Affinage

GPRASP2

G-protein coupled receptor-associated sorting protein 2 · UniProt Q96D09

Round 2 corrected
Length
838 aa
Mass
93.8 kDa
Annotated
2026-04-28
44 papers in source corpus 10 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPRASP2 is a post-endosomal sorting protein that controls the surface availability and lysosomal fate of G protein-coupled receptors and other transmembrane proteins, thereby tuning diverse signaling pathways. It bidirectionally regulates mGluR5 surface levels in hippocampal neurons, and its deletion enhances mGluR-dependent long-term depression and produces autism-spectrum-like behaviors in mice (PMID:30926797). GPRASP2 also partners with Pitchfork to form a Hedgehog-induced complex that targets Smoothened to the primary cilium; loss of GPRASP2 blocks Smoothened ciliary translocation and Hedgehog target-gene activation, and promotes lysosomal degradation of Smoothened with downstream consequences for β-catenin and GLI1 signaling (PMID:26901434, PMID:39675768). In auditory neurons, GPRASP2 deficiency activates the AMPK/DRP1 axis, driving mitochondrial fragmentation and apoptosis, and in the cochlea GPRASP2 binds NCAM1 to regulate ferritinophagy and hair-cell iron homeostasis (PMID:39253164, PMID:41688572).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2004 Medium

    Identifying a physical link between GPRASP2 and huntingtin established the first evidence that GPRASP2 participates in neuronal protein networks relevant to receptor trafficking.

    Evidence Yeast two-hybrid screen followed by reciprocal co-immunoprecipitation and co-localization in SH-SY5Y neuronal cells

    PMID:15383276 PMID:16835690

    Open questions at the time
    • Functional consequence of the huntingtin–GPRASP2 interaction on receptor sorting was not determined
    • Single-lab Y2H hit without independent replication
    • No in vivo validation
  2. 2016 Medium

    Demonstrating that GPRASP2 and Pitchfork form a Hedgehog-induced complex required for Smoothened ciliary translocation established GPRASP2 as an active participant in Hedgehog signal transduction.

    Evidence Co-immunoprecipitation of GPRASP2–Pifo complex; siRNA/shRNA depletion with immunofluorescence for Smo ciliary localization and Hh target-gene expression

    PMID:26901434

    Open questions at the time
    • Direct binding interface between GPRASP2 and Smoothened was not mapped
    • Single lab; no in vivo confirmation of ciliary targeting requirement
    • Whether GPRASP2 sorts Smo via the same endosomal mechanism as other GPCRs was not tested
  3. 2019 High

    Bidirectional manipulation of Gprasp2 in vivo revealed it as a critical determinant of mGluR5 surface levels and synaptic plasticity, linking its post-endosomal sorting function to neurodevelopmental phenotypes.

    Evidence Gprasp2 knockout mice with behavioral testing, surface biotinylation for mGluR5, hippocampal LTD electrophysiology, dendritic morphology analysis; overexpression and knockdown in neurons

    PMID:30926797

    Open questions at the time
    • Whether GPRASP2 sorts mGluR5 to lysosomes versus recycling endosomes was not resolved at the compartment level
    • Rescue of behavioral phenotypes by mGluR5 modulation was not performed
  4. 2021 Medium

    CRISPR knockout in auditory cells confirmed that GPRASP2 operates upstream of Smo/Gli signaling and that its loss triggers mitochondrial damage and apoptosis, extending the Hedgehog-regulatory role to a non-neuronal sensory context.

    Evidence CRISPR/Cas9 KO in HEI-OC1 cells; RNA-seq, Western blot, TEM of mitochondria, Purmorphamine rescue of apoptosis

    PMID:34418635

    Open questions at the time
    • Whether mitochondrial damage is a direct consequence of Hh pathway loss or an independent GPRASP2 function was not distinguished
    • Single immortalized cell line (HEI-OC1)
  5. 2024 Medium

    Identification of the AMPK/DRP1 axis downstream of GPRASP2 deficiency in primary spiral ganglion neurons established a specific mitochondrial-dynamics pathway controlled by GPRASP2, with pharmacological rescue confirming causality.

