{"gene":"JAKMIP1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2004,"finding":"Marlin-1 (JAKMIP1) associates specifically with the GABA(B)R1 subunit in yeast two-hybrid, tissue culture cells, and neurons, and binds the 3'-UTRs of both GABA(B)R1 and GABA(B)R2 mRNAs in vitro and in cultured neurons. siRNA-mediated knockdown of Marlin-1 results in enhanced intracellular levels of GABA(B)R2 protein without affecting GABA(B)R1 levels, indicating Marlin-1 regulates GABA(B)R2 subunit cellular levels.","method":"Yeast two-hybrid, co-immunoprecipitation, RNA binding assay (in vitro, 3'-UTR), siRNA knockdown with Western blot readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding shown in multiple systems (yeast, tissue culture, neurons), RNA binding confirmed in vitro and in cells, functional consequence demonstrated by siRNA knockdown","pmids":["14718537"],"is_preprint":false},{"year":2004,"finding":"JAKMIP1 (Jamip1/Marlin-1) binds the FERM homology domain of Tyk2 (a JAK family kinase) via its C-terminal region, also associates with Jak1 in Jurkat T cells, and its N-terminal region targets the protein to microtubule polymers; overexpression in fibroblasts induces formation of tight, stable microtubule bundles.","method":"Co-immunoprecipitation in Jurkat T cells, overexpression in fibroblasts with immunofluorescence microscopy, domain mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for JAK interaction, functional microtubule bundling phenotype shown in fibroblasts, domain mapping for both interactions, single lab","pmids":["15277531"],"is_preprint":false},{"year":2007,"finding":"Marlin-1 (JAKMIP1) is associated with microtubules and the molecular motor kinesin-I in neurons. A fraction of Marlin-1 is mobile in dendrites of hippocampal neurons in a microtubule-dependent manner. GABA(B) receptors interact with kinesin-I, and disruption of the Marlin-1/kinesin-I/tubulin protein complex impairs intracellular membrane transport of GABA(B) receptors; a kinesin-I dominant-negative mutant severely impairs receptor transport.","method":"Biochemical fractionation, co-immunoprecipitation, live cell imaging (FRAP), dominant-negative kinesin-I overexpression, pharmacological microtubule disruption","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, live imaging, dominant-negative mutant, biochemical disruption) in same study; functional consequence on receptor transport clearly demonstrated","pmids":["17532644"],"is_preprint":false},{"year":2008,"finding":"JAKMIP1 (Marlin-1) is expressed in testis (spermatogonia, spermatocytes, spermatozoa, Sertoli cells) and in spermatozoa it localizes predominantly to the tail. In testis, Marlin-1 associates with a microtubule fraction and with GABA(B) receptors, indicating these interactions are conserved outside the brain.","method":"Immunohistochemistry, immunofluorescence, biochemical fractionation (microtubule co-sedimentation), co-immunoprecipitation","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and fractionation confirm interactions in a new tissue context, single lab, no functional loss-of-function data","pmids":["17668444"],"is_preprint":false},{"year":2008,"finding":"Jakmip1 restrains T cell-mediated cytotoxicity: siRNA knockdown of Jakmip1 in primary CD8+ T cells enhances cytotoxic killing, whereas transduction of full-length Jakmip1 or its N-terminal region suppresses cytotoxicity.","method":"siRNA knockdown in primary human CD8+ T cells, lentiviral transduction of full-length or N-terminal domain constructs, cytotoxicity assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD and OE) in primary cells with defined functional readout, single lab","pmids":["18941173"],"is_preprint":false},{"year":2009,"finding":"Marlin-1 (JAKMIP1) in the rodent brain localizes to dendrites and axons of both GABAergic and non-GABAergic hippocampal neurons; at the ultrastructural level it associates with microtubules in dendritic shafts and occasionally with the Golgi apparatus, endoplasmic reticulum, and dendritic spines, and nuclear clusters associate with euchromatin.","method":"Immunohistochemistry, immunofluorescence, pre-embedding electron microscopy","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ultrastructural localization by electron microscopy confirms microtubule association in neurons