{"gene":"SLMAP","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2004,"finding":"A novel 91 kDa isoform of SLMAP containing an N-terminal forkhead-associated (FHA) domain localizes to the centrosome (MTOC) at all phases of the cell cycle. GFP-reporter experiments and deletion-mutant analysis showed that the N-terminal sequence is required for centrosomal targeting. Elevated centrosomal SLMAP caused cell death, while centrosome-targeting mutants inhibited cell growth and caused G2/M accumulation, establishing a role for SLMAP in cell cycle progression.","method":"Anti-peptide antibody immunofluorescence co-localization with γ-tubulin, GFP reporter targeting assays, deletion-mutant analysis, microtubule-disruption experiments, cell growth assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (IF, GFP targeting, deletion mutants, functional phenotype) in single study","pmids":["15126628"],"is_preprint":false},{"year":2004,"finding":"SLMAP isoforms in cardiac myocytes bear alternatively spliced C-terminal transmembrane domains that target the protein to distinct subcellular membranes (sarcolemma, T-tubules, sarcoplasmic reticulum). SLMAP can self-assemble via coiled-coil domains and binds myosin in cardiac muscle. These properties are consistent with a structural role in organizing the excitation-contraction coupling apparatus.","method":"Subcellular fractionation, co-immunoprecipitation (SLMAP self-assembly and myosin binding), isoform expression profiling, developmental expression analysis","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2/3 — reciprocal co-IP for self-assembly and myosin binding, direct localization, but single lab","pmids":["15591093"],"is_preprint":false},{"year":2008,"finding":"SLMAP is a component of the STRIPAK (striatin-interacting phosphatase and kinase) complex. SLMAP and the related proteins SIKE and FGFR1OP2 form a sub-complex within STRIPAK that is mutually exclusive with the CTTNBP2 sub-complex. STRIPAK contains PP2A catalytic and scaffolding subunits, striatins (PP2A B''' subunits), Mob3, STRIP1/2, and CCM3.","method":"Iterative affinity purification/mass spectrometry (AP-MS) interaction mapping","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 2 — systematic AP-MS with iterative validation, replicated in subsequent independent studies","pmids":["18782753"],"is_preprint":false},{"year":2009,"finding":"The two alternatively spliced tail anchors (TA1 and TA2) of SLMAP differ in hydrophobicity and determine subcellular targeting specificity: both TA1 and TA2 direct SLMAP to the endoplasmic reticulum, but TA2 additionally directs SLMAP to mitochondria. Substitution of moderately hydrophobic residues within the TA2 transmembrane region with leucine (increasing hydrophobicity to match TA1 levels) abolished mitochondrial targeting, demonstrating that overall hydrophobicity of the transmembrane domain governs organelle specificity.","method":"GFP-fusion targeting assays, site-directed mutagenesis of transmembrane domain residues, confocal microscopy, subcellular fractionation","journal":"BMC cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — mutagenesis with functional targeting readout, multiple mutants tested with clear structure-function conclusions","pmids":["19538755"],"is_preprint":false},{"year":2011,"finding":"Cardiac-restricted overexpression of SLMAP1-TM2 in transgenic mice causes dilation of the SR/ER, reduced expression of SR calcium-cycling proteins (ryanodine receptor, SERCA, calsequestrin, triadin but not phospholamban), diminished calcium uptake, electrophysiological abnormalities (prolonged QT interval), and progressive deterioration of cardiac contractility, establishing SLMAP as a regulator of excitation-contraction coupling at the sarcoplasmic reticulum.","method":"Transgenic mouse model with cardiac-restricted overexpression, left ventricular pressure monitoring, echocardiography, confocal imaging, biochemical fractionation, calcium uptake assays, Western blotting","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 — in vivo transgenic model with multiple orthogonal functional readouts","pmids":["22180652"],"is_preprint":false},{"year":2013,"finding":"The forkhead-associated (FHA) domain of SLMAP is required for its association with MST1 and MST2 kinases within the STRIPAK complex. Deletion of the SLMAP FHA domain prevented its association with MST1/2. STRIPAK-associated SLMAP recruits PP2A phosphatase activity to dephosphorylate and inactivate MST1/2, thereby negatively regulating the Hippo pathway.","method":"Affinity purification/mass spectrometry (AP-MS) of Hippo pathway interactome, domain deletion analysis, co-immunoprecipitation, phosphatase inhibitor (okadaic acid) treatment","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — AP-MS interactome plus deletion mutants plus functional epistasis, replicated by subsequent structural studies","pmids":["24255178"],"is_preprint":false},{"year":2014,"finding":"The fungal SLMAP homolog PRO45 in Sordaria macrospora is required for sexual propagation and cell-to-cell fusion. Its FHA domain is essential for these functions. PRO45 interacts with STRIPAK subunits PRO11 and SmMOB3, and localizes to the nuclear envelope, ER, and mitochondria. Localization to the nuclear envelope (but not mitochondria) requires STRIPAK subunits PRO11 and PRO22.","method":"Deletion and domain-mutant analysis, yeast two-hybrid and co-immunoprecipitation protein-protein interaction studies, structured-illumination microscopy (SIM), genetic epistasis with STRIPAK subunit knockouts","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including super-resolution microscopy and genetic epistasis; ortholog study consistent with mammalian SLMAP function","pmids":["25527523"],"is_preprint":false},{"year":2017,"finding":"SLMAP binding to autophosphorylated MST2 linker region recruits the STRIPAK complex to MST2, enabling PP2A-mediated dephosphorylation of the MST2 activation loop and thereby inactivating MST1/2 kinases. SAV1 directly binds STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous Hippo pathway activation and reduces the requirement for SAV1.","method":"Structural studies (crystallography/biochemistry of SAV1-MST2 SARAH domain heterotetramer), in vitro phosphatase assays, co-immunoprecipitation, SLMAP CRISPR knockout in human cells, reconstituted phosphatase activity assays, mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — structural + biochemical reconstitution + genetic KO with defined pathway phenotype; multiple orthogonal methods","pmids":["29063833"],"is_preprint":false},{"year":2019,"finding":"SLMAP-3 overexpression in cardiomyocytes increases intracellular calcium transients and promotes a positive chronotropic effect that is amplified by adrenergic (isoproterenol) stimulation. SLMAP-3 was found by proteomics to interact with striatin. Knockdown of SLMAP in cardiomyocytes reduced spontaneous contractile rate and blunted adrenergic responsiveness, phenocopying heart failure.","method":"Adeno-associated viral overexpression and shRNA knockdown in cardiomyocytes, confocal live calcium imaging, isoproterenol challenge, proteomics (SLMAP-3 interactome)","journal":"Canadian journal of physiology and pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — live calcium imaging with OE/KD plus proteomics interaction data, single lab","pmids":["30856349"],"is_preprint":false},{"year":2019,"finding":"SLMAP forms a complex with striatin (STRN) in cardiac membranes and