{"gene":"SLMAP","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2004,"finding":"A novel 91 kDa SLMAP isoform containing an N-terminal forkhead-associated (FHA) domain localizes to the centrosome (MTOC) at all phases of the cell cycle, co-localizing with gamma-tubulin. Microtubule-disrupting agents did not affect this association. Deletion of the N-terminal sequence prevented centrosomal targeting. Elevated centrosomal SLMAP was lethal, whereas centrosomal-targeting mutants inhibited cell growth and caused accumulation at G2/M.","method":"Anti-peptide antibody immunofluorescence, GFP-reporter targeting assays, deletion-mutant analysis, cell cycle profiling","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with GFP reporter and deletion mapping, functional consequence (G2/M arrest, lethality) demonstrated, single lab with two orthogonal methods","pmids":["15126628"],"is_preprint":false},{"year":2004,"finding":"SLMAP isoforms in cardiac myocytes can self-assemble (homodimerize) and bind myosin in cardiac muscle. Multiple SLMAP isoforms possess distinct C-terminal membrane anchors that target them to different subcellular membranes involved in excitation-contraction coupling (sarcolemma, T-tubules, sarcoplasmic reticulum).","method":"Protein interaction analysis (co-immunoprecipitation/pulldown), subcellular fractionation, immunolocalization","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP/pulldown for myosin interaction, supported by subcellular localization; single lab, two orthogonal methods","pmids":["15591093"],"is_preprint":false},{"year":2009,"finding":"The hydrophobicity of SLMAP's two alternatively spliced tail anchors (TA1 and TA2) determines subcellular targeting: both TA1 and TA2 direct SLMAP to the ER, but TA2 additionally directs SLMAP to mitochondria. Mitochondrial targeting by TA2 requires the hydrophobicity of its transmembrane region; substitution of moderately hydrophobic residues with leucine (SLMAP-TA2-4L mutant) converts targeting to match TA1 (ER only). Flanking positively charged residues are not required for mitochondrial targeting.","method":"GFP-fusion targeting assays, site-directed mutagenesis of tail anchor transmembrane domain, confocal microscopy","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional readout (subcellular targeting), GFP reporter, multiple mutant constructs; single lab but multiple orthogonal approaches","pmids":["19538755"],"is_preprint":false},{"year":2011,"finding":"Cardiac-specific overexpression of SLMAP1-TM2 in transgenic mice caused inappropriate homodimerization and targeting to the SR/ER, leading to SR/ER dilation, reduced expression of SR calcium-cycling proteins (ryanodine receptor, Ca2+-ATPase, calsequestrin, triadin but not phospholamban), reduced calcium uptake, impaired contractility, and elongated QT interval, demonstrating SLMAP regulates E-C coupling at the SR.","method":"Transgenic mouse model, high-resolution/confocal microscopy, biochemical fractionation, left ventricular pressure monitoring, ECG, calcium uptake assay","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic loss-of-function model with multiple orthogonal readouts (electrophysiology, biochemistry, imaging, functional assay) in single rigorous study","pmids":["22180652"],"is_preprint":false},{"year":2011,"finding":"In diabetic adipose tissue, a 45 kDa SLMAP isoform co-immunoprecipitates with GLUT-4. siRNA knockdown of SLMAP in adipocytes significantly reduced SLMAP expression and decreased glucose uptake, suggesting SLMAP is involved in GLUT-4 fusion/translocation to the plasma membrane.","method":"Co-immunoprecipitation, siRNA knockdown, glucose uptake assay","journal":"Experimental diabetes research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus functional siRNA knockdown with glucose uptake readout; single lab, two orthogonal methods","pmids":["21785580"],"is_preprint":false},{"year":2014,"finding":"The fungal SLMAP homolog PRO45 (Sordaria macrospora) localizes to the nuclear envelope, ER, and mitochondria as determined by superresolution SIM microscopy. Localization to the nuclear envelope (but not mitochondria) requires STRIPAK subunits PRO11 and PRO22. PRO45 binds STRIPAK subunits PRO11 and SmMOB3 (protein-protein interaction), and its FHA domain is essential for sexual propagation and cell-to-cell fusion.","method":"Superresolution structured-illumination microscopy (SIM), yeast two-hybrid/pulldown (protein-protein interaction), genetic deletion/complementation","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — superresolution microscopy with genetic dependency tested, protein interactions confirmed, multiple orthogonal approaches; fungal ortholog, single lab","pmids":["25527523"],"is_preprint":false},{"year":2019,"finding":"SLMAP-3 