in vivo, single lab, no functional loss-of-function in this paper","pmids":["19386132"],"is_preprint":false},{"year":2012,"finding":"RNA interference of Marlin-1/Jakmip1 in cortical neurons disrupts Golgi apparatus integrity, down-regulates kinesin-1 levels, and impairs neurite morphogenesis in vitro. In vivo RNAi causes abnormal migration of newborn pyramidal neurons during cortical layering.","method":"In vitro siRNA in cultured neurons (immunofluorescence for Golgi, Western blot for kinesin-1), in utero electroporation RNAi for cortical migration assay","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo loss-of-function with specific molecular (Golgi disruption, kinesin-1 downregulation) and cellular (migration) phenotypes, multiple orthogonal readouts","pmids":["22828129"],"is_preprint":false},{"year":2015,"finding":"JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes FMRP (fragile X mental retardation protein), DDX5 (DEAD box helicase 5), and PABPC1 (poly(A) binding protein cytoplasmic 1). JAKMIP1 loss dysregulates neuronal mRNA translation during synaptic development and impairs glutamatergic NMDA receptor signaling.","method":"Polyribosome fractionation, co-immunoprecipitation/mass spectrometry of RNP complex, JAKMIP1 knockout mouse with electrophysiology (NMDAR signaling), behavioral assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — polyribosome fractionation + RNP complex purification with MS + KO mouse with multiple orthogonal readouts (electrophysiology, translation dysregulation, behavior), multiple methods in one rigorous study","pmids":["26627310"],"is_preprint":false},{"year":2025,"finding":"JAKMIP1 deficiency impairs IL-6/STAT3 signaling and IL-6-induced neuritogenesis in SH-SY5Y cells. The C-terminus of JAKMIP1 exhibits nucleoplasmic localization and may regulate STAT3 expression.","method":"siRNA knockdown in SH-SY5Y cells, IL-6 stimulation with STAT3 signaling readout, fluorescence microscopy for C-terminal domain localization","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single cell line, limited mechanistic detail in abstract, STAT3 regulation by C-terminus described as putative","pmids":["bio_10.1101_2025.10.21.683757"],"is_preprint":true}],"current_model":"JAKMIP1 (Marlin-1) is a multifunctional scaffold protein that (1) binds GABA(B)R1 and regulates GABA(B)R2 protein levels via RNA binding and post-transcriptional control, (2) tethers GABA(B) receptors to microtubules and kinesin-I motors to enable dendritic receptor transport, (3) associates with JAK family kinases (Tyk2, Jak1) through its C-terminal region while targeting microtubule polymers through its N-terminal region, (4) forms part of a polyribosome-associated RNP translational regulatory complex (with FMRP, DDX5, and PABPC1) that controls neuronal mRNA translation during synaptic development and is required for normal NMDA receptor signaling, and (5) restrains T cell cytotoxicity and modulates neuronal IL-6/STAT3 signaling; loss of JAKMIP1 disrupts Golgi integrity, downregulates kinesin-1, impairs cortical neuron migration in vivo, and produces autistic-like behaviors in mice."},"narrative":{"mechanistic_narrative":"JAKMIP1 (Marlin-1) is a microtubule-associated scaffold protein that couples GABA(B) receptor biology to cytoskeletal transport and post-transcriptional control in neurons [PMID:14718537, PMID:17532644]. It associates specifically with the GABA(B)R1 subunit and binds the 3'-UTRs of both GABA(B)R1 and GABA(B)R2 mRNAs, restraining intracellular GABA(B)R2 protein levels [PMID:14718537]. Through its N-terminal region it targets microtubule polymers and bundles them, while its C-terminal region binds the FERM domain of the JAK kinase Tyk2 and associates with Jak1 [PMID:15277531]. JAKMIP1 bridges GABA(B) receptors to microtubules and the kinesin-I motor, and disruption of this complex impairs dendritic membrane transport of the receptors [PMID:17532644]. Beyond receptor trafficking, JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex containing FMRP, DDX5, and PABPC1; its loss dysregulates neuronal mRNA translation during synaptic development and impairs glutamatergic NMDA receptor signaling [PMID:26627310]. Loss-of-function disrupts Golgi integrity, downregulates kinesin-1, impairs neurite morphogenesis, and causes abnormal