{"gene":"JKAMP","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2005,"finding":"JAMP (JKAMP) is a predicted seven-transmembrane protein localized primarily within the plasma membrane that associates with JNK1 through its C-terminal domain. This association outcompetes JNK1 binding to MAP kinase phosphatase 5 (MKP5), resulting in increased and prolonged JNK1 activity following stress stimuli (UV or tunicamycin). Elevated JAMP expression sustains JNK activity and increases JNK-dependent apoptosis, while RNAi-mediated JAMP knockdown reduces JNK activation duration and stress-induced apoptosis.","method":"Co-immunoprecipitation, RNA interference knockdown, overexpression, domain mapping (C-terminal domain), competitive binding assay with MKP5","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, RNAi knockdown with specific phenotypic readout, and overexpression assays in a single focused study","pmids":["16166642"],"is_preprint":false},{"year":2008,"finding":"JAMP (JKAMP) is an ER-resident seven-transmembrane protein that functions as a scaffold linking ER chaperones, channel proteins, ubiquitin ligases, and 26S proteasome subunits to optimize ERAD. Elevated JAMP expression promotes localization of proteasomes at the ER and enhances degradation of specific misfolded ER-resident proteins, while JAMP inhibition has the opposite effect. C. elegans jamp-1 deletion causes hypersensitivity to ER stress and increased UPR, establishing its role via genetic loss-of-function.","method":"Biochemical fractionation, co-immunoprecipitation, overexpression and inhibition (loss-of-function), C. elegans jamp-1 deletion genetic model, UPR assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical, genetic in vivo model, proteasome localization assay) in a single focused study replicated across model systems","pmids":["18784250"],"is_preprint":false},{"year":2009,"finding":"RNF5, a ubiquitin ligase anchored to the ER membrane, associates with JAMP in the ER membrane and mediates Ubc13-dependent non-canonical (K63-linked) ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but inhibits JAMP's association with proteasome subunit Rpt5 and p97, thereby reducing ERAD efficiency and causing greater accumulation of misfolded proteins (CFTRΔ508 and TCRα). RNF5 thus limits ERAD and proteasome assembly at the ER both before and after ER stress response.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, E2 enzyme (Ubc13) identification, misfolded protein degradation assay (CFTRΔ508, TCRα), RNF5 overexpression and knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro ubiquitination assay identifying E2 enzyme, Co-IP, functional ERAD substrate degradation assays, multiple orthogonal methods in single focused study","pmids":["19269966"],"is_preprint":false},{"year":2013,"finding":"JAMP (JKAMP) interacts with G protein-coupled receptors (β2-adrenergic receptor and prostaglandin D2 receptor DP) and decreases total receptor protein levels through proteasomal degradation. Expression of DP promotes proteasome recruitment by JAMP. RNF5 ubiquitinates JAMP to prevent proteasome recruitment, thereby protecting GPCRs from JAMP-mediated proteasomal degradation. Depletion of RNF5 increases degradation of both receptors via JAMP.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, confocal microscopy colocalization, proteasome inhibitor assays, gel-free proteomics","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown, overexpression with defined proteasomal degradation phenotype, and confocal colocalization in single focused study","pmids":["23798571"],"is_preprint":false},{"year":2021,"finding":"JKAMP promotes osteogenic differentiation in adipose-derived stem cells by modulating the Wnt signaling pathway. JKAMP silencing inhibits Wnt signaling and reduces osteogenic ability (assessed by RUNX2, OPN expression, Alizarin red and ALP staining), while JKAMP overexpression in diabetic osteoporosis-derived ASCs rescues impaired osteogenic capacity. Intragenic DNA hypermethylation in DOP-ASCs suppresses JKAMP expression, linking epigenetic regulation to JKAMP function.","method":"siRNA knockdown, overexpression plasmid, immunofluorescence, qPCR, western blotting, Alizarin red staining, ALP staining, bisulfite-specific PCR (BSP) for methylation, MeDIP sequencing","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown and overexpression with defined osteogenic phenotype readouts, multiple methods in single lab study, no independent replication","pmids":["33579371"],"is_preprint":false},{"year":2026,"finding":"Bi-allelic loss-of-function variants in JKAMP cause a neurodevelopmental syndrome. JKAMP loss results in defective folding and degradation of GPR37 (a brain-enriched orphan GPCR and known JKAMP interactor), leading to GPR37 accumulation within the ER and impaired trafficking to the plasma