{"gene":"STK32A","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2023,"finding":"STK32A is a downstream effector negatively regulated by the transcription factor EMX2 in mouse inner ear hair cells. Stk32a is expressed in hair cells on one side of the line of polarity reversal (LPR) in a pattern complementary to Emx2 expression on the opposite side. STK32A is necessary to align the intrinsic polarity of the stereociliary bundle with core planar cell polarity (PCP) proteins in EMX2-negative regions, and is sufficient to reorient bundles when ectopically expressed in EMX2-positive regions. STK32A reinforces LPR formation by regulating the apical localization of the transmembrane receptor GPR156.","method":"Mouse genetic model (Stk32a knockout and ectopic expression); in vivo imaging of stereociliary bundle orientation; PCP protein localization; epistasis experiments with Emx2 and Gpr156 mutants","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function genetics in mouse with defined cellular phenotype and pathway placement; replicated and extended in a follow-up paper (PMID:41208475)","pmids":["37144879"],"is_preprint":false},{"year":2025,"finding":"Genetic epistasis experiments in mice with combined mutations in Gpr156/Stk32a or Emx2/Stk32a confirmed that: (1) GPR156 reverses stereociliary bundle orientation relative to the PCP axis but this action can be blocked by STK32A; and (2) EMX2 establishes the boundary between the two hair cell groups by repressing Stk32a transcription. These functional relationships were also demonstrated in the cochlea.","method":"Genetic epistasis in compound mouse mutants (Gpr156;Stk32a and Emx2;Stk32a double mutants); hair cell bundle orientation analysis; immunofluorescence for PCP proteins","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple compound mutants in vivo, orthogonal to and replicating/extending PMID:37144879","pmids":["41208475"],"is_preprint":false},{"year":2015,"finding":"STK32A is an N-myristoylated protein. Cell-free insect protein synthesis and metabolic labeling in transfected human cells demonstrated that the STK32A gene product undergoes protein N-myristoylation.","method":"Cell-free insect protein synthesis system and metabolic labeling in transfected human cells; N-terminal fusion protein assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal labeling systems (cell-free and cellular), single lab, no functional consequence of the modification demonstrated for STK32A specifically","pmids":["26308446"],"is_preprint":false},{"year":2020,"finding":"In NSCLC cells, RUNX2 transcription factor interacts with STK32A to promote its expression, and STK32A supports NF-κB p65 phosphorylation. miR-130a-5p directly targets RUNX2, reducing RUNX2-driven STK32A expression, thereby suppressing NSCLC proliferation, migration, invasion, and EMT. RUNX2 overexpression reversed miR-130a-5p-mediated tumor suppression in vivo via enhanced STK32A expression.","method":"Dual-luciferase reporter assay (miR-130a-5p→RUNX2); western blot (RUNX2/STK32A/NF-κB p65 phosphorylation); cell proliferation, migration, invasion assays; in vivo xenograft; RT-qPCR","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple cell-based assays and in vivo validation, single lab; RUNX2-STK32A interaction shown by co-expression and rescue but no direct biochemical binding assay reported in abstract","pmids":["32571328"],"is_preprint":false},{"year":2025,"finding":"In zebrafish, mutation of stk32a results in increased sleep and impaired sleep homeostasis. stk32a acts downstream of neurotensin signaling and the serotonergic raphe. stk32a mutation reduces phosphorylation of neurofilament proteins that are co-expressed with stk32a in neurons regulating motor activity and in lateral line hair cells. Ablation of these stk32a-expressing cells phenocopies stk32a mutation. Neurotensin signaling inhibits specific sensory and motor populations and blocks stimulus-evoked responses of neurons relaying sensory information from hair cells to the brain.","method":"Zebrafish forward genetic screen; sleep/wake behavioral assays in zebrafish and mice; phosphoproteomics (neurofilament phosphorylation); cell ablation; optogenetics/calcium imaging of sensory relay neurons","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined behavioral and molecular phenotypes, pathway placement via epistasis, replicated in mice; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.09.09.675098"],"is_preprint":true},{"year":2025,"finding":"In zebrafish, Pth4 neuron-induced sleep is suppressed in stk32a mutants, and stk32a-expressing neurons in the prethalamus express parathyroid hormone receptors, placing stk32a downstream of hypothalamic Pth4/QRFP neuronal signaling in the sleep circuit.","method":"Genetic epistasis in zebrafish stk32a mutants; optogenetic