    Evidence Lentiviral shRNA knockdown in primary spiral ganglion cells; phospho-AMPK/DRP1 Western blot, mitochondrial membrane potential assay, Mdivi-1 rescue

    PMID:39253164

    Open questions at the time
    • How GPRASP2 suppresses AMPK phosphorylation mechanistically is unknown
    • Whether AMPK/DRP1 regulation occurs downstream of GPCR sorting or through an independent mechanism was not resolved
  6. 2024 Medium

    Bidirectional manipulation in cochlear organoids showed GPRASP2 stabilizes Smoothened by preventing its lysosomal degradation, connecting the sorting function to β-catenin signaling and supporting-cell proliferation/hair-cell regeneration.

    Evidence Gprasp2 overexpression and deficiency in cochlear organoids; lysosomal degradation assays, Western blot for SMO/β-catenin/GLI1, AAV-mediated rescue

    PMID:39675768

    Open questions at the time
    • Direct structural or proximity-labeling evidence for GPRASP2–Smoothened interaction at the endosome is lacking
    • Whether Wnt/β-catenin activation is entirely Smo-dependent or partly independent was not fully dissected
  7. 2024 Medium

    Female-specific Gprasp2 knockout studies revealed roles in social memory, maternal behavior, and oxytocin receptor expression, broadening the neurobehavioral impact of GPRASP2 beyond ASD-like phenotypes to sex-specific circuits.

    Evidence Gprasp2 KO female mice; anxiety, memory, and maternal-care behavioral batteries; cross-fostering design; OxtR expression analysis

    PMID:38816497

    Open questions at the time
    • Whether OxtR surface levels are directly regulated by GPRASP2-mediated sorting was not tested biochemically
    • Cross-fostering shows non-cell-autonomous effects but does not identify the signaling mediator
  8. 2026 Medium

    Discovery of a GPRASP2–NCAM1 physical interaction linked GPRASP2 to ferritinophagy and iron homeostasis in cochlear hair cells, expanding its sorting substrate repertoire beyond GPCRs.

    Evidence Co-immunoprecipitation of GPRASP2–NCAM1; Gprasp2-deficient mice with ABR hearing assessment, ferritinophagy assays, behavioral tests

    PMID:41688572

    Open questions at the time
    • Reciprocal validation of NCAM1 interaction awaits confirmation by an independent method (e.g., proximity labeling)
    • Mechanism by which GPRASP2 controls ferritinophagy is undefined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether GPRASP2's post-endosomal sorting function operates through a unified endosomal machinery for all its cargo (mGluR5, Smoothened, NCAM1, OxtR) or through cargo-specific adaptors remains an open question, as does the structural basis for substrate recognition.
  • No structural model of GPRASP2 or its cargo-binding domains exists
  • Substrate selectivity rules are unknown
  • Relationship between GPCR-sorting and mitochondrial-dynamics functions has not been mechanistically linked