membrane, likely due to impaired ER quality control. A zebrafish jkamp knockout model recapitulated developmental abnormalities and impaired myelin production.","method":"Human genetic analysis (bi-allelic variants in 14 patients from 10 families), zebrafish jkamp knockout model, mechanistic studies of GPR37 folding/degradation and subcellular localization (ER accumulation, plasma membrane trafficking assay)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics combined with in vivo zebrafish KO model and cellular mechanistic studies of GPR37 trafficking, multiple orthogonal methods across multiple families","pmids":["41643666"],"is_preprint":false},{"year":2025,"finding":"TTC7B activates AKT signaling to upregulate JKAMP expression, and JKAMP is required downstream of TTC7B-AKT signaling to promote head and neck cancer cell migration and invasion. Pharmacological AKT inhibition abolishes TTC7B-induced JKAMP upregulation and suppresses migration/invasion; IGF-1-mediated AKT activation restores JKAMP expression in TTC7B-knockdown cells. JKAMP silencing in TTC7B-overexpressing cells markedly reduces migration and invasion, placing JKAMP downstream of the TTC7B-AKT axis.","method":"In vitro migration and invasion assays, TTC7B overexpression and knockdown, JKAMP siRNA knockdown, pharmacological AKT inhibition, IGF-1 stimulation, western blotting for phospho-AKT and JKAMP","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by pharmacological inhibition and rescue experiments, multiple functional assays, single lab study","pmids":["41392613"],"is_preprint":false}],"current_model":"JKAMP (JAMP) is an ER-resident seven-transmembrane scaffold protein that optimizes ERAD by linking ER chaperones, channel proteins, ubiquitin ligases, and 26S proteasome subunits, thereby recruiting proteasomes to the ER membrane to degrade misfolded proteins (including CFTRΔ508, TCRα, and GPR37); its activity is negatively regulated by RNF5-mediated Ubc13-dependent non-canonical ubiquitination, which prevents its association with Rpt5 and p97; outside the ER, JKAMP associates with JNK1 via its C-terminal domain to outcompete MKP5 and sustain JNK1 signaling and apoptosis in response to stress; JKAMP expression is upregulated by the TTC7B-AKT axis to promote cancer cell migration and invasion; and bi-allelic loss-of-function variants in humans cause a neurodevelopmental syndrome linked to defective GPR37 trafficking from the ER to the plasma membrane."},"narrative":{"mechanistic_narrative":"JKAMP (JAMP) is a seven-transmembrane protein that functions principally as an endoplasmic reticulum-associated degradation (ERAD) scaffold, coupling protein quality control at the ER membrane to proteasomal degradation of misfolded substrates [PMID:18784250]. At the ER it bridges chaperones, channel proteins, ubiquitin ligases, and 26S proteasome subunits, recruiting proteasomes to the ER membrane to optimize the disposal of specific misfolded ER-resident proteins; loss of the C. elegans ortholog jamp-1 sensitizes animals to ER stress and elevates the unfolded protein response [PMID:18784250]. JKAMP's degradative activity is restrained by the ER-anchored ubiquitin ligase RNF5, which directs Ubc13-dependent K63-linked non-canonical ubiquitination of JKAMP; this modification does not affect JKAMP stability but blocks its association with the proteasomal ATPase Rpt5 and with p97, thereby limiting ERAD and causing accumulation of substrates such as CFTRΔ508 and TCRα [PMID:19269966]. Through this scaffolding activity JKAMP also controls the abundance of G protein-coupled receptors, promoting proteasomal degradation of the β2-adrenergic receptor and the prostaglandin D2 receptor DP, with RNF5-mediated ubiquitination protecting these receptors from JKAMP-driven turnover [PMID:23798571]. Bi-allelic loss-of-function variants in JKAMP cause a neurodevelopmental syndrome in which defective folding and degradation of the brain-enriched orphan GPCR GPR37 leads to its ER accumulation and impaired plasma-membrane trafficking, with a zebrafish knockout recapitulating developmental abnormalities and impaired myelin production [PMID:41643666]. Independently of its ER role, JKAMP binds JNK1 through its C-terminal domain, outcompeting MAP kinase phosphatase MKP5 to sustain JNK1 activity and JNK-dependent apoptosis after UV or tunicamycin stress [PMID:16166642].","teleology":[{"year":2005,"claim":"Established the first molecular function for JKAMP by showing it modulates stress signaling rather than acting as an inert membrane protein, binding JNK1 to prolong its activity.","evidence":"Reciprocal Co-IP, domain mapping, RNAi knockdown, and competitive binding against MKP5 with apoptosis readouts in mammalian cells","pmids":["16166642"],"confidence":"High","gaps":["Localization assigned to plasma membrane here, later revised