interacts with striatin (STRN) in cardiomyocytes as detected by proteomics. Overexpression of SLMAP-3 increases intracellular calcium transients in response to isoproterenol, and knockdown of SLMAP causes reduced spontaneous contractile rate that is not rescued by isoproterenol challenge, phenocopying heart failure.","method":"Proteomics (interaction discovery), adeno-associated viral vector overexpression/knockdown, confocal live calcium imaging, contractile rate measurement","journal":"Canadian journal of physiology and pharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proteomics-based interaction plus functional live-cell imaging and KD phenotype; single lab, multiple readouts","pmids":["30856349"],"is_preprint":false},{"year":2025,"finding":"SLMAP in gut mesenchyme directly regulates MST3 kinase activity to control YAP activation. Deletion of Slmap in gut mesenchyme impairs YAP activity, reduces intestinal epithelial cell proliferation, and results in a short gut phenotype. The short gut phenotype in Slmap mesenchyme-specific mutants is partially rescued by concomitant deletion of Mst3, placing SLMAP upstream of MST3 in the YAP pathway.","method":"Conditional knockout mouse model (mesenchyme-specific Slmap deletion), genetic epistasis (double Slmap;Mst3 mesenchymal knockout), single-cell RNA-sequencing, YAP activity assays, proliferation measurements","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo conditional KO with defined cellular phenotype, genetic epistasis with Mst3 double-mutant rescue, multiple orthogonal readouts; single lab but rigorous","pmids":["40521668"],"is_preprint":false},{"year":2023,"finding":"miR-29b-3p directly targets SLMAP mRNA (validated by dual-luciferase reporter assay), and GLP-1 receptor agonist treatment upregulates miR-29b-3p to downregulate SLMAP expression in cardiomyocytes. Inhibition of GLP-1R reverses this effect, placing SLMAP downstream of the GLP-1R/miR-29b-3p axis.","method":"Dual-luciferase reporter assay, Western blotting, quantitative RT-PCR, GLP-1R inhibition experiment","journal":"Drug design, development and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct miRNA-target validation by luciferase assay plus pharmacological intervention; single lab, two orthogonal methods","pmids":["36936522"],"is_preprint":false}],"current_model":"SLMAP is a tail-anchored membrane protein with multiple isoforms whose subcellular targeting (ER, mitochondria, sarcoplasmic reticulum, centrosome) is determined by the hydrophobicity of its alternatively spliced C-terminal transmembrane domains; it functions as a component of the STRIPAK complex through its N-terminal FHA domain, regulates cardiac excitation-contraction coupling at the sarcoplasmic reticulum by controlling calcium-cycling protein expression and intracellular calcium transients (partly via interaction with striatin), promotes YAP activity in gut mesenchyme by inhibiting MST3 kinase, associates with GLUT-4 to influence glucose uptake in adipocytes, and its expression is post-transcriptionally regulated by miR-29b-3p downstream of GLP-1 receptor signaling."},"narrative":{"mechanistic_narrative":"SLMAP is a tail-anchored membrane protein expressed as multiple alternatively spliced isoforms whose distinct C-terminal transmembrane anchors dictate differential subcellular targeting, with the hydrophobicity of the tail anchor determining whether the protein localizes to the ER alone (TA1) or additionally to mitochondria (TA2) [PMID:19538755]. An N-terminal FHA domain directs a 91 kDa isoform to the centrosome throughout the cell cycle, where dysregulated levels are lethal or arrest cells at G2/M [PMID:15126628], and the conserved FHA domain mediates incorporation into the STRIPAK complex, as shown for the fungal ortholog PRO45 which binds STRIPAK subunits and depends on them for nuclear-envelope targeting [PMID:25527523]. In cardiac muscle SLMAP isoforms self-assemble and target sarcolemmal, T-tubule, and sarcoplasmic-reticulum membranes involved in excitation-contraction coupling [PMID:15591093]; SLMAP regulates E-C coupling at the SR by controlling expression of calcium-cycling proteins and intracellular calcium transients, with cardiac overexpression causing SR/ER dilation, reduced ryanodine receptor/Ca2+-ATPase/calsequestrin/triadin levels, impaired contractility, and QT prolongation [PMID:22180652], and with the SLMAP-3 isoform interacting with striatin to modulate calcium transients and contractile rate [PMID:30856349]. Through STRIPAK-linked signaling, SLMAP acts upstream of MST3 kinase to promote YAP activation in gut mesenchyme, supporting intestinal epithelial proliferation and proper gut length [PMID:40521668]. SLMAP additionally associates with GLUT-4 in adipocytes to influence