both proteins are involved in regulating excitation-contraction coupling, caveolae, T-tubule/SR junctions, and intercalated disc biology in cardiomyocytes.","method":"Review integrating in vitro and in vivo signaling data from multiple prior experimental studies","journal":"European journal of pharmacology","confidence":"Low","confidence_rationale":"Tier 4 — review/synthesis without new primary experimental data","pmids":["31233748"],"is_preprint":false},{"year":2023,"finding":"miR-29b-3p directly targets SLMAP and downregulates its expression. GLP-1 receptor agonist treatment in diabetic cardiomyopathy mice upregulates miR-29b-3p, which suppresses SLMAP expression in ventricular myocardium. Inhibition of GLP-1R reversed the effects of GLP-1RA on miR-29b-3p/SLMAP, establishing a GLP-1R → miR-29b-3p → SLMAP regulatory axis in diabetic cardiomyopathy.","method":"Dual-luciferase reporter assay (miRNA target validation), quantitative RT-PCR, Western blotting, label-free proteomics, in vivo mouse DCM model with exenatide treatment","journal":"Drug design, development and therapy","confidence":"Medium","confidence_rationale":"Tier 2 — dual-luciferase reporter confirms direct miRNA-target interaction, supported by in vivo GLP-1R inhibition rescue experiment","pmids":["36936522"],"is_preprint":false},{"year":2025,"finding":"SLMAP in gut mesenchyme regulates YAP activity by directly interacting with and controlling MST3 kinase. Deletion of Slmap in gut mesenchyme impairs YAP activity, reduces intestinal epithelial cell proliferation, and causes short gut. MST3 levels increase postnatally (peaking at P14) to slow gut elongation. Concomitant deletion of Mst3 in mesenchyme partially rescues the short gut phenotype of Slmap mutants, demonstrating genetic epistasis: SLMAP acts upstream of MST3 to activate YAP-driven gut elongation.","method":"Single-cell RNA sequencing, tissue-specific conditional knockout mice (mesenchyme-specific Slmap and Mst3 deletion), genetic epistasis (double mutant rescue), YAP activity assays, cell proliferation assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo conditional KO with defined molecular phenotype plus genetic epistasis rescue experiment","pmids":["40521668"],"is_preprint":false},{"year":2025,"finding":"SLAP (Src-Like Adaptor Protein) interacts with mLST8, a core component of mTORC2, and facilitates non-degradative ubiquitination of mLST8 at lysines 86 and 215 via the E3 ubiquitin ligase UBE3C. This ubiquitination reduces mTORC2 complex integrity and suppresses mTORC2-AKT signaling. SLAP depletion in colorectal cancer cells enhances mTORC2 activity and sensitizes xenografts to mTOR catalytic inhibitors.","method":"Co-immunoprecipitation (SLAP-mLST8 and SLAP-UBE3C interactions), site-directed mutagenesis of ubiquitination sites (K86/K215), ubiquitination assays, mTORC2 complex integrity analysis, cell invasion/growth assays, mouse xenograft model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1/2 — direct biochemical interaction plus site-specific mutagenesis of ubiquitination sites plus in vivo xenograft validation","pmids":["41398047"],"is_preprint":false},{"year":2024,"finding":"SLMAP (here termed Soluble-Lamin Associated Protein in the brain context) localizes to the nuclear envelope and when overexpressed causes changes in nuclear morphology and lengthening of mitosis. Overexpression in apical progenitors of the developing mouse brain alters asymmetric cell division, neurogenic commitment, and neuronal migration, resulting in imbalance between upper and deeper cortical layers and reduced subcortical projections, and reduced exploratory behavior.","method":"In utero electroporation for overexpression and Cas9-mediated knockdown in mouse brain, live imaging of mitosis duration, immunofluorescence for nuclear envelope localization, cortical layer composition analysis, behavioral testing","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization plus OE and KD with defined cellular and behavioral phenotypes, but SLMAP identity in this context requires clarification (nuclear envelope isoform)","pmids":["38466184"],"is_preprint":false}],"current_model":"SLMAP is a tail-anchored membrane protein with an N-terminal forkhead-associated (FHA) domain that functions as a core component of the STRIPAK (striatin-interacting phosphatase and kinase) complex; its FHA domain binds autophosphorylated MST1/2 kinases to recruit PP2A phosphatase activity, thereby dephosphorylating and inactivating MST1/2 to suppress Hippo pathway signaling, while SAV1 antagonizes this by directly inhibiting STRIPAK phosphatase activity; in the heart, SLMAP isoforms are targeted via alternatively spliced tail anchors (whose hydrophobicity determines ER vs. mitochondrial specificity) to sarcoplasmic reticulum/ER membranes where they regulate excitation-contraction coupling and calcium cycling; and in the gut mesenchyme, SLMAP activates YAP via direct regulation of MST3 kinase to govern intestinal elongation during development."},"narrative":{"teleology":[{"year":2004,"claim":"Identification of an FHA domain-containing 91 kDa SLMAP isoform at the centrosome established that SLMAP participates in cell cycle progression, not solely membrane-associated structural roles.","evidence":"GFP-reporter targeting assays, deletion-mutant analysis, and cell growth/cell cycle assays in cultured cells","pmids":["15126628"],"confidence":"High","gaps":["Centrosomal function mechanism not defined beyond targeting requirement","Unclear whether centrosomal localization is STRIPAK-dependent","No in vivo validation of cell cycle role"]},{"year":2004,"claim":"Demonstration that cardiac SLMAP isoforms bear alternatively spliced transmembrane domains targeting distinct subcellular membranes (sarcolemma, T-tubules, SR) and self-assemble via coiled-coils revealed SLMAP as a potential organizer of the excitation–contraction coupling apparatus.","evidence":"Subcellular fractionation, co-immunoprecipitation for self-assembly and myosin binding in cardiac myocytes","pmids":["15591093"],"confidence":"Medium","gaps":["Single-lab study; myosin interaction not independently validated","Functional consequence of self-assembly not tested","No loss-of-function data in heart at this stage"]},{"year":2008,"claim":"Systematic proteomics placed SLMAP as a core component of the STRIPAK complex alongside PP2A, striatins, Mob3, and STRIP1/2, fundamentally reframing SLMAP from a passive structural membrane protein to a signaling scaffold.","evidence":"Iterative affinity purification/mass spectrometry interaction mapping","pmids":["18782753"],"confidence":"High","gaps":["Stoichiometry and assembly order within STRIPAK not resolved","Functional output of SLMAP-containing STRIPAK unclear at this point"]},{"year":2009,"claim":"Structure–function mutagenesis of the alternatively spliced tail anchors showed that overall transmembrane domain hydrophobicity is the molecular determinant governing ER vs. mitochondrial targeting, resolving how SLMAP isoform diversity maps to organelle specificity.","evidence":"GFP-fusion targeting assays with site-directed mutagenesis of transmembrane residues, confocal microscopy, subcellular fractionation","pmids":["19538755"],"confidence":"High","gaps":["Physiological significance of mitochondrial SLMAP not established","No identification of membrane-insertion machinery for SLMAP tail anchors"]},{"year":2011,"claim":"Cardiac-restricted SLMAP overexpression in transgenic mice caused SR