to ER","Structural basis of the JNK1/MKP5 competition not resolved","Physiological contexts where this axis dominates over the ERAD role unclear"]},{"year":2008,"claim":"Reframed JKAMP as an ER-resident ERAD scaffold that recruits proteasomes to the ER membrane, answering where and how it acts in protein quality control.","evidence":"Biochemical fractionation, Co-IP, proteasome localization assays, and C. elegans jamp-1 deletion with UPR readouts","pmids":["18784250"],"confidence":"High","gaps":["Specific misfolded substrates incompletely enumerated","Stoichiometry and architecture of the chaperone-ligase-proteasome assembly unknown","How the same protein partitions between ER and JNK-signaling functions not addressed"]},{"year":2009,"claim":"Identified the negative regulatory switch on JKAMP, showing RNF5/Ubc13-mediated K63 ubiquitination blocks proteasome and p97 recruitment without degrading JKAMP.","evidence":"In vitro ubiquitination with E2 (Ubc13) identification, Co-IP, and CFTRΔ508/TCRα degradation assays with RNF5 manipulation","pmids":["19269966"],"confidence":"High","gaps":["Ubiquitination sites on JKAMP not mapped","Signals controlling RNF5 activity toward JKAMP unknown","Deubiquitinase reversing this mark not identified"]},{"year":2013,"claim":"Extended JKAMP substrate scope to GPCRs, showing it drives proteasomal turnover of β2-adrenergic and DP receptors under RNF5 control.","evidence":"Reciprocal Co-IP, siRNA, confocal colocalization, proteasome inhibitor assays, and proteomics in mammalian cells","pmids":["23798571"],"confidence":"High","gaps":["Selectivity rules distinguishing degraded vs spared GPCRs unclear","Whether JKAMP acts on folded vs misfolded receptor pools not resolved"]},{"year":2021,"claim":"Linked JKAMP to osteogenic differentiation and Wnt signaling, with epigenetic silencing connecting its expression to a disease state.","evidence":"siRNA and overexpression with osteogenic markers, staining assays, and methylation profiling (BSP, MeDIP-seq) in adipose-derived stem cells","pmids":["33579371"],"confidence":"Medium","gaps":["Mechanistic link between ERAD scaffolding and Wnt output not established","No independent replication","Direct Wnt-component interaction not demonstrated"]},{"year":2025,"claim":"Placed JKAMP downstream of a TTC7B-AKT axis driving cancer cell migration and invasion.","evidence":"Migration/invasion assays, TTC7B and JKAMP manipulation, AKT inhibition, and IGF-1 rescue with phospho-AKT/JKAMP blots","pmids":["41392613"],"confidence":"Medium","gaps":["How AKT signaling controls JKAMP transcription not defined","Whether the pro-invasive effect requires JKAMP's ERAD function unknown","Single-lab study without in vivo confirmation"]},{"year":2026,"claim":"Demonstrated human disease causation, tying JKAMP loss to a neurodevelopmental syndrome via failed GPR37 quality control.","evidence":"Bi-allelic variants across 10 families, zebrafish jkamp knockout, and GPR37 folding/trafficking assays showing ER accumulation","pmids":["41643666"],"confidence":"High","gaps":["Whether GPR37 mishandling alone accounts for the full phenotype unclear","Mechanism connecting JKAMP loss to myelin defects not detailed","Genotype-phenotype correlation across variants not established"]},{"year":null,"claim":"How JKAMP partitions between its ER ERAD scaffold role and its cytoplasmic JNK1-signaling role, and what determines substrate selection, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the 7TM scaffold or its complexes","Regulatory logic switching between functions unknown","Comprehensive substrate repertoire undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,2,5]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["JNK1","MKP5","RNF5","RPT5","P97","GPR37"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9P055","full_name":"JNK1/MAPK8-associated membrane protein","aliases":["JNK1-associated membrane protein","JAMP","Medulloblastoma antigen MU-MB-50.4"],"length_aa":311,"mass_kda":35.2,"function":"Regulates the duration of MAPK8 activity in response to various stress stimuli (By similarity). Facilitates degradation of misfolded endoplasmic reticulum (ER) proteins through the recruitment of components of the proteasome and endoplasmic reticulum-associated degradation (ERAD) system (PubMed:18784250)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9P055/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JKAMP","classification":"Not Classified","n_dependent_lines":36,"n_total_lines":1208,"dependency_fraction":0.029801324503311258},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/JKAMP","total_profiled":1310},"omim":[{"mim_id":"621533","title":"NEURODEVELOPMENTAL DISORDER WITH SEIZURES AND IMPAIRED INTELLECTUAL AND LANGUAGE DEVELOPMENT; NEDSIL","url":"https://www.omim.org/entry/621533"},{"mim_id":"611176","title":"JNK/MAPK8-ASSOCIATED MEMBRANE PROTEIN; JKAMP","url":"https://www.omim.org/entry/611176"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/JKAMP"},"hgnc":{"alias_symbol":["HSPC213","JAMP","HSPC327","CDA06"],"prev_symbol":["C14orf100"]},"alphafold":{"accession":"Q9P055","domains":[{"cath_id":"-","chopping":"13-295","consensus_level":"medium","plddt":88.5396,"start":13,"end":295}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P055","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P055-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P055-F1-predicted_aligned_error_v6.png","plddt_mean":86.