migration of newborn cortical pyramidal neurons in vivo [PMID:22828129]. JAKMIP1 also functions outside the nervous system, where it restrains CD8+ T cell-mediated cytotoxicity [PMID:18941173].","teleology":[{"year":2004,"claim":"Established JAKMIP1's founding link to neurotransmission by identifying it as a GABA(B)R1-binding partner that also binds GABA(B) receptor mRNAs and controls receptor subunit levels.","evidence":"Yeast two-hybrid, co-IP across yeast/cells/neurons, 3'-UTR RNA binding, and siRNA knockdown with Western readout","pmids":["14718537"],"confidence":"High","gaps":["RNA-binding motif/domain in JAKMIP1 not mapped","mechanism by which mRNA binding limits GABA(B)R2 protein not resolved (stability vs. translation)"]},{"year":2004,"claim":"Defined JAKMIP1's bipartite architecture, linking a C-terminal JAK-kinase interaction (Tyk2 FERM domain, Jak1) to an N-terminal microtubule-targeting/bundling activity.","evidence":"Co-IP in Jurkat T cells, fibroblast overexpression with immunofluorescence, domain mapping","pmids":["15277531"],"confidence":"Medium","gaps":["functional consequence of JAK binding not established","microtubule bundling shown only on overexpression in fibroblasts"]},{"year":2007,"claim":"Showed that JAKMIP1 acts as a transport adaptor by tethering GABA(B) receptors to microtubules and kinesin-I for dendritic trafficking.","evidence":"Biochemical fractionation, co-IP, FRAP live imaging, dominant-negative kinesin-I, microtubule disruption","pmids":["17532644"],"confidence":"High","gaps":["directionality and cargo specificity of transport not fully defined","whether RNA-binding and transport functions are coupled is unaddressed"]},{"year":2008,"claim":"Extended JAKMIP1's GABA(B)/microtubule associations beyond brain by demonstrating them in testis and spermatozoa.","evidence":"Immunohistochemistry, immunofluorescence, microtubule co-sedimentation, co-IP in testis","pmids":["17668444"],"confidence":"Medium","gaps":["no loss-of-function data in germ cells","functional role in spermatogenesis or sperm motility untested"]},{"year":2008,"claim":"Revealed a non-neuronal immunological function, identifying JAKMIP1 as a negative regulator of CD8+ T cell cytotoxicity.","evidence":"siRNA knockdown and lentiviral overexpression of full-length/N-terminal constructs in primary human CD8+ T cells with cytotoxicity assay","pmids":["18941173"],"confidence":"Medium","gaps":["molecular mechanism linking JAKMIP1 to cytotoxic effector pathways unknown","relationship to JAK-kinase binding not tested"]},{"year":2009,"claim":"Provided ultrastructural confirmation of JAKMIP1's microtubule association in neurons in vivo and noted minor Golgi, ER, spine, and euchromatin distribution.","evidence":"Immunohistochemistry, immunofluorescence, pre-embedding electron microscopy in rodent brain","pmids":["19386132"],"confidence":"Medium","gaps":["functional significance of nuclear/euchromatin pool not established","single-lab descriptive localization without perturbation"]},{"year":2012,"claim":"Demonstrated that JAKMIP1 is required for neuronal cytoskeletal/secretory integrity and cortical development through in vitro and in vivo loss-of-function.","evidence":"siRNA in cultured cortical neurons (Golgi, kinesin-1, neurite readouts), in utero electroporation RNAi for migration","pmids":["22828129"],"confidence":"High","gaps":["mechanism connecting JAKMIP1 loss to kinesin-1 downregulation unresolved","whether Golgi disruption is cause or consequence of migration defect unclear"]},{"year":2015,"claim":"Placed JAKMIP1 in a polyribosome-associated RNP translational regulatory complex with FMRP/DDX5/PABPC1 and linked its loss to dysregulated synaptic translation and NMDAR signaling.","evidence":"Polyribosome fractionation, RNP complex co-IP/mass spectrometry, knockout mouse with electrophysiology and behavioral assays","pmids":["26627310"],"confidence":"High","gaps":["specific mRNA targets translationally controlled by JAKMIP1 not enumerated","how RNP function integrates with microtubule/transport roles unresolved"]},{"year":2025,"claim":"Proposed a role in IL-6/STAT3 signaling and neuritogenesis, with a putative nucleoplasmic C-terminal contribution to STAT3 regulation.","evidence":"siRNA knockdown in SH-SY5Y cells with IL-6/STAT3 readout and fluorescence