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005768 endosome 3 GO:0005764 lysosome 1 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-112316 Neuronal System 2
Partners
GRM5HTTNCAM1PIFOSMO
Complex memberships
Pitchfork–GPRASP2 ciliary targeting complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 GPRASP2 (GASP2) was identified as a direct interaction partner of huntingtin (htt) via yeast two-hybrid screening, and this interaction was validated by membrane-based and classical co-immunoprecipitation assays in co-transfected mammalian cells. The two proteins co-localize in SH-SY5Y neuronal cells, suggesting that huntingtin may influence G protein-coupled receptor trafficking via its interaction with GASP2. Yeast two-hybrid screening, membrane-based co-immunoprecipitation, classical co-immunoprecipitation, immunofluorescence co-localization in SH-SY5Y cells Molecular cell / Journal of neural transmission Medium 15383276 16835690
2016 GPRASP2, together with Pitchfork (Pifo), forms a Hedgehog-induced ciliary targeting complex that is essential for translocation of the seven-transmembrane receptor Smoothened (Smo) to the primary cilium. Depletion of Gprasp2 prevents Smo ciliary translocation and abolishes Hedgehog target gene activation. Protein complex identification (co-immunoprecipitation), siRNA/shRNA depletion of Gprasp2 with readout of Smo ciliary localization by immunofluorescence and Hh target gene expression PloS one Medium 26901434
2019 Gprasp2 is involved in postendocytic sorting of G protein-coupled receptors and bidirectionally regulates the surface availability of mGluR5. Gprasp2 deletion in mice leads to enhanced hippocampal mGluR-dependent long-term depression (LTD), increased mGluR5 surface levels, and ASD-like behaviors including altered dendritic complexity, spine density, and synaptic maturation. Gprasp2 knockout mice (behavioral assays), bidirectional manipulation (overexpression and knockdown) of Gprasp2 with surface biotinylation assay for mGluR5, electrophysiology (hippocampal LTD recording), morphological analysis of dendrites and spines Nature communications High 30926797
2021 Disruption of Gprasp2 in HEI-OC1 auditory cells via CRISPR/Cas9 down-regulates the Hedgehog signaling pathway, evidenced by decreased expression of Smo, Gli1, and Gli2, and induces mitochondrial damage and apoptosis via altered Bcl2/Bax/Caspase-3 balance. Pharmacological activation of the Hh pathway with the Smoothened agonist Purmorphamine rescues apoptosis in Gprasp2-KO cells, placing GPRASP2 upstream of Smo/Gli signaling in auditory cells. CRISPR/Cas9 knockout in HEI-OC1 cells, RNA-seq, Western blot (Smo, Gli1, Gli2, Bcl2, Bax, Caspase-3), flow cytometry (apoptosis), transmission electron microscopy (mitochondrial morphology), pharmacological rescue with Smoothened agonist Biochemical and biophysical research communications Medium 34418635
2024 GPRASP2 deficiency in spiral ganglion cells leads to increased phosphorylation of AMPK and activation of the AMPK/DRP1 pathway, resulting in mitochondrial fragmentation (abnormal morphology, decreased membrane potential) and apoptosis. Treatment with the mitochondrial division inhibitor Mdivi-1 mitigates these effects, establishing GPRASP2 as a regulator of mitochondrial dynamics in auditory neurons via the AMPK/DRP1 axis. Gprasp2-shRNA knockdown via lentiviral infection of primary spiral ganglion cells, Western blot (phospho-AMPK, DRP1), mitochondrial morphology assessment, membrane potential assay, flow cytometry (apoptosis), pharmacological rescue with Mdivi-1, cochlear explant culture Heliyon Medium 39253164
2024 GPRASP2 overexpression in mouse cochlear organoids promotes proliferation of supporting cells via the Hedgehog signaling pathway and promotes hair cell formation from supporting cells via β-catenin signaling. GPRASP2 deficiency results in increased lysosomal degradation of the SMO protein, leading to decreased β-catenin and GLI1 expression, establishing GPRASP2 as a regulator of SMO protein stability at the lysosome. Gprasp2 overexpression in mouse cochlear organoids, GPRASP2 deficiency model, Western blot (SMO, β-catenin, GLI1), lysosomal degradation assays, AAV-ie-Gprasp2 delivery, smoothened agonist (SAG) rescue in neomycin-treated cochlear explant Cell proliferation Medium 39675768
2024 Gprasp2 deletion in female mice disrupts social and working memory, impairs maternal care behaviors, and alters expression of oxytocin receptor (OxtR) in the hypothalamus and mammary gland structure. Cross-fostering experiments demonstrate that mutant dam genotype negatively affects pup vocalization development, indicating that Gprasp2-dependent maternal neurological function has a non-cell-autonomous effect on early progeny neurodevelopment. Gprasp2 knockout mice (female), behavioral paradigms (anxiety, memory, maternal care, social behavior), ultrasonic vocalization recording, cross-fostering experiments, OxtR expression analysis (molecular), mammary gland histology Scientific reports Medium 38816497
2026 GPRASP2 physically binds NCAM1, and GPRASP2 deficiency reduces NCAM1 protein levels and enhances ferritinophagy in cochlear hair cells, linking GPRASP2 to iron homeostasis. Gprasp2-deficient mice display hearing loss, disordered cochlear hair cell arrangement, and depression-like behaviors. Co-immunoprecipitation (GPRASP2-NCAM1 interaction), Gprasp2-deficient mouse model, Western blot (NCAM1), ferritinophagy assays, auditory brainstem response (hearing phenotype), behavioral assays Communications biology Medium 41688572
2026 GPRASP2, a post-endosomal sorting protein, is highly expressed in quiescent hematopoietic stem cells (HSCs) and mediates elevated endocytosis that attenuates signaling through receptor internalization. Disruption of GPRASP2-mediated endocytosis induces rapid HSC proliferation and increased expression of signaling constituents, demonstrating that GPRASP2 maintains HSC quiescence and self-renewal by limiting receptor-mediated signal transduction through endocytic routing. GPRASP2 expression profiling in HSC subpopulations, loss-of-function disruption of GPRASP2-mediated endocytosis with readout of HSC proliferation, self-renewal assays, and signaling constituent expression bioRxivpreprint Low 41726907