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JKAMP","jax_strain_url":"https://www.jax.org/strain/search?query=JKAMP"},"sequence":{"accession":"Q9P055","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P055.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P055/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P055"}},"corpus_meta":[{"pmid":"29666773","id":"PMC_29666773","title":"Estimating intraspecific genetic diversity from community DNA metabarcoding data.","date":"2018","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/29666773","citation_count":70,"is_preprint":false},{"pmid":"34124627","id":"PMC_34124627","title":"New and Interesting Fungi. 4.","date":"2021","source":"Fungal systematics and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/34124627","citation_count":60,"is_preprint":false},{"pmid":"19269966","id":"PMC_19269966","title":"Regulation of endoplasmic reticulum-associated degradation by RNF5-dependent ubiquitination of JNK-associated membrane protein (JAMP).","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19269966","citation_count":54,"is_preprint":false},{"pmid":"12800201","id":"PMC_12800201","title":"Novel tumor antigens identified by autologous antibody screening of childhood medulloblastoma cDNA libraries.","date":"2003","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12800201","citation_count":46,"is_preprint":false},{"pmid":"23798571","id":"PMC_23798571","title":"Novel, gel-free proteomics approach identifies RNF5 and JAMP as modulators of GPCR stability.","date":"2013","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/23798571","citation_count":30,"is_preprint":false},{"pmid":"16166642","id":"PMC_16166642","title":"JAMP, a Jun N-terminal kinase 1 (JNK1)-associated membrane protein, regulates duration of JNK activity.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16166642","citation_count":22,"is_preprint":false},{"pmid":"33579371","id":"PMC_33579371","title":"JKAMP inhibits the osteogenic capacity of adipose-derived stem cells in diabetic osteoporosis by modulating the Wnt signaling pathway through intragenic DNA methylation.","date":"2021","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33579371","citation_count":21,"is_preprint":false},{"pmid":"24967253","id":"PMC_24967253","title":"A nutrition education intervention to combat undernutrition: experience from a developing country.","date":"2013","source":"ISRN nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/24967253","citation_count":16,"is_preprint":false},{"pmid":"18784250","id":"PMC_18784250","title":"JAMP optimizes ERAD to protect cells from unfolded proteins.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18784250","citation_count":14,"is_preprint":false},{"pmid":"15309011","id":"PMC_15309011","title":"Is angiotensin-converting enzyme inhibitor useful in a Japanese population for secondary prevention after acute myocardial infarction? A final report of the Japanese Acute Myocardial Infarction Prospective (JAMP) study.","date":"2004","source":"American heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/15309011","citation_count":11,"is_preprint":false},{"pmid":"40171194","id":"PMC_40171194","title":"Identification and validation of endoplasmic reticulum stress-related diagnostic biomarkers for type 1 diabetic cardiomyopathy based on bioinformatics and machine learning.","date":"2025","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/40171194","citation_count":3,"is_preprint":false},{"pmid":"41643666","id":"PMC_41643666","title":"Bi-allelic loss-of-function variants in JKAMP cause a neurodevelopmental syndrome associated with dysregulation of GPR37 trafficking.","date":"2026","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41643666","citation_count":0,"is_preprint":false},{"pmid":"41392613","id":"PMC_41392613","title":"TTC7B Activates the AKT-JKAMP Signaling Axis to Promote Tumor Progression in Head and Neck Cancer.","date":"2025","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/41392613","citation_count":0,"is_preprint":false},{"pmid":"42048322","id":"PMC_42048322","title":"Cytotoxicity in vitro assay in 3D vs. 2D L929 cell cultures - comparative analysis of the response to the latex