{"gene":"PPP1R9B","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2015,"finding":"Spinophilin (PPP1R9B) loss reduces PP1a (PPP1CA) phosphatase activity against the retinoblastoma protein (pRb), thereby maintaining higher levels of phosphorylated pRb. Knockdown of PPP1R9B by shRNA increased cancer stemness properties (Sox2, KLF4, Nanog, OCT4 expression; CD44+/CD24- cells), while ectopic overexpression reduced these properties. Reduction of PPP1CA levels mimicked the cancer stem-like cell phenotype of PPP1R9B downregulation, establishing that the mechanism operates through PP1a.","method":"shRNA knockdown, ectopic overexpression, PPP1CA knockdown, flow cytometry (CD44/CD24), qRT-PCR, Western blot in breast cancer cell lines and human tumor samples","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss of function experiments with multiple readouts in a single lab, no independent replication reported in abstract","pmids":["26387546"],"is_preprint":false},{"year":2009,"finding":"PPP1R9B (neurabin 2/spinophilin) is a cytoskeletal component of NK cells that accumulates at the NK immunological synapse (NKIS) in a maturation stage-dependent manner, mimics early actin kinetics at the NKIS, is recruited by CD18 stimulation but not CD28 ligation, is required for maintenance of cortical F-actin organization, and its knockdown reduces YTS-target cell conjugation frequency due to collapsed F-actin cytoskeleton.","method":"Confocal live imaging of NKIS assembly, shRNA knockdown, CD18/CD28 stimulation assays, F-actin staining in YTS NK-like cell line","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, knockdown phenotype with mechanistic readout, single lab, single cell line","pmids":["19130477"],"is_preprint":false},{"year":2021,"finding":"A point mutation in PPP1R9B found in human tumors (SPN-A566V) disrupts both the SPN-PP1 interaction and its phosphatase activity, but does not prevent PP1-SPN holoenzyme interaction with pocket proteins pRb, p107, and p130; however, it impairs dephosphorylation of these pocket proteins during G0/G1 and G1, indicating that the PP1-SPN holoenzyme regulates cell cycle progression. SPN-A566V also promoted stemness, and cells with both SPN-A566V and mutant p53 showed increased tumorigenic and stemness properties.","method":"Mutational analysis, co-immunoprecipitation, phosphatase activity assays, cell cycle analysis, stemness assays in MCF10A, T47D, and MDA-MB-468 cell lines","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, phosphatase assay, cell cycle analysis) in single lab; mechanistic mutation characterization","pmids":["33537097"],"is_preprint":false},{"year":2024,"finding":"PP1-Neurabin (PPP1R9B) and PP1-Spinophilin holoenzymes dephosphorylate 4E-BP1 and p70 S6K translational regulators as substrates. In contrast to Phactr PIPs, substrate recruitment and catalytic efficiency of PP1-Neurabin/Spinophilin fusions is primarily determined by substrate interaction with the PDZ domain adjoining the RVxF-ΦΦ-R-W motif, rather than by remodeling of the PP1 hydrophobic substrate groove, pointing to a role in mTORC1-dependent translational control.","method":"PP1-PIP fusion protein approach, in vitro phosphatase assays, biochemical substrate identification, structural experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution and structural experiments in single preprint study, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Genetic knockout of spinophilin (PPP1R9B) in mice limited locomotor suppression caused by the D2R agonist quinpirole, and mechanistically spinophilin was required for quinpirole-induced increases in the interaction of D2R with intracellular proteins, suggesting spinophilin mediates agonist-induced D2R internalization in striatal postsynaptic dendritic spines.","method":"Spinophilin knockout mice, behavioral locomotion assay, co-immunoprecipitation/interaction proteomics following quinpirole treatment","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic KO with behavioral phenotype and interaction proteomics, single preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"Using proximity labeling (Ultra-ID) and orthogonal nanobody pulldown (ID-oPD), 614 specific spinophilin-interacting proteins were identified in HEK293 cells, many involved in mRNA processing and translation. In the brain, spinophilin mRNA is highly neuropil-localized, spinophilin may limit its own expression but promote expression of other PSD-associated proteins, suggesting a role in mRNA translation and synaptic protein expression within dendritic spines.","method":"Ultra-ID proximity labeling, ALFA-tag nanobody pulldown (ID-oPD), mass spectrometry, validation by orthogonal approaches, in situ hybridization/RNA localization","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity labeling interactome (pan-catalog level for many hits) with limited mechanistic follow-up; preprint, single lab","pmids":[],"is_preprint":true}],"current_model":"PPP1R9B (spinophilin/neurabin-2) is a scaffolding protein enriched in postsynaptic dendritic spines that targets protein phosphatase 1 (PP1) to specific substrates via its RVxF motif and PDZ domain; the PP1-spinophilin holoenzyme dephosphorylates the retinoblastoma family proteins (pRb, p107, p130) to regulate cell cycle progression, dephosphorylates translational regulators 4E-BP1 and p70 S6K to modulate mTORC1-dependent translation, mediates agonist-induced D2 dopamine receptor internalization in striatal neurons, and maintains cortical F-actin organization to support NK cell immunological synapse formation."