glucose uptake [PMID:21785580], and its expression is post-transcriptionally repressed by miR-29b-3p downstream of GLP-1 receptor signaling [PMID:36936522].","teleology":[{"year":2004,"claim":"Established that an FHA-domain-containing SLMAP isoform is a cell-cycle-relevant centrosomal protein, linking SLMAP to MTOC function and mitotic progression.","evidence":"Anti-peptide immunofluorescence, GFP-reporter targeting and deletion mapping, cell cycle profiling in cultured cells","pmids":["15126628"],"confidence":"Medium","gaps":["Molecular function of SLMAP at the centrosome not defined","No partner identified mediating centrosomal targeting beyond the N-terminal sequence","Mechanism of G2/M arrest unexplained"]},{"year":2004,"claim":"Showed SLMAP isoforms self-assemble and bind myosin and partition to distinct E-C coupling membranes, framing SLMAP as a membrane-targeted structural component of cardiac muscle.","evidence":"Co-immunoprecipitation/pulldown, subcellular fractionation and immunolocalization in cardiac myocytes","pmids":["15591093"],"confidence":"Medium","gaps":["Myosin interaction rests on single Co-IP/pulldown without reciprocal validation","Functional consequence of homodimerization not tested","Which isoform binds myosin unclear"]},{"year":2009,"claim":"Defined the biophysical rule for SLMAP isoform targeting, demonstrating that tail-anchor hydrophobicity selects between ER-only and ER-plus-mitochondrial localization.","evidence":"GFP-fusion targeting assays with site-directed mutagenesis of the tail-anchor transmembrane domain and confocal microscopy","pmids":["19538755"],"confidence":"High","gaps":["Insertion machinery for the tail anchor not identified","Functional role of mitochondrial-targeted SLMAP not addressed","Targeting tested with reporter fusions, not endogenous isoforms"]},{"year":2011,"claim":"Provided in vivo proof that SLMAP controls cardiac E-C coupling by regulating SR calcium-cycling protein expression and calcium handling.","evidence":"Cardiac-specific transgenic mice with electrophysiology (ECG), pressure monitoring, calcium uptake assays, fractionation, and imaging","pmids":["22180652"],"confidence":"High","gaps":["Mechanism by which SLMAP controls calcium-protein expression unknown","Effect is from a gain-of-function/mistargeting construct rather than endogenous loss","Direct molecular targets at the SR not identified"]},{"year":2011,"claim":"Connected SLMAP to metabolic regulation by linking a 45 kDa isoform to GLUT-4 and glucose uptake in adipocytes.","evidence":"Co-immunoprecipitation with GLUT-4 and siRNA knockdown with glucose uptake assay in adipocytes","pmids":["21785580"],"confidence":"Medium","gaps":["GLUT-4 interaction from single Co-IP without reciprocal validation","Direct role in vesicle fusion/translocation not demonstrated","Relationship to other SLMAP isoforms/functions unclear"]},{"year":2014,"claim":"Established the FHA-domain-dependent association of the SLMAP ortholog with the STRIPAK complex and its requirement for STRIPAK-dependent nuclear-envelope targeting and developmental processes.","evidence":"Superresolution SIM microscopy, yeast two-hybrid/pulldown, and genetic deletion/complementation in Sordaria macrospora","pmids":["25527523"],"confidence":"Medium","gaps":["Demonstrated in fungal ortholog; mammalian STRIPAK linkage inferred","FHA-domain binding partners in the complex not fully mapped","Mechanistic link between localization and fusion phenotype unresolved"]},{"year":2019,"claim":"Identified striatin as a cardiomyocyte SLMAP-3 partner and tied SLMAP levels to calcium transients and contractile rate, reinforcing its role in cardiac function.","evidence":"Proteomics interaction discovery with AAV overexpression/knockdown, live calcium imaging and contractile rate measurement","pmids":["30856349"],"confidence":"Medium","gaps":["Striatin interaction from proteomics not orthogonally confirmed","Causal chain from STRN binding to calcium handling unmapped","Relationship to STRIPAK signaling in heart untested"]},{"year":2023,"claim":"Placed SLMAP downstream of GLP-1R signaling by identifying miR-29b-3p as a direct repressor of SLMAP mRNA in cardiomyocytes.","evidence":"Dual-luciferase reporter assay, Western blot, qRT-PCR, and pharmacological GLP-1R inhibition","pmids":["36936522"],"confidence":"Medium","gaps":["Downstream cardiac consequence of SLMAP repression not functionally dissected","Which SLMAP isoform is targeted unclear","Physiological relevance of the axis in vivo not established"]},{"year":2025,"claim":"Defined SLMAP as an upstream regulator of MST3 in the YAP pathway controlling intestinal mesenchymal-epithelial signaling and gut growth.","evidence":"Mesenchyme-specific conditional knockout mice, Slmap;Mst3 double-mutant genetic