extracts.","date":"2026","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/42048322","citation_count":0,"is_preprint":false},{"pmid":"41798178","id":"PMC_41798178","title":"Assessing fish diversity in small streams and ponds of the Peruvian Amazon using environmental DNA metabarcoding.","date":"2026","source":"ZooKeys","url":"https://pubmed.ncbi.nlm.nih.gov/41798178","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11216,"output_tokens":2447,"usd":0.035176,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9593,"output_tokens":2898,"usd":0.060207,"stage2_stop_reason":"end_turn"},"total_usd":0.095383,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"JAMP (JKAMP) is a predicted seven-transmembrane protein localized primarily within the plasma membrane that associates with JNK1 through its C-terminal domain. This association outcompetes JNK1 binding to MAP kinase phosphatase 5 (MKP5), resulting in increased and prolonged JNK1 activity following stress stimuli (UV or tunicamycin). Elevated JAMP expression sustains JNK activity and increases JNK-dependent apoptosis, while RNAi-mediated JAMP knockdown reduces JNK activation duration and stress-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference knockdown, overexpression, domain mapping (C-terminal domain), competitive binding assay with MKP5\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, RNAi knockdown with specific phenotypic readout, and overexpression assays in a single focused study\",\n      \"pmids\": [\"16166642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"JAMP (JKAMP) is an ER-resident seven-transmembrane protein that functions as a scaffold linking ER chaperones, channel proteins, ubiquitin ligases, and 26S proteasome subunits to optimize ERAD. Elevated JAMP expression promotes localization of proteasomes at the ER and enhances degradation of specific misfolded ER-resident proteins, while JAMP inhibition has the opposite effect. C. elegans jamp-1 deletion causes hypersensitivity to ER stress and increased UPR, establishing its role via genetic loss-of-function.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, overexpression and inhibition (loss-of-function), C. elegans jamp-1 deletion genetic model, UPR assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical, genetic in vivo model, proteasome localization assay) in a single focused study replicated across model systems\",\n      \"pmids\": [\"18784250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RNF5, a ubiquitin ligase anchored to the ER membrane, associates with JAMP in the ER membrane and mediates Ubc13-dependent non-canonical (K63-linked) ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but inhibits JAMP's association with proteasome subunit Rpt5 and p97, thereby reducing ERAD efficiency and causing greater accumulation of misfolded proteins (CFTRΔ508 and TCRα). RNF5 thus limits ERAD and proteasome assembly at the ER both before and after ER stress response.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, E2 enzyme (Ubc13) identification, misfolded protein degradation assay (CFTRΔ508, TCRα), RNF5 overexpression and knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro ubiquitination assay identifying E2 enzyme, Co-IP, functional ERAD substrate degradation assays, multiple orthogonal methods in single focused study\",\n      \"pmids\": [\"19269966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JAMP (JKAMP) interacts with G protein-coupled receptors (β2-adrenergic receptor and prostaglandin D2 receptor DP) and decreases total receptor protein levels through proteasomal degradation. Expression of DP promotes proteasome recruitment by JAMP. RNF5 ubiquitinates JAMP to prevent proteasome recruitment, thereby protecting GPCRs from JAMP-mediated proteasomal degradation. Depletion of RNF5 increases degradation of both receptors via JAMP.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, confocal microscopy colocalization, proteasome inhibitor assays, gel-free proteomics\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown, overexpression with defined proteasomal degradation phenotype, and confocal colocalization in single focused study\",\n      \"pmids\": [\"23798571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JKAMP promotes osteogenic differentiation in adipose-derived stem cells by modulating the Wnt signaling pathway. JKAMP silencing inhibits Wnt signaling and reduces osteogenic ability (assessed by RUNX2, OPN expression, Alizarin red and ALP staining), while JKAMP overexpression in diabetic osteoporosis-derived ASCs rescues impaired osteogenic capacity. Intragenic DNA hypermethylation in DOP-ASCs suppresses JKAMP expression, linking epigenetic regulation to JKAMP function.