microscopy (preprint)","pmids":["bio_10.1101_2025.10.21.683757"],"confidence":"Low","gaps":["preprint, single cell line","STAT3 regulation by C-terminus described as putative","mechanistic link to JAK-kinase binding not established"]},{"year":null,"claim":"How JAKMIP1's distinct activities — RNA binding/translational control, microtubule/kinesin-based transport, and JAK-kinase association — are mechanistically integrated within a single neuron remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no structural model relating the N-terminal microtubule and C-terminal JAK-binding regions to RNA-binding function","direct mRNA targets of the JAKMIP1 RNP complex undefined","whether JAK-kinase binding modulates any of the neuronal phenotypes is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,7]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6]}],"complexes":["polyribosome-associated RNP translational regulatory complex (FMRP/DDX5/PABPC1)","Marlin-1/kinesin-I/tubulin transport complex"],"partners":["GABBR1","GABBR2","TYK2","JAK1","FMR1","DDX5","PABPC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96N16","full_name":"Janus kinase and microtubule-interacting protein 1","aliases":["GABA-B receptor-binding protein","Multiple alpha-helices and RNA-linker protein 1","Marlin-1"],"length_aa":626,"mass_kda":73.2,"function":"Associates with microtubules and may play a role in the microtubule-dependent transport of the GABA-B receptor. May play a role in JAK1 signaling and regulate microtubule cytoskeleton rearrangements","subcellular_location":"Cytoplasm, cytoskeleton; Membrane","url":"https://www.uniprot.org/uniprotkb/Q96N16/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JAKMIP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CLASP2","stoichiometry":4.0},{"gene":"CLASP1","stoichiometry":0.2},{"gene":"MARK2","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JAKMIP1","total_profiled":1310},"omim":[{"mim_id":"611198","title":"JANUS KINASE AND MICROTUBULE-INTERACTING PROTEIN 3; JAKMIP3","url":"https://www.omim.org/entry/611198"},{"mim_id":"611197","title":"JANUS KINASE AND MICROTUBULE-INTERACTING PROTEIN 2; JAKMIP2","url":"https://www.omim.org/entry/611197"},{"mim_id":"611195","title":"JANUS KINASE AND MICROTUBULE-INTERACTING PROTEIN 1; JAKMIP1","url":"https://www.omim.org/entry/611195"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":70.0}],"url":"https://www.proteinatlas.org/search/JAKMIP1"},"hgnc":{"alias_symbol":["MARLIN1","JAMIP1","Gababrbp","FLJ31564"],"prev_symbol":[]},"alphafold":{"accession":"Q96N16","domains":[{"cath_id":"1.20.5","chopping":"26-124","consensus_level":"medium","plddt":94.2199,"start":26,"end":124}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96N16","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96N16-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96N16-F1-predicted_aligned_error_v6.png","plddt_mean":81.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JAKMIP1","jax_strain_url":"https://www.jax.org/strain/search?query=JAKMIP1"},"sequence":{"accession":"Q96N16","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96N16.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96N16/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96N16"}},"corpus_meta":[{"pmid":"14718537","id":"PMC_14718537","title":"Marlin-1, a novel RNA-binding protein associates with GABA receptors.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14718537","citation_count":48,"is_preprint":false},{"pmid":"15277531","id":"PMC_15277531","title":"Jamip1 (marlin-1) defines a family of proteins interacting with janus kinases and microtubules.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15277531","citation_count":40,"is_preprint":false},{"pmid":"26627310","id":"PMC_26627310","title":"JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse.","date":"2015","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/26627310","citation_count":35,"is_preprint":false},{"pmid":"17532644","id":"PMC_17532644","title":"Marlin-1 and conventional kinesin link GABAB receptors to the cytoskeleton and regulate receptor transport.","date":"2007","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/17532644","citation_count":28,"is_preprint":false},{"pmid":"17761393","id":"PMC_17761393","title":"Identification and expression analysis of novel Jakmip1 transcripts.","date":"2007","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/17761393","citation_count":16,"is_preprint":false},{"pmid":"18941173","id":"PMC_18941173","title":"Jakmip1 is expressed upon T cell differentiation and has an inhibitory function in cytotoxic T lymphocytes.