2021 High

    Revealed a second, non-neuronal function by showing SLITRK5 binds hedgehog ligands extracellularly and PTCH1 intracellularly, localizes to the primary cilium, and restrains SMO ciliary enrichment, defining it as a ciliary negative regulator of hedgehog signaling in osteoblasts.

    Evidence Co-IP of distinct extracellular and intracellular interactions, ciliary immunofluorescence, SMO enrichment assays, and gain/loss-of-function with target gene readouts in vitro and in vivo

    PMID:34326333

    Open questions at the time
    • Relationship between the synaptic and hedgehog functions unclear
    • Mechanism by which PTCH1 binding restricts SMO not defined
    • Whether ciliary localization occurs in neurons not addressed
  6. 2022 Medium

    Extended the hedgehog-regulatory role to disease by placing SLITRK5 downstream of MUC21 as a suppressed negative regulator whose loss activates hedgehog signaling and drives melanoma proliferation and invasion.

    Evidence MUC21 overexpression in melanoma cell lines with proliferation/invasion assays, pathway readouts, and cyclopamine-treated xenografts

    PMID:35579188

    Open questions at the time
    • Link to SLITRK5 inferred from expression suppression rather than direct interaction
    • How MUC21 suppresses SLITRK5 expression unknown
    • Endogenous relevance in primary melanoma not established
  7. 2022 Medium

    Placed SLITRK5 upstream of dendritic development by showing that gintonin rescues the dendritic deficit of Slitrk5-deficient striatal neurons via LPAR-mediated Akt/CREB activation, implicating a tractable signaling axis downstream of SLITRK5 loss.

    Evidence Slitrk5-deficient primary striatal neuron cultures with gintonin treatment, Akt/CREB phosphorylation assays, dendritic morphology analysis, and LPAR inhibition

    PMID:36385759

    Open questions at the time
    • SLITRK5 role inferred from pharmacological rescue rather than direct mechanism
    • Whether Akt/CREB signaling is normally controlled by SLITRK5 unresolved
    • In vivo relevance of the rescue not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SLITRK5's synaptic adhesion/neurotrophin functions and its ciliary hedgehog-regulatory functions are mechanistically and developmentally integrated within and across cell types remains unknown.
  • No structural model of SLITRK5 in complex with PTPδ, TrkB, or PTCH1
  • Whether the same protein performs both roles in the same cells is untested
  • Mechanistic basis linking variant-level synaptogenic defects to circuit and behavioral phenotypes unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 3 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005768 endosome 1 GO:0005886 plasma membrane 1 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-112316 Neuronal System 1 R-HSA-9609507 Protein localization 1
Partners
NTRK2PTCH1PTPRDRAB11FIP3

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 Loss of Slitrk5 in mice leads to selective overactivation of the orbitofrontal cortex, abnormalities in striatal anatomy and cell morphology, and alterations in glutamate receptor composition, contributing to deficient corticostriatal neurotransmission; Slitrk5 knockout mice show OCD-like behaviors (excessive self-grooming, increased anxiety) alleviated by fluoxetine, establishing Slitrk5 as an essential molecule at corticostriatal synapses. Slitrk5 knockout mouse model; behavioral assays; neuroanatomical analysis; electrophysiology; glutamate receptor composition analysis; fluoxetine rescue Nature medicine High 20418887
2015 Slitrk5 directly interacts with TrkB receptors and, upon BDNF stimulation, shifts from a transsynaptic interaction with PTPδ to cis-interaction with TrkB; Slitrk5 mediates optimal targeting of TrkB to Rab11-positive recycling endosomes through recruitment of the Rab11 effector protein Rab11-FIP3, and loss of Slitrk5 reduces the rate of ligand-dependent TrkB recycling and alters responsiveness to BDNF. Co-immunoprecipitation; structured illumination microscopy; TrkB trafficking assays in Slitrk5-deficient neurons; Rab11-FIP3 recruitment assay; BDNF stimulation experiments Developmental cell High 26004511
2015 Under basal conditions, Slitrk5 interacts primarily with the transsynaptic binding partner protein tyrosine phosphatase δ (PTPδ); upon BDNF stimulation this interaction shifts to TrkB, indicating a stimulus-dependent switch in binding partners. Co-immunoprecipitation under basal vs. BDNF-stimulated conditions Developmental cell High 26004511
2017 Rare non-synonymous mutations in SLITRK5 identified in OCD subjects impaired synaptogenic activity in vitro, whereas pseudo-matched mutations from controls had no significant effect, demonstrating that specific human SLITRK5 variants functionally disrupt synaptogenesis. Resequencing of SLITRK5 coding sequence in OCD subjects; in vitro synaptogenesis assays with recombinant mutant SLITRK5 proteins; comparison to 1000 Genomes controls PloS one Medium 28085938
2021 SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain; SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation, establishing SLITRK5 as a negative regulator of hedgehog signaling in osteoblasts that inhibits downstream hedgehog target gene expression. Co-immunoprecipitation (extracellular domain binding to hedgehog ligands; intracellular domain interaction with PTCH1); primary cilium localization by immunofluorescence; SMO ciliary enrichment assay; overexpression and loss-of-function in osteoblasts; hedgehog target gene expression assays in vitro and in vivo Nature communications High 34326333
2022 MUC21 overexpression suppresses SLITRK5 expression, leading to activation of the hedgehog pathway and sustained melanoma cell proliferation and invasion; this places SLITRK5 downstream of MUC21 as a negative regulator of hedgehog signaling in melanoma cells. Overexpression of MUC21 in melanoma cell lines (A375, A875); cell proliferation (CCK-8) and invasion (transwell) assays; measurement of SLITRK5 and hedgehog pathway activity; xenograft model with hedgehog inhibitor cyclopamine Cell biology international Medium 35579188
2003 SLITRK5 (and other SLITRK family members) are integral membrane proteins characterized by two N-terminal leucine-rich repeat (LRR) domains (similar to SLIT) and a C-terminal domain partially similar to TRK neurotrophin receptors; they are expressed predominantly in neural tissue and have neurite-modulating activity in cultured neuronal cells. cDNA cloning; domain/homology analysis; expression profiling; neurite outgrowth assays in cultured neuronal cells Gene Medium 14557068
2022 Gintonin treatment ameliorated the reduction in dendritic formation caused by Slitrk5 deficiency in striatal neurons, acting through LPA receptor (LPAR1/3)-mediated Akt/CREB activation, placing Slitrk5 upstream of dendritic development in striatal neurons. Primary striatal neuron culture from Slitrk5-deficient mice; gintonin treatment; Akt/CREB phosphorylation assays; dendritic morphology analysis; pharmacological inhibition with Ki16425 Frontiers in molecular neuroscience Medium 36385759