\",\n      \"method\": \"siRNA knockdown, overexpression plasmid, immunofluorescence, qPCR, western blotting, Alizarin red staining, ALP staining, bisulfite-specific PCR (BSP) for methylation, MeDIP sequencing\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown and overexpression with defined osteogenic phenotype readouts, multiple methods in single lab study, no independent replication\",\n      \"pmids\": [\"33579371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Bi-allelic loss-of-function variants in JKAMP cause a neurodevelopmental syndrome. JKAMP loss results in defective folding and degradation of GPR37 (a brain-enriched orphan GPCR and known JKAMP interactor), leading to GPR37 accumulation within the ER and impaired trafficking to the plasma membrane, likely due to impaired ER quality control. A zebrafish jkamp knockout model recapitulated developmental abnormalities and impaired myelin production.\",\n      \"method\": \"Human genetic analysis (bi-allelic variants in 14 patients from 10 families), zebrafish jkamp knockout model, mechanistic studies of GPR37 folding/degradation and subcellular localization (ER accumulation, plasma membrane trafficking assay)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics combined with in vivo zebrafish KO model and cellular mechanistic studies of GPR37 trafficking, multiple orthogonal methods across multiple families\",\n      \"pmids\": [\"41643666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TTC7B activates AKT signaling to upregulate JKAMP expression, and JKAMP is required downstream of TTC7B-AKT signaling to promote head and neck cancer cell migration and invasion. Pharmacological AKT inhibition abolishes TTC7B-induced JKAMP upregulation and suppresses migration/invasion; IGF-1-mediated AKT activation restores JKAMP expression in TTC7B-knockdown cells. JKAMP silencing in TTC7B-overexpressing cells markedly reduces migration and invasion, placing JKAMP downstream of the TTC7B-AKT axis.\",\n      \"method\": \"In vitro migration and invasion assays, TTC7B overexpression and knockdown, JKAMP siRNA knockdown, pharmacological AKT inhibition, IGF-1 stimulation, western blotting for phospho-AKT and JKAMP\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by pharmacological inhibition and rescue experiments, multiple functional assays, single lab study\",\n      \"pmids\": [\"41392613\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JKAMP (JAMP) is an ER-resident seven-transmembrane scaffold protein that optimizes ERAD by linking ER chaperones, channel proteins, ubiquitin ligases, and 26S proteasome subunits, thereby recruiting proteasomes to the ER membrane to degrade misfolded proteins (including CFTRΔ508, TCRα, and GPR37); its activity is negatively regulated by RNF5-mediated Ubc13-dependent non-canonical ubiquitination, which prevents its association with Rpt5 and p97; outside the ER, JKAMP associates with JNK1 via its C-terminal domain to outcompete MKP5 and sustain JNK1 signaling and apoptosis in response to stress; JKAMP expression is upregulated by the TTC7B-AKT axis to promote cancer cell migration and invasion; and bi-allelic loss-of-function variants in humans cause a neurodevelopmental syndrome linked to defective GPR37 trafficking from the ER to the plasma membrane.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JKAMP (JAMP) is a seven-transmembrane protein that functions principally as an endoplasmic reticulum-associated degradation (ERAD) scaffold, coupling protein quality control at the ER membrane to proteasomal degradation of misfolded substrates [#1]. At the ER it bridges chaperones, channel proteins, ubiquitin ligases, and 26S proteasome subunits, recruiting proteasomes to the ER membrane to optimize the disposal of specific misfolded ER-resident proteins; loss of the C. elegans ortholog jamp-1 sensitizes animals to ER stress and elevates the unfolded protein response [#1]. JKAMP's degradative activity is restrained by the ER-anchored ubiquitin ligase RNF5, which directs Ubc13-dependent K63-linked non-canonical ubiquitination of JKAMP; this modification does not affect JKAMP stability but blocks its association with the proteasomal ATPase Rpt5 and with p97, thereby limiting ERAD and causing accumulation of substrates such as CFTRΔ508 and TCRα [#2]. Through this scaffolding activity JKAMP also controls the abundance of G protein-coupled receptors, promoting proteasomal degradation of the β2-adrenergic receptor and the prostaglandin D2 receptor DP, with RNF5-mediated ubiquitination protecting these receptors from JKAMP-driven turnover [#3]. Bi-allelic loss-of-function variants in JKAMP cause a neurodevelopmental syndrome in which defective folding and degradation of the brain-enriched orphan GPCR GPR37 leads to its ER accumulation and impaired plasma-membrane trafficking, with a zebrafish knockout recapitulating developmental abnormalities and impaired myelin production [#5]. Independently of its ER role, JKAMP binds JNK1 through its C-terminal domain, outcompeting MAP kinase phosphatase MKP5 to sustain JNK1 activity and JNK-dependent apoptosis after UV or tunicamycin stress [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the first molecular function for JKAMP by showing it modulates stress signaling rather than acting as an inert membrane protein, binding JNK1 to prolong its activity.