},"narrative":{"mechanistic_narrative":"PPP1R9B (spinophilin/neurabin-2) is a scaffolding protein that targets the catalytic phosphatase PP1a (PPP1CA) to specific substrates, thereby coupling phosphatase activity to cell cycle control, translational regulation, and synaptic and cytoskeletal organization [PMID:26387546, PMID:33537097]. As a PP1 regulatory subunit it directs dephosphorylation of the retinoblastoma pocket proteins pRb, p107, and p130 during G0/G1 and G1; loss of PPP1R9B or a tumor-derived point mutation (SPN-A566V) that disrupts the SPN-PP1 interaction sustains pocket-protein phosphorylation and promotes cancer stem-like properties, an effect that is amplified together with mutant p53 [PMID:26387546, PMID:33537097]. Substrate selection by the PP1-spinophilin holoenzyme depends on substrate engagement of the PDZ domain adjoining its RVxF-ΦΦ-R-W motif rather than remodeling of the PP1 catalytic groove, which extends its substrate repertoire to the translational regulators 4E-BP1 and p70 S6K and links it to mTORC1-dependent translational control. Beyond its phosphatase-targeting role, spinophilin maintains cortical F-actin organization required for NK-cell immunological synapse formation and target conjugation [PMID:19130477], and in striatal neurons it mediates agonist-induced D2 dopamine receptor internalization, shaping locomotor responses to D2R agonists.","teleology":[{"year":2009,"claim":"Established that spinophilin acts as a cytoskeletal regulator in immune cells, not solely in neurons, by showing it organizes cortical F-actin at the NK immunological synapse.","evidence":"Confocal live imaging, shRNA knockdown, and F-actin staining with CD18/CD28 stimulation in the YTS NK-like cell line","pmids":["19130477"],"confidence":"Medium","gaps":["Molecular link between spinophilin and the actin machinery not defined","Whether PP1 targeting is involved in this role untested","Single cell line, no in vivo validation"]},{"year":2015,"claim":"Connected spinophilin to cell-cycle and cancer biology by showing it directs PP1a-mediated dephosphorylation of pRb, with loss driving cancer stemness.","evidence":"Reciprocal shRNA knockdown/overexpression, PPP1CA knockdown, flow cytometry and qRT-PCR in breast cancer lines and tumor samples","pmids":["26387546"],"confidence":"Medium","gaps":["No structural basis for substrate targeting","Single lab, no independent replication","Direct PP1-spinophilin-pRb complex not biochemically reconstituted"]},{"year":2021,"claim":"Resolved that the PP1-spinophilin holoenzyme regulates the cell cycle through phosphatase activity on pocket proteins, using a tumor mutation that separates complex assembly from catalysis.","evidence":"SPN-A566V mutational analysis, co-immunoprecipitation, phosphatase assays, and cell cycle/stemness assays in MCF10A, T47D, MDA-MB-468","pmids":["33537097"],"confidence":"Medium","gaps":["Cooperativity with mutant p53 mechanistically undefined","In vivo tumorigenicity not tested","Single lab"]},{"year":2024,"claim":"Defined the biochemical logic of substrate selection, showing PDZ-domain engagement rather than catalytic-groove remodeling determines targeting, and added 4E-BP1/p70 S6K to the substrate repertoire.","evidence":"PP1-PIP fusion proteins, in vitro phosphatase assays, and structural experiments (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Cellular consequence for mTORC1 signaling not demonstrated in vivo","Fusion-protein constructs may not reflect native holoenzyme"]},{"year":2025,"claim":"Provided in vivo evidence that spinophilin mediates D2 dopamine receptor internalization and shapes locomotor responses, and catalogued a large spinophilin interactome enriched in mRNA processing/translation factors.","evidence":"Spinophilin knockout mice with locomotion assays and quinpirole interaction proteomics; Ultra-ID proximity labeling and nanobody pulldown in HEK293 (preprints)","pmids":[],"confidence":"Low","gaps":["Preprints, single lab, awaits peer review","Direct D2R-spinophilin binding interface not mapped","Interactome hits largely uncharacterized at the mechanistic level"]},{"year":null,"claim":"How spinophilin integrates its distinct roles—PP1 substrate targeting, actin organization, receptor trafficking, and local translation—within a single cell type remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model linking scaffolding domains to context-specific functions","Tissue-specific substrate repertoire undefined","Structural model of the native holoenzyme on physiological substrates lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3]}],"complexes":["PP1-spinophilin holoenzyme"],"partners":["PPP1CA","RB1","P107","P130","EIF4EBP1","RPS6KB1","DRD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96SB3","full_name":"Neurabin-2","aliases":["Neurabin-II","Protein phosphatase 1 regulatory subunit 9B","Spinophilin"],"length_aa":817,"mass_kda":89.3,"function":"Seems to act as a scaffold protein in multiple signaling pathways. Modulates excitatory synaptic transmission and dendritic spine morphology. Binds to actin filaments (F-actin) and shows cross-linking activity. Binds along the sides of the F-actin. May play an important role in linking the actin cytoskeleton to the plasma membrane at the synaptic junction. Believed to target protein phosphatase 1/PP1 to dendritic spines, which are rich in F-actin, and regulates its specificity toward ion channels and other substrates, such as AMPA-type and NMDA-type glutamate receptors. Plays a role in regulation of G-protein coupled receptor signaling, including dopamine