stimulation of Pth4 neurons; behavioral sleep assays","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined behavioral phenotype and circuit-level pathway placement; single lab, single publication, peer-reviewed","pmids":["41406966"],"is_preprint":false}],"current_model":"STK32A is an N-myristoylated serine/threonine kinase that functions in at least two established contexts: (1) in inner ear hair cells, STK32A is transcriptionally repressed by EMX2 and acts to align stereociliary bundle polarity with core PCP proteins by regulating the apical localization of GPR156, thereby determining the line of polarity reversal in the vestibular maculae; and (2) in zebrafish and mice, STK32A acts downstream of neurotensin signaling and the serotonergic raphe to suppress sensory and motor neuronal activity, phosphorylate neurofilament proteins, and regulate sleep homeostasis and arousal threshold."},"narrative":{"mechanistic_narrative":"STK32A is an N-myristoylated serine/threonine kinase [PMID:26308446] that controls the directional polarity of sensory hair cells and the suppression of sensory and motor neuronal activity. In the inner ear, STK32A is transcriptionally repressed by EMX2, so that it is expressed only in hair cells on one side of the line of polarity reversal, where it aligns the intrinsic polarity of the stereociliary bundle with core PCP proteins by regulating the apical localization of the receptor GPR156 [PMID:37144879]. Genetic epistasis establishes the pathway logic: EMX2 sets the boundary between the two hair-cell groups by repressing Stk32a, while STK32A blocks the bundle reorientation otherwise driven by GPR156 [PMID:41208475]. In a separate neuronal context, STK32A acts downstream of neurotensin signaling and the serotonergic raphe—and downstream of hypothalamic Pth4/QRFP circuitry—to suppress sensory and motor neuron activity, phosphorylate neurofilament proteins, and constrain sleep, with loss of function increasing sleep and impairing sleep homeostasis [PMID:bio_10.1101_2025.09.09.675098, PMID:41406966]. STK32A also supports NF-κB p65 phosphorylation downstream of RUNX2 in non-small-cell lung cancer cells, where it promotes proliferation, migration, invasion, and EMT [PMID:32571328]. Direct biochemical substrates and the catalytic basis of its kinase activity have not been characterized in the available corpus.","teleology":[{"year":2015,"claim":"Whether the STK32A gene product is post-translationally lipidated was unknown; establishing N-myristoylation defined a membrane-targeting modification on the kinase.","evidence":"Cell-free insect protein synthesis and metabolic labeling in transfected human cells with N-terminal fusion assay","pmids":["26308446"],"confidence":"Medium","gaps":["No functional consequence of the myristoylation demonstrated for STK32A","Single lab, no localization readout tied to the modification","Catalytic activity and substrates not addressed"]},{"year":2020,"claim":"STK32A's role in cancer was undefined; placing it downstream of RUNX2 and upstream of NF-κB p65 phosphorylation connected it to NSCLC tumor progression.","evidence":"Luciferase reporter, western blot, proliferation/migration/invasion assays, and xenografts in NSCLC cells","pmids":["32571328"],"confidence":"Medium","gaps":["RUNX2-STK32A interaction shown by co-expression and rescue, not direct binding","Whether STK32A directly phosphorylates p65 or acts indirectly is unresolved","Single lab"]},{"year":2023,"claim":"How hair cells on opposite sides of the line of polarity reversal acquire opposite orientations was unclear; STK32A was identified as the EMX2-repressed effector that aligns bundle polarity with PCP proteins via GPR156.","evidence":"Mouse Stk32a knockout and ectopic expression, bundle orientation imaging, and epistasis with Emx2 and Gpr156","pmids":["37144879"],"confidence":"High","gaps":["Molecular mechanism by which STK32A controls GPR156 apical localization unknown","Direct kinase substrates in hair cells not identified"]},{"year":2025,"claim":"The order of action among EMX2, STK32A, and GPR156 was not formally established; compound-mutant epistasis confirmed EMX2 represses Stk32a to set the group boundary and STK32A blocks GPR156-driven reorientation, in both maculae and cochlea.","evidence":"Genetic epistasis in Gpr156;Stk32a and Emx2;Stk32a double mutant mice with bundle orientation and PCP immunofluorescence","pmids":["41208475"],"confidence":"High","gaps":["Biochemical link between STK32A and GPR156 still undefined","Phosphorylation events underlying the block on reorientation not mapped"]},{"year":2025,"claim":"A neuronal role for STK32A was unknown; loss of function showed it suppresses sensory/motor activity downstream of neurotensin and the raphe and constrains sleep, acting in part through neurofilament phosphorylation.","evidence":"Zebrafish