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mapping, RNAi knockdown, and competitive binding against MKP5 with apoptosis readouts in mammalian cells\",\n      \"pmids\": [\"16166642\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Localization assigned to plasma membrane here, later revised to ER\", \"Structural basis of the JNK1/MKP5 competition not resolved\", \"Physiological contexts where this axis dominates over the ERAD role unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reframed JKAMP as an ER-resident ERAD scaffold that recruits proteasomes to the ER membrane, answering where and how it acts in protein quality control.\",\n      \"evidence\": \"Biochemical fractionation, Co-IP, proteasome localization assays, and C. elegans jamp-1 deletion with UPR readouts\",\n      \"pmids\": [\"18784250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific misfolded substrates incompletely enumerated\", \"Stoichiometry and architecture of the chaperone-ligase-proteasome assembly unknown\", \"How the same protein partitions between ER and JNK-signaling functions not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the negative regulatory switch on JKAMP, showing RNF5/Ubc13-mediated K63 ubiquitination blocks proteasome and p97 recruitment without degrading JKAMP.\",\n      \"evidence\": \"In vitro ubiquitination with E2 (Ubc13) identification, Co-IP, and CFTRΔ508/TCRα degradation assays with RNF5 manipulation\",\n      \"pmids\": [\"19269966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitination sites on JKAMP not mapped\", \"Signals controlling RNF5 activity toward JKAMP unknown\", \"Deubiquitinase reversing this mark not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended JKAMP substrate scope to GPCRs, showing it drives proteasomal turnover of β2-adrenergic and DP receptors under RNF5 control.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA, confocal colocalization, proteasome inhibitor assays, and proteomics in mammalian cells\",\n      \"pmids\": [\"23798571\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity rules distinguishing degraded vs spared GPCRs unclear\", \"Whether JKAMP acts on folded vs misfolded receptor pools not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked JKAMP to osteogenic differentiation and Wnt signaling, with epigenetic silencing connecting its expression to a disease state.\",\n      \"evidence\": \"siRNA and overexpression with osteogenic markers, staining assays, and methylation profiling (BSP, MeDIP-seq) in adipose-derived stem cells\",\n      \"pmids\": [\"33579371\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between ERAD scaffolding and Wnt output not established\", \"No independent replication\", \"Direct Wnt-component interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed JKAMP downstream of a TTC7B-AKT axis driving cancer cell migration and invasion.\",\n      \"evidence\": \"Migration/invasion assays, TTC7B and JKAMP manipulation, AKT inhibition, and IGF-1 rescue with phospho-AKT/JKAMP blots\",\n      \"pmids\": [\"41392613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How AKT signaling controls JKAMP transcription not defined\", \"Whether the pro-invasive effect requires JKAMP's ERAD function unknown\", \"Single-lab study without in vivo confirmation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated human disease causation, tying JKAMP loss to a neurodevelopmental syndrome via failed GPR37 quality control.\",\n      \"evidence\": \"Bi-allelic variants across 10 families, zebrafish jkamp knockout, and GPR37 folding/trafficking assays showing ER accumulation\",\n      \"pmids\": [\"41643666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GPR37 mishandling alone accounts for the full phenotype unclear\", \"Mechanism connecting JKAMP loss to myelin defects not detailed\", \"Genotype-phenotype correlation across variants not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How JKAMP partitions between its ER ERAD scaffold role and its cytoplasmic JNK1-signaling role, and what determines substrate selection, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the 7TM scaffold or its complexes\", \"Regulatory logic switching between functions unknown\", \"Comprehensive substrate repertoire undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"JNK1\", \"MKP5\", \"RNF5\", \"Rpt5\", \"p97\", \"GPR37\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}