epistasis, scRNA-seq, YAP activity and proliferation assays","pmids":["40521668"],"confidence":"High","gaps":["Biochemical mechanism by which SLMAP inhibits MST3 not resolved","Role of STRIPAK in this regulation not directly tested","Partial rescue indicates additional MST3-independent effectors"]},{"year":null,"claim":"How SLMAP's shared FHA/STRIPAK module is mechanistically coupled to its diverse isoform-specific outputs (centrosome, cardiac SR calcium handling, GLUT-4, MST3/YAP) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FHA-domain partner engagement","Direct enzymatic or scaffold mechanism toward MST3 undefined","Unifying principle linking tail-anchor targeting to downstream signaling absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[3,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7]}],"complexes":["STRIPAK"],"partners":["STRN","MST3","SLC2A4","PRO11","SMMOB3","MYOSIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14BN4","full_name":"Sarcolemmal membrane-associated protein","aliases":[],"length_aa":828,"mass_kda":95.2,"function":"Associates with the striatin-interacting phosphatase and kinase (STRIPAK) core complex, forming the extended (SIKE1:SLMAP)STRIPAK complex (PubMed:29063833, PubMed:30622739). The (SIKE1:SLMAP)STRIPAK complex dephosphorylates STK3 leading to the inhibition of Hippo signaling and the control of cell growth (PubMed:29063833, PubMed:30622739). May play a role during myoblast fusion (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q14BN4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLMAP","classification":"Not Classified","n_dependent_lines":253,"n_total_lines":1208,"dependency_fraction":0.20943708609271522},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ATXN2L","stoichiometry":0.2},{"gene":"CDS2","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"PPP2CA","stoichiometry":0.2},{"gene":"RTN4","stoichiometry":0.2},{"gene":"STK24","stoichiometry":0.2},{"gene":"STK25","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SLMAP","total_profiled":1310},"omim":[{"mim_id":"602701","title":"SARCOLEMMAL-ASSOCIATED PROTEIN; SLMAP","url":"https://www.omim.org/entry/602701"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SLMAP"},"hgnc":{"alias_symbol":["SLAP","KIAA1601"],"prev_symbol":[]},"alphafold":{"accession":"Q14BN4","domains":[{"cath_id":"2.60.200.20","chopping":"2-137","consensus_level":"medium","plddt":85.5619,"start":2,"end":137}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14BN4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14BN4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14BN4-F1-predicted_aligned_error_v6.png","plddt_mean":77.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLMAP","jax_strain_url":"https://www.jax.org/strain/search?query=SLMAP"},"sequence":{"accession":"Q14BN4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14BN4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14BN4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14BN4"}},"corpus_meta":[{"pmid":"25527523","id":"PMC_25527523","title":"A fungal sarcolemmal membrane-associated protein (SLMAP) homolog plays a fundamental role in development and localizes to the nuclear envelope, endoplasmic reticulum, and mitochondria.","date":"2014","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/25527523","citation_count":49,"is_preprint":false},{"pmid":"15126628","id":"PMC_15126628","title":"A novel isoform of sarcolemmal membrane-associated protein (SLMAP) is a component of the microtubule organizing centre.","date":"2004","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/15126628","citation_count":40,"is_preprint":false},{"pmid":"15591093","id":"PMC_15591093","title":"Molecular properties of cardiac tail-anchored membrane protein SLMAP are consistent with structural role in arrangement of excitation-contraction coupling apparatus.","date":"2004","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15591093","citation_count":30,"is_preprint":false},{"pmid":"19538755","id":"PMC_19538755","title":"Hydrophobic profiles of the tail anchors in SLMAP dictate subcellular targeting.","date":"2009","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19538755","citation_count":29,"is_preprint":false},{"pmid":"22180652","id":"PMC_22180652","title":"Tail-anchored membrane protein SLMAP is a novel regulator of cardiac function at the sarcoplasmic reticulum.","date":"2011","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22180652","citation_count":25,"is_preprint":false},{"pmid":"15764684","id":"PMC_15764684","title":"Endothelial dysfunction in Type 2 diabetes correlates with deregulated expression of the tail-anchored membrane protein SLMAP.","date":"2005","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15764684","citation_count":20,"is_preprint":false},{"pmid":"31233748","id":"PMC_31233748","title":"The