dilation, loss of SR calcium-cycling proteins, reduced calcium uptake, and progressive contractile failure, providing the first in vivo evidence that SLMAP levels directly regulate excitation–contraction coupling.","evidence":"Transgenic mouse model with echocardiography, LV pressure monitoring, calcium uptake assays, confocal imaging, biochemical fractionation","pmids":["22180652"],"confidence":"High","gaps":["Gain-of-function only; cardiac-specific knockout not yet performed","Molecular mechanism linking SLMAP to SR protein expression not identified","Whether STRIPAK signaling mediates the cardiac phenotype unknown"]},{"year":2013,"claim":"The FHA domain of SLMAP was shown to be required for MST1/2 binding within STRIPAK, connecting SLMAP directly to Hippo pathway regulation by enabling PP2A-mediated dephosphorylation and inactivation of MST1/2.","evidence":"AP-MS Hippo interactome mapping, FHA domain deletion, co-immunoprecipitation, okadaic acid phosphatase inhibitor treatment","pmids":["24255178"],"confidence":"High","gaps":["Structural basis of FHA–MST interaction not yet resolved","Whether SLMAP recognizes MST autophosphorylation sites directly not shown"]},{"year":2014,"claim":"Fungal ortholog studies confirmed deep conservation of SLMAP/FHA–STRIPAK interaction and revealed that STRIPAK subunits are required for nuclear-envelope targeting of SLMAP, establishing a conserved targeting hierarchy.","evidence":"Deletion/domain-mutant analysis, yeast two-hybrid, co-IP, structured-illumination microscopy, genetic epistasis in Sordaria macrospora","pmids":["25527523"],"confidence":"High","gaps":["Nuclear envelope targeting mechanism not mapped to specific STRIPAK subunit","Whether mammalian SLMAP nuclear-envelope localization is similarly STRIPAK-dependent not tested"]},{"year":2017,"claim":"Biochemical reconstitution and SLMAP CRISPR knockout demonstrated that SLMAP-STRIPAK dephosphorylates the MST2 activation loop after binding MST2's autophosphorylated linker, while SAV1 protects MST2 by directly inhibiting STRIPAK phosphatase activity — resolving the antagonistic SAV1/STRIPAK toggle that controls Hippo kinase output.","evidence":"Crystal structure of SAV1-MST2 SARAH domain, in vitro reconstituted phosphatase assays, SLMAP CRISPR KO in human cells, co-IP, mutagenesis","pmids":["29063833"],"confidence":"High","gaps":["Atomic-resolution structure of FHA–MST2 linker interaction still lacking","How membrane anchoring of SLMAP spatially constrains STRIPAK-MST2 interaction in vivo unknown"]},{"year":2019,"claim":"SLMAP-3 overexpression in cardiomyocytes increased calcium transients and beating rate while knockdown blunted adrenergic responsiveness, linking SLMAP-striatin signaling to the adrenergic regulation of cardiac contractility.","evidence":"AAV-mediated overexpression and shRNA knockdown in cardiomyocytes, confocal live calcium imaging, isoproterenol challenge, proteomics","pmids":["30856349"],"confidence":"Medium","gaps":["Single-lab study; adrenergic signaling mechanism downstream of SLMAP-striatin not defined","No in vivo cardiac-specific loss-of-function data at this stage"]},{"year":2024,"claim":"SLMAP localizes to the nuclear envelope in neural progenitors, and overexpression prolongs mitosis and alters asymmetric division, neuronal migration, and cortical layer formation, expanding SLMAP's roles to brain development.","evidence":"In utero electroporation (OE and Cas9-KD) in developing mouse cortex, live imaging of mitosis, cortical layer analysis, behavioral testing","pmids":["38466184"],"confidence":"Medium","gaps":["Nuclear-envelope isoform identity needs clarification relative to known splice variants","Whether mitosis-lengthening effect is STRIPAK-dependent not tested","Single study without independent replication"]},{"year":2025,"claim":"Conditional deletion of Slmap in gut mesenchyme revealed that SLMAP activates YAP by restraining MST3 kinase, driving intestinal elongation; genetic epistasis with Mst3 deletion confirmed SLMAP acts upstream of MST3 in this tissue.","evidence":"Mesenchyme-specific conditional KO mice, Slmap/Mst3 double KO rescue, scRNA-seq, YAP activity and proliferation assays","pmids":["40521668"],"confidence":"High","gaps":["Whether SLMAP–MST3 interaction operates through canonical STRIPAK or a distinct complex is unresolved","Whether intestinal phenotype extends to adult gut homeostasis or tumorigenesis not tested"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution structure of the SLMAP FHA domain bound to MST kinase phospho-peptides, how membrane-anchored SLMAP spatially organizes STRIPAK signaling at distinct organelles, whether cardiac-specific SLMAP knockout recapitulates loss-of-function phenotypes, and the relative contributions of STRIPAK-dependent versus -independent functions across tissues.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of FHA–MST interaction","No cardiac-specific conditional knockout model reported","Relative contribution of STRIPAK-dependent vs. independent SLMAP functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7,11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,3,4]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[6,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[4,8]}],"complexes":["STRIPAK"],"partners":["MST1","MST2","MST3","STRN","PPP2CA","SAV1","STRIP1","MOB4"],"other_free_text":[]},"mechanistic_narrative":"SLMAP is a tail-anchored membrane protein and core component of the STRIPAK complex that functions as a scaffold linking PP2A phosphatase activity to Hippo pathway kinases, thereby governing cell growth, tissue morphogenesis, and cardiac physiology. Its N-terminal forkhead-associated (FHA) domain binds autophosphorylated MST1/2 kinases to recruit STRIPAK-associated PP2A, which dephosphorylates and inactivates MST1/2; genetic ablation of SLMAP leads to spontaneous Hippo pathway activation, while SAV1 counteracts STRIPAK by directly inhibiting its phosphatase activity [PMID:24255178, PMID:29063833]. Alternatively spliced C-terminal transmembrane domains of differing hydrophobicity target cardiac SLMAP isoforms to sarcoplasmic reticulum versus mitochondrial membranes, and perturbation of SLMAP expression alters SR calcium cycling, excitation–contraction coupling, and cardiac contractility [PMID:19538755, PMID:22180652, PMID:30856349]. In gut mesenchyme, SLMAP activates YAP-driven intestinal elongation by restraining MST3 kinase, as demonstrated by conditional knockout and genetic epistasis [PMID:40521668]."},"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":"11567141","id":"PMC_11567141","title":"Coupling of the TCR to 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glycolysis through LDHA and PKM2.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32572027","citation_count":167,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11042152","id":"PMC_11042152","title":"Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells.","date":"2000","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/11042152","citation_count":161,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32877691","id":"PMC_32877691","title":"A High-Density Human Mitochondrial Proximity Interaction Network.