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Nature medicine 272 20418887
1998 Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 190 10048485
2003 Human SLITRK family genes: genomic organization and expression profiling in normal brain and brain tumor tissue. Gene 119 14557068
2015 Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling. Developmental cell 77 26004511
2021 Exome sequencing in obsessive-compulsive disorder reveals a burden of rare damaging coding variants. Nature neuroscience 73 34183866
2017 Corticostriatal circuit defects in Hoxb8 mutant mice. Molecular psychiatry 69 28948967
2013 Repetitive behavior profile and supersensitivity to amphetamine in the C58/J mouse model of autism. Behavioural brain research 53 24211371
2022 Integrative RNA profiling of TBEV-infected neurons and astrocytes reveals potential pathogenic effectors. Computational and structural biotechnology journal 31 35685361
2021 SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts. Nature communications 31 34326333
2017 Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder. PloS one 29 28085938
2019 New Gene Markers of Angiogenesis and Blood Vessels Development in Porcine Ovarian Granulosa Cells during Short-Term Primary Culture In Vitro. BioMed research international 27 30834271
2016 Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors. Molecular cancer research : MCR 21 27671336
2015 Quantitative candidate gene association studies of metabolic traits in Han Chinese type 2 diabetes patients. Genetics and molecular research : GMR 21 26634513
2012 Novel candidate genes of thyroid tumourigenesis identified in Trk-T1 transgenic mice. Endocrine-related cancer 19 22454401
2014 Highly Expressed Genes within Hippocampal Sector CA1: Implications for the Physiology of Memory. Neurology international 17 24987507
2022 The Role of SliTrk5 in Central Nervous System. BioMed research international 14 35872846
2019 Amelioration of obsessive-compulsive disorder in three mouse models treated with one epigenetic drug: unraveling the underlying mechanism. Scientific reports 8 31217515
2018 Precision medicine validation: identifying the MYBPC3 A31P variant with whole-genome sequencing in two Maine Coon cats with hypertrophic cardiomyopathy. Journal of feline medicine and surgery 8 30558461
2024 Archetypal clustering reveals physiological mechanisms linking milk yield and fertility in dairy cattle. Journal of dairy science 7 38369117
2023 Upregulation of SLITRK5 in patients with epilepsy and in a rat model. Synapse (New York, N.Y.) 7 36811190
2015 Association study of the SLITRK5 gene and Tourette syndrome. Psychiatric genetics 7 25426764
2022 MUC21 controls melanoma progression via regulating SLITRK5 and hedgehog signaling pathway. Cell biology international 6 35579188
2022 The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors. PloS one 4 35089926
2022 Identification of 4 New Loci Associated With Primary Hyperparathyroidism (PHPT) and a Polygenic Risk Score for PHPT. The Journal of clinical endocrinology and metabolism 4 36102151
2022 Gintonin stimulates dendritic growth in striatal neurons by activating Akt and CREB. Frontiers in molecular neuroscience 4 36385759
2018 Born This Way: Using Intrinsic Disorder to Map the Connections between SLITRKs, TSHR, and Male Sexual Orientation. Proteomics 3 30156382
2025 Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses. BMC neurology 2 40033250
2025 Pharmacogenetics of obsessive-compulsive disorder: Investigations of intragenic and regulatory region genetic variations. Progress in neuro-psychopharmacology & biological psychiatry 1 40054571
2025 Oligogenic risk score for Gilles de la Tourette syndrome reveals a genetic continuum of tic disorders. Journal of applied genetics 0 39792217

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