SLMAP/Striatin complex: An emerging regulator of normal and abnormal cardiac excitation-contraction coupling.","date":"2019","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31233748","citation_count":13,"is_preprint":false},{"pmid":"36936522","id":"PMC_36936522","title":"Glucagon-Like Peptide-1 Receptor Agonist Protects Against Diabetic Cardiomyopathy by Modulating microRNA-29b-3p/SLMAP.","date":"2023","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36936522","citation_count":12,"is_preprint":false},{"pmid":"25880194","id":"PMC_25880194","title":"Role of SLMAP genetic variants in susceptibility of diabetes and diabetic retinopathy in Qatari population.","date":"2015","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25880194","citation_count":11,"is_preprint":false},{"pmid":"31160357","id":"PMC_31160357","title":"Targeting SLMAP-ALK-a novel gene fusion in lung adenocarcinoma.","date":"2019","source":"Cold Spring Harbor molecular case studies","url":"https://pubmed.ncbi.nlm.nih.gov/31160357","citation_count":9,"is_preprint":false},{"pmid":"21785580","id":"PMC_21785580","title":"Increased expression of the tail-anchored membrane protein SLMAP in adipose tissue from type 2 Tally Ho diabetic mice.","date":"2011","source":"Experimental diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/21785580","citation_count":8,"is_preprint":false},{"pmid":"30856349","id":"PMC_30856349","title":"SLMAP-3 is downregulated in human dilated ventricles and its overexpression promotes cardiomyocyte response to adrenergic stimuli by increasing intracellular calcium.","date":"2019","source":"Canadian journal of physiology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30856349","citation_count":6,"is_preprint":false},{"pmid":"38606111","id":"PMC_38606111","title":"Case report: Primary sarcoma of the mandible with a novel SLMAP-BRAF fusion.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38606111","citation_count":4,"is_preprint":false},{"pmid":"40521668","id":"PMC_40521668","title":"Mesenchymal SLMAP coordinates with MST3 to govern gut elongation during development.","date":"2025","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40521668","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.11.25339992","title":"Multi-ancestry proteogenomic analysis identifies risk proteins for intracranial aneurysms","date":"2025-11-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.11.25339992","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.06.606879","title":"The  <i>Cryptococcus neoformans</i>  STRIPAK complex controls genome stability, sexual development, and virulence","date":"2024-08-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.06.606879","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10704,"output_tokens":2572,"usd":0.035346,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9870,"output_tokens":3736,"usd":0.071375,"stage2_stop_reason":"end_turn"},"total_usd":0.106721,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"A novel 91 kDa SLMAP isoform containing an N-terminal forkhead-associated (FHA) domain localizes to the centrosome (MTOC) at all phases of the cell cycle, co-localizing with gamma-tubulin. Microtubule-disrupting agents did not affect this association. Deletion of the N-terminal sequence prevented centrosomal targeting. Elevated centrosomal SLMAP was lethal, whereas centrosomal-targeting mutants inhibited cell growth and caused accumulation at G2/M.\",\n      \"method\": \"Anti-peptide antibody immunofluorescence, GFP-reporter targeting assays, deletion-mutant analysis, cell cycle profiling\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with GFP reporter and deletion mapping, functional consequence (G2/M arrest, lethality) demonstrated, single lab with two orthogonal methods\",\n      \"pmids\": [\"15126628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SLMAP isoforms in cardiac myocytes can self-assemble (homodimerize) and bind myosin in cardiac muscle. Multiple SLMAP isoforms possess distinct C-terminal membrane anchors that target them to different subcellular membranes involved in excitation-contraction coupling (sarcolemma, T-tubules, sarcoplasmic reticulum).\",\n      \"method\": \"Protein interaction analysis (co-immunoprecipitation/pulldown), subcellular fractionation, immunolocalization\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP/pulldown for myosin interaction, supported by subcellular localization; single lab, two orthogonal methods\",\n      \"pmids\": [\"15591093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The hydrophobicity of SLMAP's two alternatively spliced tail anchors (TA1 and TA2) determines subcellular targeting: both TA1 and TA2 direct SLMAP to the ER, but TA2 additionally directs SLMAP to mitochondria. Mitochondrial targeting by TA2 requires the hydrophobicity of its transmembrane region; substitution of moderately hydrophobic residues with leucine (SLMAP-TA2-4L mutant) converts targeting to match TA1 (ER only). Flanking positively charged residues are not required for mitochondrial targeting.