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32877691","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25609649","id":"PMC_25609649","title":"Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.","date":"2015","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/25609649","citation_count":120,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29063833","id":"PMC_29063833","title":"SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29063833","citation_count":119,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32862,"output_tokens":2941,"usd":0.07135},"stage2":{"model":"claude-opus-4-6","input_tokens":6272,"output_tokens":2490,"usd":0.140415},"total_usd":0.48774,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":45153,"output_tokens":4595,"usd":0.102192},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7666,"output_tokens":3101,"usd":0.173783}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"A novel N-terminal isoform of SLMAP containing a forkhead-associated (FHA) domain localizes to the centrosome (MTOC) at all phases of the cell cycle, and elevated centrosomal SLMAP is lethal; centrosome-targeting mutants that lack the N-terminal sequence inhibit cell growth and cause G2/M accumulation.\",\n      \"method\": \"Anti-peptide antibody colocalization with gamma-tubulin, GFP reporter targeting assay, deletion-mutant analysis, cell cycle analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (immunofluorescence, GFP targeting, deletion mapping, cell cycle profiling) in a single study\",\n      \"pmids\": [\"15126628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SLMAP isoforms in cardiac myocytes self-assemble (homodimerize) and bind myosin; COOH-terminal membrane anchors target distinct subcellular membranes (sarcolemma, SR/T-tubules), consistent with a structural role in organizing the excitation-contraction coupling apparatus.\",\n      \"method\": \"Protein interaction analysis (co-IP/pulldown), developmental expression profiling, subcellular fractionation, confocal immunofluorescence\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — co-IP/pulldown plus localization but functional consequences inferred rather than directly tested\",\n      \"pmids\": [\"15591093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The hydrophobicity profile of the two alternatively spliced tail anchors (TA1 and TA2) of SLMAP determines subcellular targeting: TA1 directs SLMAP to the ER, while TA2 (less hydrophobic) additionally directs SLMAP to mitochondria; leucine substitutions that increase TA2 hydrophobicity to match TA1 redirect SLMAP away from mitochondria.\",\n      \"method\": \"GFP fusion targeting assays, site-directed mutagenesis of transmembrane residues, subcellular fractionation\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis of transmembrane domain combined with GFP targeting and fractionation demonstrating direct structure-function relationship\",\n      \"pmids\": [\"19538755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cardiac-restricted overexpression of SLMAP1-TM2 causes SR/ER dilation through inappropriate homodimerization and SR/ER targeting, leading to reduced expression of ryanodine receptor, SERCA, calsequestrin, and triadin, decreased SR calcium uptake, elongated QT interval, and progressive ventricular dysfunction.\",\n      \"method\": \"Transgenic mouse overexpression, high-resolution microscopy, confocal imaging, biochemical fractionation, left ventricular pressure monitoring, ECG, microsomal calcium uptake assay\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic model with multiple orthogonal functional readouts demonstrating SLMAP's role at the SR in E-C coupling\",\n      \"pmids\": [\"22180652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLMAP-3 interacts with striatin in cardiomyocytes; overexpression of SLMAP-3 increases intracellular calcium transients and promotes a positive chronotropic response to adrenergic stimulation, while SLMAP knockdown reduces spontaneous contractile rate and impairs isoproterenol response, phenocopying heart failure.\",\n      \"method\": \"Proteomics (SLMAP-3 interactome), co-IP with striatin, adeno-associated viral overexpression/knockdown in cardiomyocytes, confocal live calcium imaging, contractile rate measurement\",\n      \"journal\": \"Canadian journal of physiology and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomics-identified interaction plus functional live-imaging with KD/OE, but single lab\",\n      \"pmids\": [\"30856349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLAP controls SRC/EPHA2/AKT signaling in colorectal cancer by destabilizing EPHA2: SLAP SH3 domain recruits the ubiquitination factor UBE4A, while SLAP SH2 domain binds pTyr594-EPHA2 (phosphorylated by SRC), leading to EPHA2 degradation independent of CBL.\",\n      \"method\": \"Co-IP, GST pulldown, site-directed mutagenesis of SLAP SH2/SH3 domains, ubiquitination assays, siRNA knockdown, cell tumorigenicity/invasion assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal methods (pulldown, mutagenesis, ubiquitination assay, functional rescue) establishing molecular mechanism\",\n      \"pmids\": [\"24457997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLAP interacts with mLST8 (a component of mTORC2) and, together with the E3 ubiquitin ligase UBE3C, promotes non-degradative ubiquitination of mLST8 at lysines 86 and 215, thereby reducing mTORC2 complex integrity and suppressing mTORC2-AKT signaling in colorectal cancer.\",\n      \"method\": \"Co-IP (SLAP-mLST8, SLAP-UBE3C), site-directed mutagenesis (mLST8 K86/K215), ubiquitination assays, xenograft mouse models, mTOR inhibitor sensitivity assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — biochemical reconstitution of ubiquitination, mutagenesis of target lysines, and in vivo xenograft validation\",\n      \"pmids\": [\"41398047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In gut mesenchyme, SLMAP directly regulates MST3 kinase activity to activate YAP; mesenchyme-specific Slmap deletion impairs YAP activity and causes a short-gut phenotype with reduced epithelial proliferation, which is partially rescued by concomitant mesenchymal Mst3 deletion.\",\n      \"method\": \"Single-cell RNA-seq, mesenchyme-specific conditional knockout, genetic epistasis (double Slmap/Mst3 KO), YAP activity reporters, intestinal length measurement, epithelial proliferation assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with double KO rescue, conditional KO with defined cellular phenotype, multiple orthogonal readouts\",\n      \"pmids\": [\"40521668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLMAP (here termed Soluble-Lamin Associated Protein) localizes to the nuclear envelope in mammalian neural progenitors; overexpression causes nuclear morphology changes, lengthening of mitosis, altered asymmetric cell division, impaired neurogenic commitment and neuronal migration, leading to imbalance of cortical layer composition and reduced subcortical projections.\",\n      \"method\": \"In utero electroporation overexpression and Cas9-mediated knockdown, live imaging of mitosis, immunofluorescence for cortical layer markers, behavioral testing (exploratory behavior)\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function with defined cellular phenotype, but single lab and limited mechanistic depth beyond nuclear envelope localization\",\n      \"pmids\": [\"38466184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The fungal SLMAP homolog PRO45 localizes to the nuclear envelope, ER, and mitochondria; its FHA domain is essential for sexual propagation and cell-to-cell fusion; PRO45 physically interacts with STRIPAK subunits PRO11 and SmMOB3; nuclear envelope localization requires PRO11 and PRO22, whereas mitochondrial localization does not.