D2 receptors and alpha-adrenergic receptors. May establish a signaling complex for dopaminergic neurotransmission through D2 receptors by linking receptors downstream signaling molecules and the actin cytoskeleton. Binds to ADRA1B and RGS2 and mediates regulation of ADRA1B signaling. May confer to Rac signaling specificity by binding to both, RacGEFs and Rac effector proteins. Probably regulates p70 S6 kinase activity by forming a complex with TIAM1 (By similarity). Required for hepatocyte growth factor (HGF)-induced cell migration","subcellular_location":"Cytoplasm, cytoskeleton; Nucleus; Cell projection, dendritic spine; Postsynaptic density; Synapse; Cell junction, adherens junction; Cytoplasm; Cell membrane; Cell projection, lamellipodium; Cell projection, filopodium; Cell projection, ruffle membrane","url":"https://www.uniprot.org/uniprotkb/Q96SB3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPP1R9B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTN4","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CDC42","stoichiometry":0.2},{"gene":"CDIPT","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2},{"gene":"CYP51A1","stoichiometry":0.2},{"gene":"FDPS","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PPP1R9B","total_profiled":1310},"omim":[{"mim_id":"615162","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 35; MRT35","url":"https://www.omim.org/entry/615162"},{"mim_id":"613324","title":"SPERMATOGENESIS-ASSOCIATED PROTEIN 13; SPATA13","url":"https://www.omim.org/entry/613324"},{"mim_id":"607876","title":"EPILEPSY, FAMILIAL ADULT MYOCLONIC, 2; FAME2","url":"https://www.omim.org/entry/607876"},{"mim_id":"603325","title":"PROTEIN PHOSPHATASE 1, REGULATORY SUBUNIT 9B; PPP1R9B","url":"https://www.omim.org/entry/603325"},{"mim_id":"600160","title":"CYCLIN-DEPENDENT KINASE INHIBITOR 2A; CDKN2A","url":"https://www.omim.org/entry/600160"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":107.1}],"url":"https://www.proteinatlas.org/search/PPP1R9B"},"hgnc":{"alias_symbol":["Spn","SPINO"],"prev_symbol":["PPP1R6","PPP1R9"]},"alphafold":{"accession":"Q96SB3","domains":[{"cath_id":"2.30.42.10","chopping":"477-615","consensus_level":"high","plddt":87.0872,"start":477,"end":615}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96SB3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96SB3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96SB3-F1-predicted_aligned_error_v6.png","plddt_mean":62.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPP1R9B","jax_strain_url":"https://www.jax.org/strain/search?query=PPP1R9B"},"sequence":{"accession":"Q96SB3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96SB3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96SB3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96SB3"}},"corpus_meta":[{"pmid":"2329357","id":"PMC_2329357","title":"The spino(trigemino)pontoamygdaloid pathway: electrophysiological evidence for an involvement in pain processes.","date":"1990","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/2329357","citation_count":348,"is_preprint":false},{"pmid":"9133395","id":"PMC_9133395","title":"Transneuronal labeling of a nociceptive pathway, the spino-(trigemino-)parabrachio-amygdaloid, in the rat.","date":"1997","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9133395","citation_count":175,"is_preprint":false},{"pmid":"2474780","id":"PMC_2474780","title":"A possible spino (trigemino)-ponto-amygdaloid pathway for pain.","date":"1989","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/2474780","citation_count":133,"is_preprint":false},{"pmid":"7760119","id":"PMC_7760119","title":"Spino (trigemino) parabrachiohypothalamic pathway: electrophysiological evidence for an involvement in pain processes.","date":"1995","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/7760119","citation_count":109,"is_preprint":false},{"pmid":"6087196","id":"PMC_6087196","title":"A spino-reticulo-thalamic pathway in the rat: an anatomical study with reference to pain transmission.","date":"1984","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/6087196","citation_count":105,"is_preprint":false},{"pmid":"1721691","id":"PMC_1721691","title":"The spino-latero-reticular system of the rat: projections from the superficial dorsal horn and structural characterization of marginal neurons involved.","date":"1991","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/1721691","citation_count":103,"is_preprint":false},{"pmid":"1303195","id":"PMC_1303195","title":"Moderate instability of the trinucleotide repeat in spino bulbar muscular atrophy.","date":"1992","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1303195","citation_count":92,"is_preprint":false},{"pmid":"5639763","id":"PMC_5639763","title":"Responses to a spino-olivo-cerebellar pathway in the cat.","date":"1968","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/5639763","citation_count":89,"is_preprint":false},{"pmid":"3282296","id":"PMC_3282296","title":"Spinal and trigeminal projections to the parabrachial nucleus in the rat: electron-microscopic evidence of a spino-ponto-amygdalian somatosensory pathway.","date":"1988","source":"Somatosensory research","url":"https://pubmed.ncbi.nlm.nih.gov/3282296","citation_count":78,"is_preprint":false},{"pmid":"5272211","id":"PMC_5272211","title":"Termination and functional organization of the dorsolateral spino-olivocerebellar path.","date":"1969","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/5272211","citation_count":68,"is_preprint":false},{"pmid":"7722653","id":"PMC_7722653","title":"Antinociception