\",\n      \"method\": \"GFP-fusion targeting assays, site-directed mutagenesis of tail anchor transmembrane domain, confocal microscopy\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional readout (subcellular targeting), GFP reporter, multiple mutant constructs; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"19538755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cardiac-specific overexpression of SLMAP1-TM2 in transgenic mice caused inappropriate homodimerization and targeting to the SR/ER, leading to SR/ER dilation, reduced expression of SR calcium-cycling proteins (ryanodine receptor, Ca2+-ATPase, calsequestrin, triadin but not phospholamban), reduced calcium uptake, impaired contractility, and elongated QT interval, demonstrating SLMAP regulates E-C coupling at the SR.\",\n      \"method\": \"Transgenic mouse model, high-resolution/confocal microscopy, biochemical fractionation, left ventricular pressure monitoring, ECG, calcium uptake assay\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic loss-of-function model with multiple orthogonal readouts (electrophysiology, biochemistry, imaging, functional assay) in single rigorous study\",\n      \"pmids\": [\"22180652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In diabetic adipose tissue, a 45 kDa SLMAP isoform co-immunoprecipitates with GLUT-4. siRNA knockdown of SLMAP in adipocytes significantly reduced SLMAP expression and decreased glucose uptake, suggesting SLMAP is involved in GLUT-4 fusion/translocation to the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, glucose uptake assay\",\n      \"journal\": \"Experimental diabetes research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus functional siRNA knockdown with glucose uptake readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"21785580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The fungal SLMAP homolog PRO45 (Sordaria macrospora) localizes to the nuclear envelope, ER, and mitochondria as determined by superresolution SIM microscopy. Localization to the nuclear envelope (but not mitochondria) requires STRIPAK subunits PRO11 and PRO22. PRO45 binds STRIPAK subunits PRO11 and SmMOB3 (protein-protein interaction), and its FHA domain is essential for sexual propagation and cell-to-cell fusion.\",\n      \"method\": \"Superresolution structured-illumination microscopy (SIM), yeast two-hybrid/pulldown (protein-protein interaction), genetic deletion/complementation\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — superresolution microscopy with genetic dependency tested, protein interactions confirmed, multiple orthogonal approaches; fungal ortholog, single lab\",\n      \"pmids\": [\"25527523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLMAP-3 interacts with striatin (STRN) in cardiomyocytes as detected by proteomics. Overexpression of SLMAP-3 increases intracellular calcium transients in response to isoproterenol, and knockdown of SLMAP causes reduced spontaneous contractile rate that is not rescued by isoproterenol challenge, phenocopying heart failure.\",\n      \"method\": \"Proteomics (interaction discovery), adeno-associated viral vector overexpression/knockdown, confocal live calcium imaging, contractile rate measurement\",\n      \"journal\": \"Canadian journal of physiology and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proteomics-based interaction plus functional live-cell imaging and KD phenotype; single lab, multiple readouts\",\n      \"pmids\": [\"30856349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLMAP in gut mesenchyme directly regulates MST3 kinase activity to control YAP activation. Deletion of Slmap in gut mesenchyme impairs YAP activity, reduces intestinal epithelial cell proliferation, and results in a short gut phenotype. The short gut phenotype in Slmap mesenchyme-specific mutants is partially rescued by concomitant deletion of Mst3, placing SLMAP upstream of MST3 in the YAP pathway.\",\n      \"method\": \"Conditional knockout mouse model (mesenchyme-specific Slmap deletion), genetic epistasis (double Slmap;Mst3 mesenchymal knockout), single-cell RNA-sequencing, YAP activity assays, proliferation measurements\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo conditional KO with defined cellular phenotype, genetic epistasis with Mst3 double-mutant rescue, multiple orthogonal readouts; single lab but rigorous\",\n      \"pmids\": [\"40521668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-29b-3p directly targets SLMAP mRNA (validated by dual-luciferase reporter assay), and GLP-1 receptor agonist treatment upregulates miR-29b-3p to downregulate SLMAP expression in cardiomyocytes. Inhibition of GLP-1R reverses this effect, placing SLMAP downstream of the GLP-1R/miR-29b-3p axis.