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18941173","citation_count":15,"is_preprint":false},{"pmid":"23481296","id":"PMC_23481296","title":"Overexpression of JAKMIP1 associates with Wnt/β-catenin pathway activation and promotes cancer cell proliferation in vitro.","date":"2013","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/23481296","citation_count":12,"is_preprint":false},{"pmid":"17668444","id":"PMC_17668444","title":"Marlin-1 is expressed in testis and associates to the cytoskeleton and GABAB receptors.","date":"2008","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17668444","citation_count":9,"is_preprint":false},{"pmid":"19386132","id":"PMC_19386132","title":"Cellular and subcellular localization of Marlin-1 in the brain.","date":"2009","source":"BMC neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19386132","citation_count":8,"is_preprint":false},{"pmid":"22828129","id":"PMC_22828129","title":"RNA interference of Marlin-1/Jakmip1 results in abnormal morphogenesis and migration of cortical pyramidal neurons.","date":"2012","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/22828129","citation_count":5,"is_preprint":false},{"pmid":"26687214","id":"PMC_26687214","title":"JAKMIP1: Translating the Message for Social Behavior.","date":"2015","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/26687214","citation_count":4,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.21.683757","title":"Exploring the functions of JAKMIP1 in neuronal IL-6/STAT3 signaling and its relevance to chromosome 15q-duplication syndrome","date":"2025-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.21.683757","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.23.684145","title":"Sleeping ORANGE: A CRISPR-Transposase Hybrid Approach to Boost Endogenous Protein Tagging Efficiency","date":"2025-10-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.23.684145","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7748,"output_tokens":2651,"usd":0.031504,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9818,"output_tokens":3436,"usd":0.067495,"stage2_stop_reason":"end_turn"},"total_usd":0.098999,"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\": 2004,\n      \"finding\": \"Marlin-1 (JAKMIP1) associates specifically with the GABA(B)R1 subunit in yeast two-hybrid, tissue culture cells, and neurons, and binds the 3'-UTRs of both GABA(B)R1 and GABA(B)R2 mRNAs in vitro and in cultured neurons. siRNA-mediated knockdown of Marlin-1 results in enhanced intracellular levels of GABA(B)R2 protein without affecting GABA(B)R1 levels, indicating Marlin-1 regulates GABA(B)R2 subunit cellular levels.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, RNA binding assay (in vitro, 3'-UTR), siRNA knockdown with Western blot readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding shown in multiple systems (yeast, tissue culture, neurons), RNA binding confirmed in vitro and in cells, functional consequence demonstrated by siRNA knockdown\",\n      \"pmids\": [\"14718537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"JAKMIP1 (Jamip1/Marlin-1) binds the FERM homology domain of Tyk2 (a JAK family kinase) via its C-terminal region, also associates with Jak1 in Jurkat T cells, and its N-terminal region targets the protein to microtubule polymers; overexpression in fibroblasts induces formation of tight, stable microtubule bundles.\",\n      \"method\": \"Co-immunoprecipitation in Jurkat T cells, overexpression in fibroblasts with immunofluorescence microscopy, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for JAK interaction, functional microtubule bundling phenotype shown in fibroblasts, domain mapping for both interactions, single lab\",\n      \"pmids\": [\"15277531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Marlin-1 (JAKMIP1) is associated with microtubules and the molecular motor kinesin-I in neurons. A fraction of Marlin-1 is mobile in dendrites of hippocampal neurons in a microtubule-dependent manner. GABA(B) receptors interact with kinesin-I, and disruption of the Marlin-1/kinesin-I/tubulin protein complex impairs intracellular membrane transport of GABA(B) receptors; a kinesin-I dominant-negative mutant severely impairs receptor transport.