produced by an ascending spino-supraspinal pathway.","date":"1995","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/7722653","citation_count":63,"is_preprint":false},{"pmid":"20699616","id":"PMC_20699616","title":"Injury of the spino-thalamo-cortical pathway is necessary for central post-stroke pain.","date":"2010","source":"European neurology","url":"https://pubmed.ncbi.nlm.nih.gov/20699616","citation_count":63,"is_preprint":false},{"pmid":"27147646","id":"PMC_27147646","title":"Prolonged Type 1 Metabotropic Glutamate Receptor Dependent Synaptic Signaling Contributes to Spino-Cerebellar Ataxia Type 1.","date":"2016","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/27147646","citation_count":40,"is_preprint":false},{"pmid":"10456112","id":"PMC_10456112","title":"A neural model of cerebellar learning for arm movement control: cortico-spino-cerebellar dynamics.","date":"1997","source":"Learning & memory (Cold Spring Harbor, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/10456112","citation_count":40,"is_preprint":false},{"pmid":"29172480","id":"PMC_29172480","title":"Myricetin Reduces Toxic Level of CAG Repeats RNA in Huntington's Disease (HD) and Spino Cerebellar Ataxia (SCAs).","date":"2017","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/29172480","citation_count":38,"is_preprint":false},{"pmid":"6723862","id":"PMC_6723862","title":"Origin of signals conveyed by the ventral spino-cerebellar tract and spino-reticulo-cerebellar pathway.","date":"1984","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/6723862","citation_count":32,"is_preprint":false},{"pmid":"7776251","id":"PMC_7776251","title":"Step phase-related excitability changes in spino-olivocerebellar paths to the c1 and c3 zones in cat cerebellum.","date":"1995","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7776251","citation_count":31,"is_preprint":false},{"pmid":"8440306","id":"PMC_8440306","title":"Morphine depresses the transmission of noxious messages in the spino(trigemino)-ponto-amygdaloid pathway.","date":"1993","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/8440306","citation_count":31,"is_preprint":false},{"pmid":"3019134","id":"PMC_3019134","title":"Subclinical cervico-spino-bulbar effects of lead: a study of short-latency somatosensory evoked potentials in workers exposed to lead, zinc, and copper.","date":"1986","source":"American journal of industrial medicine","url":"https://pubmed.ncbi.nlm.nih.gov/3019134","citation_count":30,"is_preprint":false},{"pmid":"25657619","id":"PMC_25657619","title":"The spino-bulbar-cerebellar pathway: organization and neurochemical properties of spinal cells that project to the lateral reticular nucleus in the rat.","date":"2015","source":"Frontiers in neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/25657619","citation_count":28,"is_preprint":false},{"pmid":"22142796","id":"PMC_22142796","title":"The prevalence of central poststroke pain according to the integrity of the spino-thalamo-cortical pathway.","date":"2011","source":"European neurology","url":"https://pubmed.ncbi.nlm.nih.gov/22142796","citation_count":28,"is_preprint":false},{"pmid":"26387546","id":"PMC_26387546","title":"Loss of the tumor suppressor spinophilin (PPP1R9B) increases the cancer stem cell population in breast tumors.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/26387546","citation_count":27,"is_preprint":false},{"pmid":"31766565","id":"PMC_31766565","title":"In Human and Mouse Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31766565","citation_count":27,"is_preprint":false},{"pmid":"2323387","id":"PMC_2323387","title":"Spatio-temporal organization of the somaesthetic projections in the red nucleus transmitted through the spino-rubral pathway in the cat.","date":"1990","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/2323387","citation_count":27,"is_preprint":false},{"pmid":"19346009","id":"PMC_19346009","title":"Distinct spatiotemporal pattern of CNS lesions revealed by USPIO-enhanced MRI in MOG-induced EAE rats implicates the involvement of spino-olivocerebellar pathways.","date":"2009","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/19346009","citation_count":23,"is_preprint":false},{"pmid":"3422677","id":"PMC_3422677","title":"Spino-cerebellar degeneration with polyneuropathy associated with ceroid lipofuscinosis in one family.","date":"1988","source":"Journal of child neurology","url":"https://pubmed.ncbi.nlm.nih.gov/3422677","citation_count":22,"is_preprint":false},{"pmid":"212284","id":"PMC_212284","title":"The ventral spino-olivocerebellar system in the cat. IV. Spinal transmission after administration of clonidine and L-dopa.","date":"1978","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/212284","citation_count":19,"is_preprint":false},{"pmid":"31848358","id":"PMC_31848358","title":"Distinct mechanisms of signal processing by lamina I spino-parabrachial neurons.