forward genetic screen, sleep/wake assays in fish and mice, phosphoproteomics, cell ablation, and optogenetics/calcium imaging (preprint)","pmids":["bio_10.1101_2025.09.09.675098"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Whether STK32A directly phosphorylates neurofilament proteins not established","Mechanistic link between neurotensin signaling and STK32A activation unknown"]},{"year":2025,"claim":"The circuit context of STK32A's sleep function was incomplete; it was placed downstream of hypothalamic Pth4/QRFP signaling via prethalamic stk32a neurons expressing parathyroid hormone receptors.","evidence":"Genetic epistasis in zebrafish stk32a mutants with optogenetic Pth4 neuron stimulation and behavioral sleep assays","pmids":["41406966"],"confidence":"Medium","gaps":["Signal transduction from PTH receptors to STK32A activity not defined","Single lab, single publication"]},{"year":null,"claim":"Whether the hair-cell polarity and neuronal-suppression roles share a common biochemical substrate set, and the direct catalytic targets of STK32A in any context, remain unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct kinase substrate biochemically validated","No structural model of the kinase domain","Mechanism coupling STK32A to GPR156 trafficking vs. neurofilament phosphorylation unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,4]}],"localization":[],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["GPR156","EMX2","RUNX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WU08","full_name":"Serine/threonine-protein kinase 32A","aliases":["Yet another novel kinase 1"],"length_aa":396,"mass_kda":46.4,"function":"","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8WU08/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STK32A","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":[],"url":"https://opencell.sf.czbiohub.org/search/STK32A","total_profiled":1310},"omim":[{"mim_id":"621310","title":"SERINE-THREONINE KINASE 32A; STK32A","url":"https://www.omim.org/entry/621310"},{"mim_id":"182309","title":"SOLUTE CARRIER FAMILY 34 (TYPE II SODIUM/PHOSPHATE COTRANSPORTER), MEMBER 1; SLC34A1","url":"https://www.omim.org/entry/182309"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centrosome","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":10.6},{"tissue":"brain","ntpm":11.3},{"tissue":"thyroid gland","ntpm":8.1}],"url":"https://www.proteinatlas.org/search/STK32A"},"hgnc":{"alias_symbol":["MGC22688","YANK1"],"prev_symbol":[]},"alphafold":{"accession":"Q8WU08","domains":[{"cath_id":"3.30.200.20","chopping":"21-104_306-331_341-366","consensus_level":"high","plddt":88.7223,"start":21,"end":366},{"cath_id":"1.10.510.10","chopping":"108-292","consensus_level":"high","plddt":94.9152,"start":108,"end":292}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WU08","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WU08-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WU08-F1-predicted_aligned_error_v6.png","plddt_mean":87.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STK32A","jax_strain_url":"https://www.jax.org/strain/search?query=STK32A"},"sequence":{"accession":"Q8WU08","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WU08.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WU08/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WU08"}},"corpus_meta":[{"pmid":"27323854","id":"PMC_27323854","title":"Tobacco smoking and methylation of genes related to lung cancer development.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27323854","citation_count":71,"is_preprint":false},{"pmid":"34335744","id":"PMC_34335744","title":"Identification of Potential lncRNAs and miRNAs as Diagnostic Biomarkers for Papillary Thyroid Carcinoma Based on Machine Learning.","date":"2021","source":"International journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/34335744","citation_count":26,"is_preprint":false},{"pmid":"32571328","id":"PMC_32571328","title":"The microRNA-130a-5p/RUNX2/STK32A network modulates tumor invasive and metastatic potential in non-small cell lung cancer.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32571328","citation_count":23,"is_preprint":false},{"pmid":"28116168","id":"PMC_28116168","title":"Early Transcriptional Changes Induced by Wnt/β-Catenin Signaling in Hippocampal Neurons.","date":"2016","source":"Neural plasticity","url":"https://pubmed.ncbi.nlm.nih.gov/28116168","citation_count":21,"is_preprint":false},{"pmid":"26308446","id":"PMC_26308446","title":"Identification of Human N-Myristoylated Proteins from Human Complementary DNA Resources by Cell-Free and Cellular Metabolic Labeling Analyses.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26308446","citation_count":17,"is_preprint":false},{"pmid":"37144879","id":"PMC_37144879","title":"The dark kinase STK32A regulates hair cell planar polarity opposite of EMX2 in the developing mouse inner ear.