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, live cell imaging (FRAP), dominant-negative kinesin-I overexpression, pharmacological microtubule disruption\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, live imaging, dominant-negative mutant, biochemical disruption) in same study; functional consequence on receptor transport clearly demonstrated\",\n      \"pmids\": [\"17532644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"JAKMIP1 (Marlin-1) is expressed in testis (spermatogonia, spermatocytes, spermatozoa, Sertoli cells) and in spermatozoa it localizes predominantly to the tail. In testis, Marlin-1 associates with a microtubule fraction and with GABA(B) receptors, indicating these interactions are conserved outside the brain.\",\n      \"method\": \"Immunohistochemistry, immunofluorescence, biochemical fractionation (microtubule co-sedimentation), co-immunoprecipitation\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and fractionation confirm interactions in a new tissue context, single lab, no functional loss-of-function data\",\n      \"pmids\": [\"17668444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Jakmip1 restrains T cell-mediated cytotoxicity: siRNA knockdown of Jakmip1 in primary CD8+ T cells enhances cytotoxic killing, whereas transduction of full-length Jakmip1 or its N-terminal region suppresses cytotoxicity.\",\n      \"method\": \"siRNA knockdown in primary human CD8+ T cells, lentiviral transduction of full-length or N-terminal domain constructs, cytotoxicity assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD and OE) in primary cells with defined functional readout, single lab\",\n      \"pmids\": [\"18941173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Marlin-1 (JAKMIP1) in the rodent brain localizes to dendrites and axons of both GABAergic and non-GABAergic hippocampal neurons; at the ultrastructural level it associates with microtubules in dendritic shafts and occasionally with the Golgi apparatus, endoplasmic reticulum, and dendritic spines, and nuclear clusters associate with euchromatin.\",\n      \"method\": \"Immunohistochemistry, immunofluorescence, pre-embedding electron microscopy\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ultrastructural localization by electron microscopy confirms microtubule association in neurons in vivo, single lab, no functional loss-of-function in this paper\",\n      \"pmids\": [\"19386132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RNA interference of Marlin-1/Jakmip1 in cortical neurons disrupts Golgi apparatus integrity, down-regulates kinesin-1 levels, and impairs neurite morphogenesis in vitro. In vivo RNAi causes abnormal migration of newborn pyramidal neurons during cortical layering.\",\n      \"method\": \"In vitro siRNA in cultured neurons (immunofluorescence for Golgi, Western blot for kinesin-1), in utero electroporation RNAi for cortical migration assay\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo loss-of-function with specific molecular (Golgi disruption, kinesin-1 downregulation) and cellular (migration) phenotypes, multiple orthogonal readouts\",\n      \"pmids\": [\"22828129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes FMRP (fragile X mental retardation protein), DDX5 (DEAD box helicase 5), and PABPC1 (poly(A) binding protein cytoplasmic 1). JAKMIP1 loss dysregulates neuronal mRNA translation during synaptic development and impairs glutamatergic NMDA receptor signaling.\",\n      \"method\": \"Polyribosome fractionation, co-immunoprecipitation/mass spectrometry of RNP complex, JAKMIP1 knockout mouse with electrophysiology (NMDAR signaling), behavioral assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — polyribosome fractionation + RNP complex purification with MS + KO mouse with multiple orthogonal readouts (electrophysiology, translation dysregulation, behavior), multiple methods in one rigorous study\",\n      \"pmids\": [\"26627310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"JAKMIP1 deficiency impairs IL-6/STAT3 signaling and IL-6-induced neuritogenesis in SH-SY5Y cells. The C-terminus of JAKMIP1 exhibits nucleoplasmic localization and may regulate STAT3 expression.