\",\n      \"method\": \"Superresolution structured-illumination microscopy (SIM), yeast two-hybrid and co-IP protein-protein interaction assays, FHA domain deletion mutants, genetic knockouts\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ortholog in filamentous fungus; multiple localization and interaction methods, but organism is distant from human\",\n      \"pmids\": [\"25527523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SLMAP co-immunoprecipitates with GLUT-4 in adipose tissue; siRNA knockdown of SLMAP in adipocytes reduces glucose uptake, suggesting SLMAP regulates GLUT-4 fusion/translocation to the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation (SLMAP-GLUT-4), SLMAP siRNA knockdown, glucose uptake assay in adipocytes\",\n      \"journal\": \"Experimental diabetes research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP plus siRNA with functional readout but limited mechanistic follow-up; single lab\",\n      \"pmids\": [\"21785580\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLMAP is a tail-anchored membrane protein whose subcellular targeting (ER vs. mitochondria) is determined by the hydrophobicity of alternatively spliced C-terminal transmembrane domains; it contains an N-terminal FHA domain that directs an isoform to the centrosome to regulate cell cycle progression, participates in the STRIPAK complex via interaction with striatin to regulate cardiomyocyte excitation-contraction coupling and calcium cycling at the SR/ER, activates YAP by suppressing MST3 kinase in gut mesenchyme to govern organ morphogenesis, and localizes to the nuclear envelope where it influences mitotic duration and neuronal progenitor fate; in immune and cancer cells, SLAP (a structurally distinct SH3-SH2 adaptor protein sharing the gene symbol) negatively regulates receptor tyrosine kinase and antigen receptor signaling by recruiting c-Cbl and UBE4A/UBE3C to promote ubiquitination and degradation of activated receptors including TCR-ζ, BCR, EPHA2, Flt3, c-Kit, and FcεRI, and separately controls mTORC2 integrity through UBE3C-mediated non-degradative ubiquitination of mLST8.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nPapers about canonical SLMAP (sarcolemmal membrane-associated protein, tail-anchored, FHA domain, STRIPAK component):\n- KEEP: [13], [16], [23], [26], [30], [32], [38], [42], [50], [53], [62], [63], and from curated: [18], [21], [23 curated], [29 curated], [30 curated]\n\nPapers about SLAP/SLAP-2/SLAP-130/Fyb/ADAP (immune adaptor proteins - different genes):\n- EXCLUDE (alias collision): [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[14],[15],[17],[18],[19],[20],[24],[27],[28],[31],[34],[35],[36],[37],[40],[45],[46],[47],[48],[51],[52],[54],[55],[57],[58],[61],[33]\n\nPapers about SLAP (shoulder labrum anterior-posterior) - orthopedic term:\n- EXCLUDE: [21 corpus], [25], [41], [44], [65], [66]\n\nOther unrelated SLAP acronyms:\n- EXCLUDE: [22], [29 corpus], [39], [56], [59]\n\nSLMAP-ALK fusion / SLMAP-BRAF fusion (clinical case reports, no mechanistic findings):\n- EXCLUDE (no mechanism): [49], [60]\n\nCurated papers - large proteomics/interactome studies (KEEP if they contain specific SLMAP findings):\n- KEEP: [18 curated] (Couzens - STRIPAK/Hippo network, SLMAP-MST interaction), [21 curated] (Goudreault - STRIPAK complex definition with SLMAP), [30 curated] (Bae - SAV1/STRIPAK^SLMAP mechanism)\n- EXCLUDE (SLMAP mentioned incidentally in large datasets with no specific mechanistic finding extracted): [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13 curated],[14],[15],[16],[17],[19],[20],[22],[23 curated],[24],[25],[26],[27],[28],[29]\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"A novel 91 kDa isoform of SLMAP containing an N-terminal forkhead-associated (FHA) domain localizes to the centrosome (MTOC) at all phases of the cell cycle. GFP-reporter experiments and deletion-mutant analysis showed that the N-terminal sequence is required for centrosomal targeting. Elevated centrosomal SLMAP caused cell death, while centrosome-targeting mutants inhibited cell growth and caused G2/M accumulation, establishing a role for SLMAP in cell cycle progression.\",\n      \"method\": \"Anti-peptide antibody immunofluorescence co-localization with γ-tubulin, GFP reporter targeting assays, deletion-mutant analysis, microtubule-disruption experiments, cell growth assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (IF, GFP targeting, deletion mutants, functional phenotype) in single study\",\n      \"pmids\": [\"15126628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SLMAP isoforms in cardiac myocytes bear alternatively spliced C-terminal transmembrane domains that target the protein to distinct subcellular membranes (sarcolemma, T-tubules, sarcoplasmic reticulum). SLMAP can self-assemble via coiled-coil domains and binds myosin in cardiac muscle. These properties are consistent with a structural role in organizing the excitation-contraction coupling apparatus.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation (SLMAP self-assembly and myosin binding), isoform expression profiling, developmental expression analysis\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — reciprocal co-IP for self-assembly and myosin binding, direct localization, but single lab\",\n      \"pmids\": [\"15591093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SLMAP is a component of the STRIPAK (striatin-interacting phosphatase and kinase) complex. SLMAP and the related proteins SIKE and FGFR1OP2 form a sub-complex within STRIPAK that is mutually exclusive with the CTTNBP2 sub-complex. STRIPAK contains PP2A catalytic and scaffolding subunits, striatins (PP2A B''' subunits), Mob3, STRIP1/2, and CCM3.\",\n      \"method\": \"Iterative affinity purification/mass spectrometry (AP-MS) interaction mapping\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic AP-MS with iterative validation, replicated in subsequent independent studies\",\n      \"pmids\": [\"18782753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The two alternatively spliced tail anchors (TA1 and TA2) of SLMAP differ in hydrophobicity and determine subcellular targeting specificity: both TA1 and TA2 direct SLMAP to the endoplasmic reticulum, but TA2 additionally directs SLMAP to mitochondria. Substitution of moderately hydrophobic residues within the TA2 transmembrane region with leucine (increasing hydrophobicity to match TA1 levels) abolished mitochondrial targeting, demonstrating that overall hydrophobicity of the transmembrane domain governs organelle specificity.\",\n      \"method\": \"GFP-fusion targeting assays, site-directed mutagenesis of transmembrane domain residues, confocal microscopy, subcellular fractionation\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — mutagenesis with functional targeting readout, multiple mutants tested with clear structure-function conclusions\",\n      \"pmids\": [\"19538755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cardiac-restricted overexpression of SLMAP1-TM2 in transgenic mice causes dilation of the SR/ER, reduced expression of SR calcium-cycling proteins (ryanodine receptor, SERCA, calsequestrin, triadin but not phospholamban), diminished calcium uptake, electrophysiological abnormalities (prolonged QT interval), and progressive deterioration of cardiac contractility, establishing SLMAP as a regulator of excitation-contraction coupling at the sarcoplasmic reticulum.