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2005 The DNA sequence of the human X chromosome. Nature 816 15772651
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2006 Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular psychiatry 345 17043677
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2004 A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. Molecular cell 339 15383276
2014 A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 325 25036637
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2010 Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Molecular psychiatry 247 20479760
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2014 Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nature communications 111 24722188
2018 The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses. The Journal of experimental medicine 109 30068544
2017 Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair. Nature communications 89 29229926
2016 Pooled-matrix protein interaction screens using Barcode Fusion Genetics. Molecular systems biology 89 27107012
2013 Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2. Proceedings of the National Academy of Sciences of the United States of America 83 24019467
2019 Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice. Nature communications 46 30926797
2016 Pitchfork and Gprasp2 Target Smoothened to the Primary Cilium for Hedgehog Pathway Activation. PloS one 24 26901434
2006 Huntingtin interacts with the receptor sorting family protein GASP2. Journal of neural transmission (Vienna, Austria : 1996) 19 16835690
2016 Enhancement of C2C12 myoblast proliferation and differentiation by GASP-2, a myostatin inhibitor. Biochemistry and biophysics reports 12 28955860
2017 GPRASP2, a novel causative gene mutated in an X-linked recessive syndromic hearing loss. Journal of medical genetics 9 28096187
2020 GASP-2 overexpressing mice exhibit a hypermuscular phenotype with contrasting molecular effects compared to GASP-1 transgenics. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 31960486
2021 Disruption of Gprasp2 down-regulates Hedgehog signaling and leads to apoptosis in auditory cells. Biochemical and biophysical research communications 3 34418635
2024 Implication of GPRASP2 in the Proliferation and Hair Cell-Forming of Cochlear Supporting Cells. Cell proliferation 1 39675768
2017 Dynamic expression analysis of armc10, the homologous gene of human GPRASP2, in zebrafish embryos. Molecular medicine reports 1 28849214
2026 Abnormal iron homeostasis mediates cochlear hair cell impairment and hearing loss in Gprasp2-deficient mice. Communications biology 0 41688572
2026 Elevated endocytic trafficking mediated by GPRASP2 maintains HSC fidelity. bioRxiv : the preprint server for biology 0 41726907
2024 Maternal behaviours disrupted by Gprasp2 deletion modulate neurodevelopmental trajectory in progeny. Scientific reports 0 38816497
2024 GPRASP2 deficiency contributes to apoptosis in the spiral ganglion cells via the AMPK/DRP1 signaling pathway. Heliyon 0 39253164