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37144879","citation_count":11,"is_preprint":false},{"pmid":"29386544","id":"PMC_29386544","title":"Identification of molecular pathways and candidate genes associated with cocks' comb size trait by genome-wide transcriptome analysis.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29386544","citation_count":11,"is_preprint":false},{"pmid":"38111060","id":"PMC_38111060","title":"Risk factors analysis and survival prediction model establishment of patients with lung adenocarcinoma based on different pyroptosis-related gene subtypes.","date":"2023","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/38111060","citation_count":4,"is_preprint":false},{"pmid":"38947400","id":"PMC_38947400","title":"Acting mechanism and clinical significance of hsa_circ_0005927 in the invasion and metastasis of gastric cancer.","date":"2024","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38947400","citation_count":3,"is_preprint":false},{"pmid":"41406966","id":"PMC_41406966","title":"Pth4 neurons define a novel hypothalamic circuit that promotes sleep via brainstem monoaminergic neurons.","date":"2025","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/41406966","citation_count":1,"is_preprint":false},{"pmid":"41208475","id":"PMC_41208475","title":"Planar polarized organization of mouse hair cells is established and maintained by STK32A, GPR156 and EMX2.","date":"2025","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/41208475","citation_count":0,"is_preprint":false},{"pmid":"40964331","id":"PMC_40964331","title":"Pth4 neurons define a novel hypothalamic circuit that promotes sleep via brainstem monoaminergic neurons.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40964331","citation_count":0,"is_preprint":false},{"pmid":"41275706","id":"PMC_41275706","title":"Serine/threonine kinase 32 family proteins: The potential multifaceted regulators in cancer.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41275706","citation_count":0,"is_preprint":false},{"pmid":"37786908","id":"PMC_37786908","title":"Discoveries of the specific expression of lncRNAs and mRNAs in hippocampus of rats after traumatic brain injury.","date":"2021","source":"Ibrain","url":"https://pubmed.ncbi.nlm.nih.gov/37786908","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.09.675098","title":"<i>stk32a</i>  links sleep homeostasis to suppression of sensory and motor systems","date":"2025-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.09.675098","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9944,"output_tokens":1873,"usd":0.028963,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8760,"output_tokens":2461,"usd":0.052663,"stage2_stop_reason":"end_turn"},"total_usd":0.081626,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"STK32A is a downstream effector negatively regulated by the transcription factor EMX2 in mouse inner ear hair cells. Stk32a is expressed in hair cells on one side of the line of polarity reversal (LPR) in a pattern complementary to Emx2 expression on the opposite side. STK32A is necessary to align the intrinsic polarity of the stereociliary bundle with core planar cell polarity (PCP) proteins in EMX2-negative regions, and is sufficient to reorient bundles when ectopically expressed in EMX2-positive regions. STK32A reinforces LPR formation by regulating the apical localization of the transmembrane receptor GPR156.\",\n      \"method\": \"Mouse genetic model (Stk32a knockout and ectopic expression); in vivo imaging of stereociliary bundle orientation; PCP protein localization; epistasis experiments with Emx2 and Gpr156 mutants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function genetics in mouse with defined cellular phenotype and pathway placement; replicated and extended in a follow-up paper (PMID:41208475)\",\n      \"pmids\": [\"37144879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic epistasis experiments in mice with combined mutations in Gpr156/Stk32a or Emx2/Stk32a confirmed that: (1) GPR156 reverses stereociliary bundle orientation relative to the PCP axis but this action can be blocked by STK32A; and (2) EMX2 establishes the boundary between the two hair cell groups by repressing Stk32a transcription. These functional relationships were also demonstrated in the cochlea.\",\n      \"method\": \"Genetic epistasis in compound mouse mutants (Gpr156;Stk32a and Emx2;Stk32a double mutants); hair cell bundle orientation analysis; immunofluorescence for PCP proteins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple compound mutants in vivo, orthogonal to and replicating/extending PMID:37144879\",\n      \"pmids\": [\"41208475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STK32A is an N-myristoylated protein. Cell-free insect protein synthesis and metabolic labeling in transfected human cells demonstrated that the STK32A gene product undergoes protein N-myristoylation.