\",\n      \"method\": \"Dual-luciferase reporter assay, Western blotting, quantitative RT-PCR, GLP-1R inhibition experiment\",\n      \"journal\": \"Drug design, development and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct miRNA-target validation by luciferase assay plus pharmacological intervention; single lab, two orthogonal methods\",\n      \"pmids\": [\"36936522\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLMAP is a tail-anchored membrane protein with multiple isoforms whose subcellular targeting (ER, mitochondria, sarcoplasmic reticulum, centrosome) is determined by the hydrophobicity of its alternatively spliced C-terminal transmembrane domains; it functions as a component of the STRIPAK complex through its N-terminal FHA domain, regulates cardiac excitation-contraction coupling at the sarcoplasmic reticulum by controlling calcium-cycling protein expression and intracellular calcium transients (partly via interaction with striatin), promotes YAP activity in gut mesenchyme by inhibiting MST3 kinase, associates with GLUT-4 to influence glucose uptake in adipocytes, and its expression is post-transcriptionally regulated by miR-29b-3p downstream of GLP-1 receptor signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLMAP is a tail-anchored membrane protein expressed as multiple alternatively spliced isoforms whose distinct C-terminal transmembrane anchors dictate differential subcellular targeting, with the hydrophobicity of the tail anchor determining whether the protein localizes to the ER alone (TA1) or additionally to mitochondria (TA2) [#2]. An N-terminal FHA domain directs a 91 kDa isoform to the centrosome throughout the cell cycle, where dysregulated levels are lethal or arrest cells at G2/M [#0], and the conserved FHA domain mediates incorporation into the STRIPAK complex, as shown for the fungal ortholog PRO45 which binds STRIPAK subunits and depends on them for nuclear-envelope targeting [#5]. In cardiac muscle SLMAP isoforms self-assemble and target sarcolemmal, T-tubule, and sarcoplasmic-reticulum membranes involved in excitation-contraction coupling [#1]; SLMAP regulates E-C coupling at the SR by controlling expression of calcium-cycling proteins and intracellular calcium transients, with cardiac overexpression causing SR/ER dilation, reduced ryanodine receptor/Ca2+-ATPase/calsequestrin/triadin levels, impaired contractility, and QT prolongation [#3], and with the SLMAP-3 isoform interacting with striatin to modulate calcium transients and contractile rate [#6]. Through STRIPAK-linked signaling, SLMAP acts upstream of MST3 kinase to promote YAP activation in gut mesenchyme, supporting intestinal epithelial proliferation and proper gut length [#7]. SLMAP additionally associates with GLUT-4 in adipocytes to influence glucose uptake [#4], and its expression is post-transcriptionally repressed by miR-29b-3p downstream of GLP-1 receptor signaling [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that an FHA-domain-containing SLMAP isoform is a cell-cycle-relevant centrosomal protein, linking SLMAP to MTOC function and mitotic progression.\",\n      \"evidence\": \"Anti-peptide immunofluorescence, GFP-reporter targeting and deletion mapping, cell cycle profiling in cultured cells\",\n      \"pmids\": [\"15126628\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular function of SLMAP at the centrosome not defined\", \"No partner identified mediating centrosomal targeting beyond the N-terminal sequence\", \"Mechanism of G2/M arrest unexplained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed SLMAP isoforms self-assemble and bind myosin and partition to distinct E-C coupling membranes, framing SLMAP as a membrane-targeted structural component of cardiac muscle.\",\n      \"evidence\": \"Co-immunoprecipitation/pulldown, subcellular fractionation and immunolocalization in cardiac myocytes\",\n      \"pmids\": [\"15591093\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Myosin interaction rests on single Co-IP/pulldown without reciprocal validation\", \"Functional consequence of homodimerization not tested\", \"Which isoform binds myosin unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the biophysical rule for SLMAP isoform targeting, demonstrating that tail-anchor hydrophobicity selects between ER-only and ER-plus-mitochondrial localization.