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31848358","citation_count":17,"is_preprint":false},{"pmid":"27103674","id":"PMC_27103674","title":"Adaptive plasticity of spino-extraocular motor coupling during locomotion in metamorphosing Xenopus laevis.","date":"2016","source":"The Journal of experimental biology","url":"https://pubmed.ncbi.nlm.nih.gov/27103674","citation_count":17,"is_preprint":false},{"pmid":"11313448","id":"PMC_11313448","title":"Spino-bulbo-spinal pathway mediating vagal modulation of nociceptive-neuroendocrine control of inflammation in the rat.","date":"2001","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11313448","citation_count":16,"is_preprint":false},{"pmid":"30004124","id":"PMC_30004124","title":"Central sensitization of the spino-parabrachial-amygdala pathway that outlasts a brief nociceptive stimulus.","date":"2018","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30004124","citation_count":15,"is_preprint":false},{"pmid":"35250493","id":"PMC_35250493","title":"The Spino-Parabrachial Pathway for Itch.","date":"2022","source":"Frontiers in neural circuits","url":"https://pubmed.ncbi.nlm.nih.gov/35250493","citation_count":13,"is_preprint":false},{"pmid":"1377978","id":"PMC_1377978","title":"A re-examination of the spino-reticulo-diencephalic pathway in the cat.","date":"1992","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/1377978","citation_count":12,"is_preprint":false},{"pmid":"17052848","id":"PMC_17052848","title":"Correlation of noxious evoked c-fos expression in areas of the somatosensory system during chronic pain: involvement of spino-medullary and intra-medullary connections.","date":"2006","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/17052848","citation_count":12,"is_preprint":false},{"pmid":"192931","id":"PMC_192931","title":"Ascending spinal tracts of the spino-bulbo-spinal reflex in cats.","date":"1976","source":"The Japanese journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/192931","citation_count":12,"is_preprint":false},{"pmid":"37311832","id":"PMC_37311832","title":"A direct spino-cortical circuit bypassing the thalamus modulates nociception.","date":"2023","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/37311832","citation_count":11,"is_preprint":false},{"pmid":"6295561","id":"PMC_6295561","title":"Convergence of muscle spindle afferents on single neurons of the cat dorsal spino-cerebellar tract and their synaptic efficacy.","date":"1982","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/6295561","citation_count":11,"is_preprint":false},{"pmid":"19130477","id":"PMC_19130477","title":"PPP1R9B (Neurabin 2): involvement and dynamics in the NK immunological synapse.","date":"2009","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19130477","citation_count":10,"is_preprint":false},{"pmid":"32701841","id":"PMC_32701841","title":"Physical disuse contributes to widespread chronic mechanical hyperalgesia, tactile allodynia, and cold allodynia through neurogenic inflammation and spino-parabrachio-amygdaloid pathway activation.","date":"2020","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/32701841","citation_count":10,"is_preprint":false},{"pmid":"2576271","id":"PMC_2576271","title":"Modification of spino-bulbar autonomic cholinergic systems by activation of alpha-adrenergic receptors.","date":"1989","source":"Journal of the autonomic nervous system","url":"https://pubmed.ncbi.nlm.nih.gov/2576271","citation_count":10,"is_preprint":false},{"pmid":"24357064","id":"PMC_24357064","title":"Spino-olivary projections in the rat are anatomically separate from postsynaptic dorsal column projections.","date":"2014","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24357064","citation_count":7,"is_preprint":false},{"pmid":"6194187","id":"PMC_6194187","title":"The inferior olive of a prosimian primate Galago senegalensis. I. Conformation and spino-olivary projections.","date":"1983","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/6194187","citation_count":7,"is_preprint":false},{"pmid":"33537097","id":"PMC_33537097","title":"Mutation of SPINOPHILIN (PPP1R9B) found in human tumors promotes the tumorigenic and stemness properties of cells.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33537097","citation_count":6,"is_preprint":false},{"pmid":"1717518","id":"PMC_1717518","title":"Gracile projection to the cat medial accessory olive: ultrastructural termination patterns and convergence with spino-olivary projection.","date":"1991","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/1717518","citation_count":6,"is_preprint":false},{"pmid":"24101804","id":"PMC_24101804","title":"An update on Spino-cerebellar ataxias.","date":"2013","source":"Annals of Indian Academy of Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24101804","citation_count":5,"is_preprint":false},{"pmid":"16973230","id":"PMC_16973230","title":"Reticulo-collicular and spino-collicular projections involved in eye and eyelid movements during the blink reflex.","date":"2006","source":"Neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/16973230","citation_count":5,"is_preprint":false},{"pmid":"25711799","id":"PMC_25711799","title":"The spino-bulbar-cerebellar pathway: Activation of neurons projecting to the lateral reticular nucleus in the rat in response to noxious mechanical stimuli.","date":"2015","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/25711799","citation_count":5,"is_preprint":false},{"pmid":"1239007","id":"PMC_1239007","title":"Neuronal activity in the lateral vestibular nucleus of the cat. V. Topographical distribution of inhibitory effects mediated by the spino-olivocerebellar pathway.","date":"1975","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1239007","citation_count":5,"is_preprint":false},{"pmid":"36137740","id":"PMC_36137740","title":"Reliable virtual clinical assessment in spino-bulbar muscular atrophy (SBMA).","date":"2022","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/36137740","citation_count":4,"is_preprint":false},{"pmid":"35933444","id":"PMC_35933444","title":"Effects of the administration of Elovl5-dependent fatty acids on a spino-cerebellar ataxia 38 mouse model.","date":"2022","source":"Behavioral and brain