\",\n      \"method\": \"Transgenic mouse model with cardiac-restricted overexpression, left ventricular pressure monitoring, echocardiography, confocal imaging, biochemical fractionation, calcium uptake assays, Western blotting\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo transgenic model with multiple orthogonal functional readouts\",\n      \"pmids\": [\"22180652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The forkhead-associated (FHA) domain of SLMAP is required for its association with MST1 and MST2 kinases within the STRIPAK complex. Deletion of the SLMAP FHA domain prevented its association with MST1/2. STRIPAK-associated SLMAP recruits PP2A phosphatase activity to dephosphorylate and inactivate MST1/2, thereby negatively regulating the Hippo pathway.\",\n      \"method\": \"Affinity purification/mass spectrometry (AP-MS) of Hippo pathway interactome, domain deletion analysis, co-immunoprecipitation, phosphatase inhibitor (okadaic acid) treatment\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — AP-MS interactome plus deletion mutants plus functional epistasis, replicated by subsequent structural studies\",\n      \"pmids\": [\"24255178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The fungal SLMAP homolog PRO45 in Sordaria macrospora is required for sexual propagation and cell-to-cell fusion. Its FHA domain is essential for these functions. PRO45 interacts with STRIPAK subunits PRO11 and SmMOB3, and localizes to the nuclear envelope, ER, and mitochondria. Localization to the nuclear envelope (but not mitochondria) requires STRIPAK subunits PRO11 and PRO22.\",\n      \"method\": \"Deletion and domain-mutant analysis, yeast two-hybrid and co-immunoprecipitation protein-protein interaction studies, structured-illumination microscopy (SIM), genetic epistasis with STRIPAK subunit knockouts\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including super-resolution microscopy and genetic epistasis; ortholog study consistent with mammalian SLMAP function\",\n      \"pmids\": [\"25527523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SLMAP binding to autophosphorylated MST2 linker region recruits the STRIPAK complex to MST2, enabling PP2A-mediated dephosphorylation of the MST2 activation loop and thereby inactivating MST1/2 kinases. SAV1 directly binds STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous Hippo pathway activation and reduces the requirement for SAV1.\",\n      \"method\": \"Structural studies (crystallography/biochemistry of SAV1-MST2 SARAH domain heterotetramer), in vitro phosphatase assays, co-immunoprecipitation, SLMAP CRISPR knockout in human cells, reconstituted phosphatase activity assays, mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural + biochemical reconstitution + genetic KO with defined pathway phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"29063833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLMAP-3 overexpression in cardiomyocytes increases intracellular calcium transients and promotes a positive chronotropic effect that is amplified by adrenergic (isoproterenol) stimulation. SLMAP-3 was found by proteomics to interact with striatin. Knockdown of SLMAP in cardiomyocytes reduced spontaneous contractile rate and blunted adrenergic responsiveness, phenocopying heart failure.\",\n      \"method\": \"Adeno-associated viral overexpression and shRNA knockdown in cardiomyocytes, confocal live calcium imaging, isoproterenol challenge, proteomics (SLMAP-3 interactome)\",\n      \"journal\": \"Canadian journal of physiology and pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live calcium imaging with OE/KD plus proteomics interaction data, single lab\",\n      \"pmids\": [\"30856349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SLMAP forms a complex with striatin (STRN) in cardiac membranes and both proteins are involved in regulating excitation-contraction coupling, caveolae, T-tubule/SR junctions, and intercalated disc biology in cardiomyocytes.\",\n      \"method\": \"Review integrating in vitro and in vivo signaling data from multiple prior experimental studies\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — review/synthesis without new primary experimental data\",\n      \"pmids\": [\"31233748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-29b-3p directly targets SLMAP and downregulates its expression. GLP-1 receptor agonist treatment in diabetic cardiomyopathy mice upregulates miR-29b-3p, which suppresses SLMAP expression in ventricular myocardium. Inhibition of GLP-1R reversed the effects of GLP-1RA on miR-29b-3p/SLMAP, establishing a GLP-1R → miR-29b-3p → SLMAP regulatory axis in diabetic cardiomyopathy.\",\n      \"method\": \"Dual-luciferase reporter assay (miRNA target validation), quantitative RT-PCR, Western blotting, label-free proteomics, in vivo mouse DCM model with exenatide treatment\",\n      \"journal\": \"Drug design, development and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — dual-luciferase reporter confirms direct miRNA-target interaction, supported by in vivo GLP-1R inhibition rescue experiment\",\n      \"pmids\": [\"36936522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLMAP in gut mesenchyme regulates YAP activity by directly interacting with and controlling MST3 kinase. Deletion of Slmap in gut mesenchyme impairs YAP activity, reduces intestinal epithelial cell proliferation, and causes short gut. MST3 levels increase postnatally (peaking at P14) to slow gut elongation. Concomitant deletion of Mst3 in mesenchyme partially rescues the short gut phenotype of Slmap mutants, demonstrating genetic epistasis: SLMAP acts upstream of MST3 to activate YAP-driven gut elongation.\",\n      \"method\": \"Single-cell RNA sequencing, tissue-specific conditional knockout mice (mesenchyme-specific Slmap and Mst3 deletion), genetic epistasis (double mutant rescue), YAP activity assays, cell proliferation assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo conditional KO with defined molecular phenotype plus genetic epistasis rescue experiment\",\n      \"pmids\": [\"40521668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLAP (Src-Like Adaptor Protein) interacts with mLST8, a core component of mTORC2, and facilitates non-degradative ubiquitination of mLST8 at lysines 86 and 215 via the E3 ubiquitin ligase UBE3C. This ubiquitination reduces mTORC2 complex integrity and suppresses mTORC2-AKT signaling. SLAP depletion in colorectal cancer cells enhances mTORC2 activity and sensitizes xenografts to mTOR catalytic inhibitors.\",\n      \"method\": \"Co-immunoprecipitation (SLAP-mLST8 and SLAP-UBE3C interactions), site-directed mutagenesis of ubiquitination sites (K86/K215), ubiquitination assays, mTORC2 complex integrity analysis, cell invasion/growth assays, mouse xenograft model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct biochemical interaction plus site-specific mutagenesis of ubiquitination sites plus in vivo xenograft validation\",\n      \"pmids\": [\"41398047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLMAP (here termed Soluble-Lamin Associated Protein in the brain context) localizes to the nuclear envelope and when overexpressed causes changes in nuclear morphology and lengthening of mitosis. Overexpression in apical progenitors of the developing mouse brain alters asymmetric cell division, neurogenic commitment, and neuronal migration, resulting in imbalance between upper and deeper cortical layers and reduced subcortical projections, and reduced exploratory behavior.