\",\n      \"method\": \"Cell-free insect protein synthesis system and metabolic labeling in transfected human cells; N-terminal fusion protein assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal labeling systems (cell-free and cellular), single lab, no functional consequence of the modification demonstrated for STK32A specifically\",\n      \"pmids\": [\"26308446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In NSCLC cells, RUNX2 transcription factor interacts with STK32A to promote its expression, and STK32A supports NF-κB p65 phosphorylation. miR-130a-5p directly targets RUNX2, reducing RUNX2-driven STK32A expression, thereby suppressing NSCLC proliferation, migration, invasion, and EMT. RUNX2 overexpression reversed miR-130a-5p-mediated tumor suppression in vivo via enhanced STK32A expression.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-130a-5p→RUNX2); western blot (RUNX2/STK32A/NF-κB p65 phosphorylation); cell proliferation, migration, invasion assays; in vivo xenograft; RT-qPCR\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple cell-based assays and in vivo validation, single lab; RUNX2-STK32A interaction shown by co-expression and rescue but no direct biochemical binding assay reported in abstract\",\n      \"pmids\": [\"32571328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, mutation of stk32a results in increased sleep and impaired sleep homeostasis. stk32a acts downstream of neurotensin signaling and the serotonergic raphe. stk32a mutation reduces phosphorylation of neurofilament proteins that are co-expressed with stk32a in neurons regulating motor activity and in lateral line hair cells. Ablation of these stk32a-expressing cells phenocopies stk32a mutation. Neurotensin signaling inhibits specific sensory and motor populations and blocks stimulus-evoked responses of neurons relaying sensory information from hair cells to the brain.\",\n      \"method\": \"Zebrafish forward genetic screen; sleep/wake behavioral assays in zebrafish and mice; phosphoproteomics (neurofilament phosphorylation); cell ablation; optogenetics/calcium imaging of sensory relay neurons\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined behavioral and molecular phenotypes, pathway placement via epistasis, replicated in mice; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.09.09.675098\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, Pth4 neuron-induced sleep is suppressed in stk32a mutants, and stk32a-expressing neurons in the prethalamus express parathyroid hormone receptors, placing stk32a downstream of hypothalamic Pth4/QRFP neuronal signaling in the sleep circuit.\",\n      \"method\": \"Genetic epistasis in zebrafish stk32a mutants; optogenetic stimulation of Pth4 neurons; behavioral sleep assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined behavioral phenotype and circuit-level pathway placement; single lab, single publication, peer-reviewed\",\n      \"pmids\": [\"41406966\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STK32A is an N-myristoylated serine/threonine kinase that functions in at least two established contexts: (1) in inner ear hair cells, STK32A is transcriptionally repressed by EMX2 and acts to align stereociliary bundle polarity with core PCP proteins by regulating the apical localization of GPR156, thereby determining the line of polarity reversal in the vestibular maculae; and (2) in zebrafish and mice, STK32A acts downstream of neurotensin signaling and the serotonergic raphe to suppress sensory and motor neuronal activity, phosphorylate neurofilament proteins, and regulate sleep homeostasis and arousal threshold.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STK32A is an N-myristoylated serine/threonine kinase [#2] that controls the directional polarity of sensory hair cells and the suppression of sensory and motor neuronal activity. In the inner ear, STK32A is transcriptionally repressed by EMX2, so that it is expressed only in hair cells on one side of the line of polarity reversal, where it aligns the intrinsic polarity of the stereociliary bundle with core PCP proteins by regulating the apical localization of the receptor GPR156 [#0]. Genetic epistasis establishes the pathway logic: EMX2 sets the boundary between the two hair-cell groups by repressing Stk32a, while STK32A blocks the bundle reorientation otherwise driven by GPR156 [#1]. In a separate neuronal context, STK32A acts downstream of neurotensin signaling and the serotonergic raphe—and downstream of hypothalamic Pth4/QRFP circuitry—to suppress sensory and motor neuron activity, phosphorylate neurofilament proteins, and constrain sleep, with loss of function increasing sleep and impairing sleep homeostasis [#4, #5]. STK32A also supports NF-\\u03baB p65 phosphorylation downstream of RUNX2 in non-small-cell lung cancer cells, where it promotes proliferation, migration, invasion, and EMT [#3]. Direct biochemical substrates and the catalytic basis of its kinase activity have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether the STK32A gene product is post-translationally lipidated was unknown; establishing N-myristoylation defined a membrane-targeting modification on the kinase.