functions : BBF","url":"https://pubmed.ncbi.nlm.nih.gov/35933444","citation_count":4,"is_preprint":false},{"pmid":"26330755","id":"PMC_26330755","title":"Functional Connections of the Vestibulo-spino-adrenal Axis in the Control of Blood Pressure Via the Vestibulosympathetic Reflex in Conscious Rats.","date":"2015","source":"The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26330755","citation_count":4,"is_preprint":false},{"pmid":"26713133","id":"PMC_26713133","title":"Management of Sacral Tumors Requiring Spino-Pelvic Reconstruction with Different Histopathologic Diagnosis: Evaluation with Four Cases.","date":"2015","source":"Asian spine journal","url":"https://pubmed.ncbi.nlm.nih.gov/26713133","citation_count":4,"is_preprint":false},{"pmid":"6886703","id":"PMC_6886703","title":"Autosomal recessive spino-olivo-cerebellar degeneration without ataxia.","date":"1983","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/6886703","citation_count":4,"is_preprint":false},{"pmid":"1967529","id":"PMC_1967529","title":"Different spinal effects of opioid agonists on spinal and spino-bulbo-spinal reflexes in rats.","date":"1990","source":"Journal of neural transmission. General section","url":"https://pubmed.ncbi.nlm.nih.gov/1967529","citation_count":2,"is_preprint":false},{"pmid":"41922770","id":"PMC_41922770","title":"Deconstruction of a spino-brain-spinal cord circuit that drives chronic pain.","date":"2026","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/41922770","citation_count":1,"is_preprint":false},{"pmid":"38050062","id":"PMC_38050062","title":"Low-Frequency Stimulation of Trpv1-Lineage Peripheral Afferents Potentiates the Excitability of Spino-Periaqueductal Gray Projection Neurons.","date":"2024","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38050062","citation_count":1,"is_preprint":false},{"pmid":"39125760","id":"PMC_39125760","title":"The New Face of Dynamic Mutation-The CAA [CAG]n CAA CAG Motif as a Mutable Unit in the TBP Gene Causative for Spino-Cerebellar Ataxia Type 17.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39125760","citation_count":1,"is_preprint":false},{"pmid":"37396760","id":"PMC_37396760","title":"A blended neurostimulation protocol to delineate cortico-muscular and spino-muscular dynamics following neuroplastic adaptation.","date":"2023","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37396760","citation_count":1,"is_preprint":false},{"pmid":"2456470","id":"PMC_2456470","title":"[Spatial organization of the sources of the spino-reticulo-cerebellar pathway].","date":"1988","source":"Neirofiziologiia = Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/2456470","citation_count":1,"is_preprint":false},{"pmid":"41695473","id":"PMC_41695473","title":"Erratum: Mutation of SPINOPHILIN (PPP1R9B) found in human tumors promotes the tumorigenic and stemness properties of cells: Erratum.","date":"2026","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/41695473","citation_count":0,"is_preprint":false},{"pmid":"41282163","id":"PMC_41282163","title":"Deconstruction of a spino-brain-spinal cord circuit drives chronic mechanical pain.","date":"2025","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/41282163","citation_count":0,"is_preprint":false},{"pmid":"36994015","id":"PMC_36994015","title":"Carrier frequency of Spino-muscular atrophy in individuals of a reproductive age group from North India.","date":"2023","source":"Journal of family medicine and primary care","url":"https://pubmed.ncbi.nlm.nih.gov/36994015","citation_count":0,"is_preprint":false},{"pmid":"26901084","id":"PMC_26901084","title":"A rapidly progressive defective spermatogenesis in a Mexican family affected by spino-bulbar muscular atrophy.","date":"2016","source":"Systems biology in reproductive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26901084","citation_count":0,"is_preprint":false},{"pmid":"11905153","id":"PMC_11905153","title":"Electrophysiological investigation of spino-olivary projections originating from sacral segments of the cat spinal cord.","date":"2001","source":"Acta neurobiologiae experimentalis","url":"https://pubmed.ncbi.nlm.nih.gov/11905153","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.09.675136","title":"Striatal spinophilin enhances D2R interaction with cytosolic proteins to mediate persistent D2R agonist-induced locomotor suppression","date":"2025-09-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.09.675136","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.20.629596","title":"Identifying the Brain Circuits that Regulate Pain-Induced Sleep Disturbances","date":"2024-12-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.20.629596","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.29.24316352","title":"Integrating Multidimensional Data Analytics for Precision Diagnosis of Chronic Low Back Pain","date":"2024-10-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.29.24316352","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.11.687864","title":"Spinal electrophysiology reveals frequency-specific spatial patterns of neural activity and corticospinal coherence during pincer-grip","date":"2025-11-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.11.687864","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.23.614477","title":"PDZ-directed substrate recruitment is the primary determinant of specific 4E- BP1 dephosphorylation by PP1-Neurabin","date":"2024-09-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.23.614477","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.23.634546","title":"Proximity