\",\n      \"method\": \"In utero electroporation for overexpression and Cas9-mediated knockdown in mouse brain, live imaging of mitosis duration, immunofluorescence for nuclear envelope localization, cortical layer composition analysis, behavioral testing\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization plus OE and KD with defined cellular and behavioral phenotypes, but SLMAP identity in this context requires clarification (nuclear envelope isoform)\",\n      \"pmids\": [\"38466184\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLMAP is a tail-anchored membrane protein with an N-terminal forkhead-associated (FHA) domain that functions as a core component of the STRIPAK (striatin-interacting phosphatase and kinase) complex; its FHA domain binds autophosphorylated MST1/2 kinases to recruit PP2A phosphatase activity, thereby dephosphorylating and inactivating MST1/2 to suppress Hippo pathway signaling, while SAV1 antagonizes this by directly inhibiting STRIPAK phosphatase activity; in the heart, SLMAP isoforms are targeted via alternatively spliced tail anchors (whose hydrophobicity determines ER vs. mitochondrial specificity) to sarcoplasmic reticulum/ER membranes where they regulate excitation-contraction coupling and calcium cycling; and in the gut mesenchyme, SLMAP activates YAP via direct regulation of MST3 kinase to govern intestinal elongation during development.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SLMAP is a tail-anchored membrane protein and STRIPAK complex component that regulates calcium homeostasis in cardiomyocytes, cell cycle progression, and Hippo pathway signaling in diverse tissues. Alternative splicing of its C-terminal transmembrane domain controls subcellular targeting: the more hydrophobic TA1 anchor directs SLMAP to the ER/SR, while the less hydrophobic TA2 additionally targets mitochondria, and leucine substitutions that increase TA2 hydrophobicity redirect the protein away from mitochondria [PMID:19538755]. An N-terminal FHA domain directs a specific isoform to the centrosome and is required for normal G2/M progression [PMID:15126628], while in cardiomyocytes SLMAP interacts with striatin and modulates SR calcium cycling and excitation-contraction coupling such that its overexpression dilates the SR, reduces ryanodine receptor and SERCA expression, and causes progressive ventricular dysfunction [PMID:22180652, PMID:30856349]. In gut mesenchyme, SLMAP suppresses MST3 kinase to activate YAP and promote intestinal elongation, as demonstrated by genetic epistasis with Mst3 deletion [PMID:40521668].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of an FHA-domain-containing SLMAP isoform at the centrosome established a direct link between SLMAP and cell cycle regulation, resolving how a membrane-anchored protein could influence mitotic progression.\",\n      \"evidence\": \"Anti-peptide antibody colocalization with γ-tubulin, GFP targeting, deletion-mutant mapping, cell cycle analysis in cultured cells\",\n      \"pmids\": [\"15126628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Centrosomal binding partner(s) of the FHA domain unidentified\", \"Mechanism linking centrosomal SLMAP to G2/M checkpoint not resolved\", \"Kinase or phospho-dependent regulation of centrosome targeting untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that cardiac SLMAP isoforms homodimerize and bind myosin, with different tail anchors targeting distinct membrane compartments (sarcolemma vs. SR/T-tubules), positioned SLMAP as a structural organizer of excitation-contraction coupling.\",\n      \"evidence\": \"Co-immunoprecipitation, pulldown, developmental expression profiling, subcellular fractionation, and confocal imaging in cardiomyocytes\",\n      \"pmids\": [\"15591093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of SLMAP–myosin interaction not directly tested\", \"Homodimerization interface not mapped\", \"Whether homodimerization is required for membrane targeting unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Structure-function dissection of the two alternatively spliced tail anchors revealed that transmembrane hydrophobicity is the biophysical determinant of ER versus mitochondrial targeting, providing a molecular code for SLMAP isoform-specific localization.\",\n      \"evidence\": \"GFP fusion targeting assays with site-directed leucine substitutions in TA1 and TA2 transmembrane domains, subcellular fractionation\",\n      \"pmids\": [\"19538755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TOM/TIM or GET pathway receptor mediating TA2 mitochondrial insertion not identified\", \"Physiological consequence of mitochondrial SLMAP uncharacterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Cardiac-restricted overexpression of SLMAP1-TM2 in transgenic mice proved that excess SLMAP at the SR is sufficient to disrupt calcium handling, connecting the tail-anchor-targeting mechanism to in vivo cardiac pathology.\",\n      \"evidence\": \"Transgenic mouse model with SR ultrastructure imaging, calcium uptake assays, ECG, and hemodynamic measurements\",\n      \"pmids\": [\"22180652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Loss-of-function cardiac phenotype not established at this stage\", \"Direct protein-level mechanism of SR dilation (beyond homodimerization) unknown\", \"Whether ryanodine receptor/SERCA reduction is transcriptional or degradative not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterization of the fungal SLMAP ortholog PRO45 showed conserved STRIPAK complex membership and FHA-domain-dependent function, and revealed that nuclear envelope localization requires STRIPAK subunits PRO11/PRO22 while mitochondrial localization does not.\",\n      \"evidence\": \"Superresolution SIM, yeast two-hybrid, co-IP, FHA deletion mutants, genetic knockouts in Sordaria macrospora\",\n      \"pmids\": [\"25527523\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether human SLMAP nuclear envelope targeting similarly depends on striatin/STRIP1 untested at this point\", \"FHA domain binding partner at the nuclear envelope not identified\", \"Distant organism limits direct translation to mammalian mechanism\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Proteomic identification of striatin as an SLMAP-3 interactor in cardiomyocytes, combined with knockdown and overexpression studies, established that SLMAP regulates calcium transients and chronotropic response through the STRIPAK complex in the heart.\",\n      \"evidence\": \"SLMAP-3 interactome proteomics, co-IP with striatin, AAV-mediated overexpression/knockdown, confocal live calcium imaging in cardiomyocytes\",\n      \"pmids\": [\"30856349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which STRIPAK kinase mediates the calcium phenotype downstream of SLMAP–striatin not determined\", \"Whether SLMAP–striatin interaction is direct or scaffolded unresolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Localization of SLMAP to the nuclear envelope in neural progenitors and demonstration that its dosage alters mitotic duration, asymmetric division, and cortical neurogenesis extended SLMAP's functions to brain development and provided a mammalian parallel to the fungal PRO45 nuclear envelope role.