\",\n      \"evidence\": \"GFP-fusion targeting assays with site-directed mutagenesis of the tail-anchor transmembrane domain and confocal microscopy\",\n      \"pmids\": [\"19538755\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Insertion machinery for the tail anchor not identified\", \"Functional role of mitochondrial-targeted SLMAP not addressed\", \"Targeting tested with reporter fusions, not endogenous isoforms\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided in vivo proof that SLMAP controls cardiac E-C coupling by regulating SR calcium-cycling protein expression and calcium handling.\",\n      \"evidence\": \"Cardiac-specific transgenic mice with electrophysiology (ECG), pressure monitoring, calcium uptake assays, fractionation, and imaging\",\n      \"pmids\": [\"22180652\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which SLMAP controls calcium-protein expression unknown\", \"Effect is from a gain-of-function/mistargeting construct rather than endogenous loss\", \"Direct molecular targets at the SR not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected SLMAP to metabolic regulation by linking a 45 kDa isoform to GLUT-4 and glucose uptake in adipocytes.\",\n      \"evidence\": \"Co-immunoprecipitation with GLUT-4 and siRNA knockdown with glucose uptake assay in adipocytes\",\n      \"pmids\": [\"21785580\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"GLUT-4 interaction from single Co-IP without reciprocal validation\", \"Direct role in vesicle fusion/translocation not demonstrated\", \"Relationship to other SLMAP isoforms/functions unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the FHA-domain-dependent association of the SLMAP ortholog with the STRIPAK complex and its requirement for STRIPAK-dependent nuclear-envelope targeting and developmental processes.\",\n      \"evidence\": \"Superresolution SIM microscopy, yeast two-hybrid/pulldown, and genetic deletion/complementation in Sordaria macrospora\",\n      \"pmids\": [\"25527523\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Demonstrated in fungal ortholog; mammalian STRIPAK linkage inferred\", \"FHA-domain binding partners in the complex not fully mapped\", \"Mechanistic link between localization and fusion phenotype unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified striatin as a cardiomyocyte SLMAP-3 partner and tied SLMAP levels to calcium transients and contractile rate, reinforcing its role in cardiac function.\",\n      \"evidence\": \"Proteomics interaction discovery with AAV overexpression/knockdown, live calcium imaging and contractile rate measurement\",\n      \"pmids\": [\"30856349\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Striatin interaction from proteomics not orthogonally confirmed\", \"Causal chain from STRN binding to calcium handling unmapped\", \"Relationship to STRIPAK signaling in heart untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed SLMAP downstream of GLP-1R signaling by identifying miR-29b-3p as a direct repressor of SLMAP mRNA in cardiomyocytes.\",\n      \"evidence\": \"Dual-luciferase reporter assay, Western blot, qRT-PCR, and pharmacological GLP-1R inhibition\",\n      \"pmids\": [\"36936522\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Downstream cardiac consequence of SLMAP repression not functionally dissected\", \"Which SLMAP isoform is targeted unclear\", \"Physiological relevance of the axis in vivo not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined SLMAP as an upstream regulator of MST3 in the YAP pathway controlling intestinal mesenchymal-epithelial signaling and gut growth.\",\n      \"evidence\": \"Mesenchyme-specific conditional knockout mice, Slmap;Mst3 double-mutant genetic epistasis, scRNA-seq, YAP activity and proliferation assays\",\n      \"pmids\": [\"40521668\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Biochemical mechanism by which SLMAP inhibits MST3 not resolved\", \"Role of STRIPAK in this regulation not directly tested\", \"Partial rescue indicates additional MST3-independent effectors\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLMAP's shared FHA/STRIPAK module is mechanistically coupled to its diverse isoform-specific outputs (centrosome, cardiac SR calcium handling, GLUT-4, MST3/YAP) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of FHA-domain partner engagement\", \"Direct enzymatic or scaffold mechanism toward MST3 undefined\", \"Unifying principle linking tail-anchor targeting to downstream signaling absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [3, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"STRIPAK\"\n    ],\n    \"partners\": [\n      \"STRN\",\n      \"MST3\",\n      \"SLC2A4\",\n      \"PRO11\",\n      \"SmMOB3\",\n      \"myosin\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}