labeling and orthogonal nanobody pulldown (ID-oPD) approaches to map the spinophilin interactome uncover a putative role for spinophilin in protein homeostasis","date":"2025-01-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.23.634546","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":34796,"output_tokens":1889,"usd":0.066362,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8766,"output_tokens":2377,"usd":0.051627,"stage2_stop_reason":"end_turn"},"total_usd":0.117989,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Spinophilin (PPP1R9B) loss reduces PP1a (PPP1CA) phosphatase activity against the retinoblastoma protein (pRb), thereby maintaining higher levels of phosphorylated pRb. Knockdown of PPP1R9B by shRNA increased cancer stemness properties (Sox2, KLF4, Nanog, OCT4 expression; CD44+/CD24- cells), while ectopic overexpression reduced these properties. Reduction of PPP1CA levels mimicked the cancer stem-like cell phenotype of PPP1R9B downregulation, establishing that the mechanism operates through PP1a.\",\n      \"method\": \"shRNA knockdown, ectopic overexpression, PPP1CA knockdown, flow cytometry (CD44/CD24), qRT-PCR, Western blot in breast cancer cell lines and human tumor samples\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss of function experiments with multiple readouts in a single lab, no independent replication reported in abstract\",\n      \"pmids\": [\"26387546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PPP1R9B (neurabin 2/spinophilin) is a cytoskeletal component of NK cells that accumulates at the NK immunological synapse (NKIS) in a maturation stage-dependent manner, mimics early actin kinetics at the NKIS, is recruited by CD18 stimulation but not CD28 ligation, is required for maintenance of cortical F-actin organization, and its knockdown reduces YTS-target cell conjugation frequency due to collapsed F-actin cytoskeleton.\",\n      \"method\": \"Confocal live imaging of NKIS assembly, shRNA knockdown, CD18/CD28 stimulation assays, F-actin staining in YTS NK-like cell line\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, knockdown phenotype with mechanistic readout, single lab, single cell line\",\n      \"pmids\": [\"19130477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A point mutation in PPP1R9B found in human tumors (SPN-A566V) disrupts both the SPN-PP1 interaction and its phosphatase activity, but does not prevent PP1-SPN holoenzyme interaction with pocket proteins pRb, p107, and p130; however, it impairs dephosphorylation of these pocket proteins during G0/G1 and G1, indicating that the PP1-SPN holoenzyme regulates cell cycle progression. SPN-A566V also promoted stemness, and cells with both SPN-A566V and mutant p53 showed increased tumorigenic and stemness properties.\",\n      \"method\": \"Mutational analysis, co-immunoprecipitation, phosphatase activity assays, cell cycle analysis, stemness assays in MCF10A, T47D, and MDA-MB-468 cell lines\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, phosphatase assay, cell cycle analysis) in single lab; mechanistic mutation characterization\",\n      \"pmids\": [\"33537097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PP1-Neurabin (PPP1R9B) and PP1-Spinophilin holoenzymes dephosphorylate 4E-BP1 and p70 S6K translational regulators as substrates. In contrast to Phactr PIPs, substrate recruitment and catalytic efficiency of PP1-Neurabin/Spinophilin fusions is primarily determined by substrate interaction with the PDZ domain adjoining the RVxF-ΦΦ-R-W motif, rather than by remodeling of the PP1 hydrophobic substrate groove, pointing to a role in mTORC1-dependent translational control.\",\n      \"method\": \"PP1-PIP fusion protein approach, in vitro phosphatase assays, biochemical substrate identification, structural experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution and structural experiments in single preprint study, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic knockout of spinophilin (PPP1R9B) in mice limited locomotor suppression caused by the D2R agonist quinpirole, and mechanistically spinophilin was required for quinpirole-induced increases in the interaction of D2R with intracellular proteins, suggesting spinophilin mediates agonist-induced D2R internalization in striatal postsynaptic dendritic spines.\",\n      \"method\": \"Spinophilin knockout mice, behavioral locomotion assay, co-immunoprecipitation/interaction proteomics following quinpirole treatment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic KO with behavioral phenotype and interaction proteomics, single preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Using proximity labeling (Ultra-ID) and orthogonal nanobody pulldown (ID-oPD), 614 specific spinophilin-interacting proteins were identified in HEK293 cells, many involved in mRNA processing and translation. In the brain, spinophilin mRNA is highly neuropil-localized, spinophilin may limit its own expression but promote expression of other PSD-associated proteins, suggesting a role in mRNA translation and synaptic protein expression within dendritic spines.