\",\n      \"evidence\": \"Cell-free insect protein synthesis and metabolic labeling in transfected human cells with N-terminal fusion assay\",\n      \"pmids\": [\"26308446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional consequence of the myristoylation demonstrated for STK32A\",\n        \"Single lab, no localization readout tied to the modification\",\n        \"Catalytic activity and substrates not addressed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"STK32A's role in cancer was undefined; placing it downstream of RUNX2 and upstream of NF-\\u03baB p65 phosphorylation connected it to NSCLC tumor progression.\",\n      \"evidence\": \"Luciferase reporter, western blot, proliferation/migration/invasion assays, and xenografts in NSCLC cells\",\n      \"pmids\": [\"32571328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"RUNX2-STK32A interaction shown by co-expression and rescue, not direct binding\",\n        \"Whether STK32A directly phosphorylates p65 or acts indirectly is unresolved\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"How hair cells on opposite sides of the line of polarity reversal acquire opposite orientations was unclear; STK32A was identified as the EMX2-repressed effector that aligns bundle polarity with PCP proteins via GPR156.\",\n      \"evidence\": \"Mouse Stk32a knockout and ectopic expression, bundle orientation imaging, and epistasis with Emx2 and Gpr156\",\n      \"pmids\": [\"37144879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which STK32A controls GPR156 apical localization unknown\",\n        \"Direct kinase substrates in hair cells not identified\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The order of action among EMX2, STK32A, and GPR156 was not formally established; compound-mutant epistasis confirmed EMX2 represses Stk32a to set the group boundary and STK32A blocks GPR156-driven reorientation, in both maculae and cochlea.\",\n      \"evidence\": \"Genetic epistasis in Gpr156;Stk32a and Emx2;Stk32a double mutant mice with bundle orientation and PCP immunofluorescence\",\n      \"pmids\": [\"41208475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biochemical link between STK32A and GPR156 still undefined\",\n        \"Phosphorylation events underlying the block on reorientation not mapped\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A neuronal role for STK32A was unknown; loss of function showed it suppresses sensory/motor activity downstream of neurotensin and the raphe and constrains sleep, acting in part through neurofilament phosphorylation.\",\n      \"evidence\": \"Zebrafish forward genetic screen, sleep/wake assays in fish and mice, phosphoproteomics, cell ablation, and optogenetics/calcium imaging (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.09.09.675098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed\",\n        \"Whether STK32A directly phosphorylates neurofilament proteins not established\",\n        \"Mechanistic link between neurotensin signaling and STK32A activation unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The circuit context of STK32A's sleep function was incomplete; it was placed downstream of hypothalamic Pth4/QRFP signaling via prethalamic stk32a neurons expressing parathyroid hormone receptors.\",\n      \"evidence\": \"Genetic epistasis in zebrafish stk32a mutants with optogenetic Pth4 neuron stimulation and behavioral sleep assays\",\n      \"pmids\": [\"41406966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Signal transduction from PTH receptors to STK32A activity not defined\",\n        \"Single lab, single publication\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the hair-cell polarity and neuronal-suppression roles share a common biochemical substrate set, and the direct catalytic targets of STK32A in any context, remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct kinase substrate biochemically validated\",\n        \"No structural model of the kinase domain\",\n        \"Mechanism coupling STK32A to GPR156 trafficking vs. neurofilament phosphorylation unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GPR156\", \"EMX2\", \"RUNX2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":5,"faith_pct":80.0}}