\",\n      \"method\": \"siRNA knockdown in SH-SY5Y cells, IL-6 stimulation with STAT3 signaling readout, fluorescence microscopy for C-terminal domain localization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single cell line, limited mechanistic detail in abstract, STAT3 regulation by C-terminus described as putative\",\n      \"pmids\": [\"bio_10.1101_2025.10.21.683757\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"JAKMIP1 (Marlin-1) is a multifunctional scaffold protein that (1) binds GABA(B)R1 and regulates GABA(B)R2 protein levels via RNA binding and post-transcriptional control, (2) tethers GABA(B) receptors to microtubules and kinesin-I motors to enable dendritic receptor transport, (3) associates with JAK family kinases (Tyk2, Jak1) through its C-terminal region while targeting microtubule polymers through its N-terminal region, (4) forms part of a polyribosome-associated RNP translational regulatory complex (with FMRP, DDX5, and PABPC1) that controls neuronal mRNA translation during synaptic development and is required for normal NMDA receptor signaling, and (5) restrains T cell cytotoxicity and modulates neuronal IL-6/STAT3 signaling; loss of JAKMIP1 disrupts Golgi integrity, downregulates kinesin-1, impairs cortical neuron migration in vivo, and produces autistic-like behaviors in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"JAKMIP1 (Marlin-1) is a microtubule-associated scaffold protein that couples GABA(B) receptor biology to cytoskeletal transport and post-transcriptional control in neurons [#0, #2]. It associates specifically with the GABA(B)R1 subunit and binds the 3'-UTRs of both GABA(B)R1 and GABA(B)R2 mRNAs, restraining intracellular GABA(B)R2 protein levels [#0]. Through its N-terminal region it targets microtubule polymers and bundles them, while its C-terminal region binds the FERM domain of the JAK kinase Tyk2 and associates with Jak1 [#1]. JAKMIP1 bridges GABA(B) receptors to microtubules and the kinesin-I motor, and disruption of this complex impairs dendritic membrane transport of the receptors [#2]. Beyond receptor trafficking, JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex containing FMRP, DDX5, and PABPC1; its loss dysregulates neuronal mRNA translation during synaptic development and impairs glutamatergic NMDA receptor signaling [#7]. Loss-of-function disrupts Golgi integrity, downregulates kinesin-1, impairs neurite morphogenesis, and causes abnormal migration of newborn cortical pyramidal neurons in vivo [#6]. JAKMIP1 also functions outside the nervous system, where it restrains CD8+ T cell-mediated cytotoxicity [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established JAKMIP1's founding link to neurotransmission by identifying it as a GABA(B)R1-binding partner that also binds GABA(B) receptor mRNAs and controls receptor subunit levels.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP across yeast/cells/neurons, 3'-UTR RNA binding, and siRNA knockdown with Western readout\",\n      \"pmids\": [\"14718537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding motif/domain in JAKMIP1 not mapped\", \"mechanism by which mRNA binding limits GABA(B)R2 protein not resolved (stability vs. translation)\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined JAKMIP1's bipartite architecture, linking a C-terminal JAK-kinase interaction (Tyk2 FERM domain, Jak1) to an N-terminal microtubule-targeting/bundling activity.\",\n      \"evidence\": \"Co-IP in Jurkat T cells, fibroblast overexpression with immunofluorescence, domain mapping\",\n      \"pmids\": [\"15277531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence of JAK binding not established\", \"microtubule bundling shown only on overexpression in fibroblasts\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that JAKMIP1 acts as a transport adaptor by tethering GABA(B) receptors to microtubules and kinesin-I for dendritic trafficking.