\",\n      \"method\": \"Ultra-ID proximity labeling, ALFA-tag nanobody pulldown (ID-oPD), mass spectrometry, validation by orthogonal approaches, in situ hybridization/RNA localization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity labeling interactome (pan-catalog level for many hits) with limited mechanistic follow-up; preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PPP1R9B (spinophilin/neurabin-2) is a scaffolding protein enriched in postsynaptic dendritic spines that targets protein phosphatase 1 (PP1) to specific substrates via its RVxF motif and PDZ domain; the PP1-spinophilin holoenzyme dephosphorylates the retinoblastoma family proteins (pRb, p107, p130) to regulate cell cycle progression, dephosphorylates translational regulators 4E-BP1 and p70 S6K to modulate mTORC1-dependent translation, mediates agonist-induced D2 dopamine receptor internalization in striatal neurons, and maintains cortical F-actin organization to support NK cell immunological synapse formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PPP1R9B (spinophilin/neurabin-2) is a scaffolding protein that targets the catalytic phosphatase PP1a (PPP1CA) to specific substrates, thereby coupling phosphatase activity to cell cycle control, translational regulation, and synaptic and cytoskeletal organization [#0, #2]. As a PP1 regulatory subunit it directs dephosphorylation of the retinoblastoma pocket proteins pRb, p107, and p130 during G0/G1 and G1; loss of PPP1R9B or a tumor-derived point mutation (SPN-A566V) that disrupts the SPN-PP1 interaction sustains pocket-protein phosphorylation and promotes cancer stem-like properties, an effect that is amplified together with mutant p53 [#0, #2]. Substrate selection by the PP1-spinophilin holoenzyme depends on substrate engagement of the PDZ domain adjoining its RVxF-\\u03a6\\u03a6-R-W motif rather than remodeling of the PP1 catalytic groove, which extends its substrate repertoire to the translational regulators 4E-BP1 and p70 S6K and links it to mTORC1-dependent translational control [#3]. Beyond its phosphatase-targeting role, spinophilin maintains cortical F-actin organization required for NK-cell immunological synapse formation and target conjugation [#1], and in striatal neurons it mediates agonist-induced D2 dopamine receptor internalization, shaping locomotor responses to D2R agonists [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that spinophilin acts as a cytoskeletal regulator in immune cells, not solely in neurons, by showing it organizes cortical F-actin at the NK immunological synapse.\",\n      \"evidence\": \"Confocal live imaging, shRNA knockdown, and F-actin staining with CD18/CD28 stimulation in the YTS NK-like cell line\",\n      \"pmids\": [\"19130477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between spinophilin and the actin machinery not defined\", \"Whether PP1 targeting is involved in this role untested\", \"Single cell line, no in vivo validation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected spinophilin to cell-cycle and cancer biology by showing it directs PP1a-mediated dephosphorylation of pRb, with loss driving cancer stemness.\",\n      \"evidence\": \"Reciprocal shRNA knockdown/overexpression, PPP1CA knockdown, flow cytometry and qRT-PCR in breast cancer lines and tumor samples\",\n      \"pmids\": [\"26387546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for substrate targeting\", \"Single lab, no independent replication\", \"Direct PP1-spinophilin-pRb complex not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved that the PP1-spinophilin holoenzyme regulates the cell cycle through phosphatase activity on pocket proteins, using a tumor mutation that separates complex assembly from catalysis.\",\n      \"evidence\": \"SPN-A566V mutational analysis, co-immunoprecipitation, phosphatase assays, and cell cycle/stemness assays in MCF10A, T47D, MDA-MB-468\",\n      \"pmids\": [\"33537097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cooperativity with mutant p53 mechanistically undefined\", \"In vivo tumorigenicity not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined the biochemical logic of substrate selection, showing PDZ-domain engagement rather than catalytic-groove remodeling determines targeting, and added 4E-BP1/p70 S6K to the substrate repertoire.\",\n      \"evidence\": \"PP1-PIP fusion proteins, in vitro phosphatase assays, and structural experiments (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Cellular consequence for mTORC1 signaling not demonstrated in vivo\", \"Fusion-protein constructs may not reflect native holoenzyme\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided in vivo evidence that spinophilin mediates D2 dopamine receptor internalization and shapes locomotor responses, and catalogued a large spinophilin interactome enriched in mRNA processing/translation factors.\",\n      \"evidence\": \"Spinophilin knockout mice with locomotion assays and quinpirole interaction proteomics; Ultra-ID proximity labeling and nanobody pulldown in HEK293 (preprints)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprints, single lab, awaits peer review\", \"Direct D2R-spinophilin binding interface not mapped\", \"Interactome hits largely uncharacterized at the mechanistic level\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How spinophilin integrates its distinct roles—PP1 substrate targeting, actin organization, receptor trafficking, and local translation—within a single cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model linking scaffolding domains to context-specific functions\", \"Tissue-specific substrate repertoire undefined\", \"Structural model of the native holoenzyme on physiological substrates lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"PP1-spinophilin holoenzyme\"\n    ],\n    \"partners\": [\n      \"PPP1CA\",\n      \"RB1\",\n      \"p107\",\n      \"p130\",\n      \"EIF4EBP1\",\n      \"RPS6KB1\",\n      \"DRD2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}