\",\n      \"evidence\": \"Biochemical fractionation, co-IP, FRAP live imaging, dominant-negative kinesin-I, microtubule disruption\",\n      \"pmids\": [\"17532644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"directionality and cargo specificity of transport not fully defined\", \"whether RNA-binding and transport functions are coupled is unaddressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended JAKMIP1's GABA(B)/microtubule associations beyond brain by demonstrating them in testis and spermatozoa.\",\n      \"evidence\": \"Immunohistochemistry, immunofluorescence, microtubule co-sedimentation, co-IP in testis\",\n      \"pmids\": [\"17668444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no loss-of-function data in germ cells\", \"functional role in spermatogenesis or sperm motility untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a non-neuronal immunological function, identifying JAKMIP1 as a negative regulator of CD8+ T cell cytotoxicity.\",\n      \"evidence\": \"siRNA knockdown and lentiviral overexpression of full-length/N-terminal constructs in primary human CD8+ T cells with cytotoxicity assay\",\n      \"pmids\": [\"18941173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular mechanism linking JAKMIP1 to cytotoxic effector pathways unknown\", \"relationship to JAK-kinase binding not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided ultrastructural confirmation of JAKMIP1's microtubule association in neurons in vivo and noted minor Golgi, ER, spine, and euchromatin distribution.\",\n      \"evidence\": \"Immunohistochemistry, immunofluorescence, pre-embedding electron microscopy in rodent brain\",\n      \"pmids\": [\"19386132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional significance of nuclear/euchromatin pool not established\", \"single-lab descriptive localization without perturbation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that JAKMIP1 is required for neuronal cytoskeletal/secretory integrity and cortical development through in vitro and in vivo loss-of-function.\",\n      \"evidence\": \"siRNA in cultured cortical neurons (Golgi, kinesin-1, neurite readouts), in utero electroporation RNAi for migration\",\n      \"pmids\": [\"22828129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism connecting JAKMIP1 loss to kinesin-1 downregulation unresolved\", \"whether Golgi disruption is cause or consequence of migration defect unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed JAKMIP1 in a polyribosome-associated RNP translational regulatory complex with FMRP/DDX5/PABPC1 and linked its loss to dysregulated synaptic translation and NMDAR signaling.\",\n      \"evidence\": \"Polyribosome fractionation, RNP complex co-IP/mass spectrometry, knockout mouse with electrophysiology and behavioral assays\",\n      \"pmids\": [\"26627310\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"specific mRNA targets translationally controlled by JAKMIP1 not enumerated\", \"how RNP function integrates with microtubule/transport roles unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a role in IL-6/STAT3 signaling and neuritogenesis, with a putative nucleoplasmic C-terminal contribution to STAT3 regulation.\",\n      \"evidence\": \"siRNA knockdown in SH-SY5Y cells with IL-6/STAT3 readout and fluorescence microscopy (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.10.21.683757\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"preprint, single cell line\", \"STAT3 regulation by C-terminus described as putative\", \"mechanistic link to JAK-kinase binding not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How JAKMIP1's distinct activities — RNA binding/translational control, microtubule/kinesin-based transport, and JAK-kinase association — are mechanistically integrated within a single neuron remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no structural model relating the N-terminal microtubule and C-terminal JAK-binding regions to RNA-binding function\", \"direct mRNA targets of the JAKMIP1 RNP complex undefined\", \"whether JAK-kinase binding modulates any of the neuronal phenotypes is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"polyribosome-associated RNP translational regulatory complex (FMRP/DDX5/PABPC1)\",\n      \"Marlin-1/kinesin-I/tubulin transport complex\"\n    ],\n    \"partners\": [\n      \"GABBR1\",\n      \"GABBR2\",\n      \"TYK2\",\n      \"JAK1\",\n      \"FMR1\",\n      \"DDX5\",\n      \"PABPC1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}