\",\n      \"evidence\": \"In utero electroporation overexpression and CRISPR knockdown, live mitosis imaging, cortical layer marker immunofluorescence in mouse embryonic brain\",\n      \"pmids\": [\"38466184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear envelope binding partner(s) in neural progenitors unidentified\", \"Mechanism linking SLMAP to mitotic spindle or nuclear lamina not resolved\", \"Single lab with limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic epistasis in mesenchyme-specific conditional knockouts demonstrated that SLMAP suppresses MST3 to activate YAP, providing the first direct kinase target for SLMAP in the Hippo pathway and linking it to organ size control during gut morphogenesis.\",\n      \"evidence\": \"scRNA-seq, mesenchyme-specific Slmap cKO, Slmap/Mst3 double KO rescue, YAP activity reporters, intestinal length and proliferation assays\",\n      \"pmids\": [\"40521668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism by which SLMAP inhibits MST3 kinase activity not defined\", \"Whether SLMAP–MST3 axis operates through STRIPAK in this context not confirmed\", \"Relevance to human intestinal disease unexplored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which SLMAP inhibits MST3 and other STRIPAK-associated kinases, the identity of FHA domain phospho-binding partners at centrosomes and nuclear envelope, and the physiological role of mitochondrial SLMAP remain major open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of SLMAP or its FHA domain–target interactions\", \"Mitochondrial SLMAP function entirely uncharacterized\", \"Whether cardiac and Hippo pathway roles converge through shared STRIPAK mechanisms unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [2, 9]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\n      \"STRIPAK\"\n    ],\n    \"partners\": [\n      \"STRN\",\n      \"MYH7\",\n      \"MST3\",\n      \"PRO11\",\n      \"SmMOB3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SLMAP is a tail-anchored membrane protein and core component of the STRIPAK complex that functions as a scaffold linking PP2A phosphatase activity to Hippo pathway kinases, thereby governing cell growth, tissue morphogenesis, and cardiac physiology. Its N-terminal forkhead-associated (FHA) domain binds autophosphorylated MST1/2 kinases to recruit STRIPAK-associated PP2A, which dephosphorylates and inactivates MST1/2; genetic ablation of SLMAP leads to spontaneous Hippo pathway activation, while SAV1 counteracts STRIPAK by directly inhibiting its phosphatase activity [PMID:24255178, PMID:29063833]. Alternatively spliced C-terminal transmembrane domains of differing hydrophobicity target cardiac SLMAP isoforms to sarcoplasmic reticulum versus mitochondrial membranes, and perturbation of SLMAP expression alters SR calcium cycling, excitation–contraction coupling, and cardiac contractility [PMID:19538755, PMID:22180652, PMID:30856349]. In gut mesenchyme, SLMAP activates YAP-driven intestinal elongation by restraining MST3 kinase, as demonstrated by conditional knockout and genetic epistasis [PMID:40521668].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of an FHA domain-containing 91 kDa SLMAP isoform at the centrosome established that SLMAP participates in cell cycle progression, not solely membrane-associated structural roles.\",\n      \"evidence\": \"GFP-reporter targeting assays, deletion-mutant analysis, and cell growth/cell cycle assays in cultured cells\",\n      \"pmids\": [\"15126628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Centrosomal function mechanism not defined beyond targeting requirement\",\n        \"Unclear whether centrosomal localization is STRIPAK-dependent\",\n        \"No in vivo validation of cell cycle role\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that cardiac SLMAP isoforms bear alternatively spliced transmembrane domains targeting distinct subcellular membranes (sarcolemma, T-tubules, SR) and self-assemble via coiled-coils revealed SLMAP as a potential organizer of the excitation–contraction coupling apparatus.\",\n      \"evidence\": \"Subcellular fractionation, co-immunoprecipitation for self-assembly and myosin binding in cardiac myocytes\",\n      \"pmids\": [\"15591093\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; myosin interaction not independently validated\",\n        \"Functional consequence of self-assembly not tested\",\n        \"No loss-of-function data in heart at this stage\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Systematic proteomics placed SLMAP as a core component of the STRIPAK complex alongside PP2A, striatins, Mob3, and STRIP1/2, fundamentally reframing SLMAP from a passive structural membrane protein to a signaling scaffold.\",\n      \"evidence\": \"Iterative affinity purification/mass spectrometry interaction mapping\",\n      \"pmids\": [\"18782753\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and assembly order within STRIPAK not resolved\",\n        \"Functional output of SLMAP-containing STRIPAK unclear at this point\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Structure–function mutagenesis of the alternatively spliced tail anchors showed that overall transmembrane domain hydrophobicity is the molecular determinant governing ER vs. mitochondrial targeting, resolving how SLMAP isoform diversity maps to organelle specificity.\",\n      \"evidence\": \"GFP-fusion targeting assays with site-directed mutagenesis of transmembrane residues, confocal microscopy, subcellular fractionation\",\n      \"pmids\": [\"19538755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological significance of mitochondrial SLMAP not established\",\n        \"No identification of membrane-insertion machinery for SLMAP tail anchors\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Cardiac-restricted SLMAP overexpression in transgenic mice caused SR dilation, loss of SR calcium-cycling proteins, reduced calcium uptake, and progressive contractile failure, providing the first in vivo evidence that SLMAP levels directly regulate excitation–contraction coupling.\",\n      \"evidence\": \"Transgenic mouse model with echocardiography, LV pressure monitoring, calcium uptake assays, confocal imaging, biochemical fractionation\",\n      \"pmids\": [\"22180652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Gain-of-function only; cardiac-specific knockout not yet performed\",\n        \"Molecular mechanism linking SLMAP to SR protein expression not identified\",\n        \"Whether STRIPAK signaling mediates the cardiac phenotype unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The FHA domain of SLMAP was shown to be required for MST1/2 binding within STRIPAK, connecting SLMAP directly to Hippo pathway regulation by enabling PP2A-mediated dephosphorylation and inactivation of MST1/2.\",\n      \"evidence\": \"AP-MS Hippo interactome mapping, FHA domain deletion, co-immunoprecipitation, okadaic acid phosphatase inhibitor treatment\",\n      \"pmids\": [\"24255178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of FHA–MST interaction not yet resolved\",\n        \"Whether SLMAP recognizes MST autophosphorylation sites directly not shown\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Fungal ortholog studies confirmed deep conservation of SLMAP/FHA–STRIPAK interaction and revealed that STRIPAK subunits are required for nuclear-envelope targeting of SLMAP, establishing a conserved targeting hierarchy.\",\n      \"evidence\": \"Deletion/domain-mutant analysis, yeast two-hybrid, co-IP, structured-illumination microscopy, genetic epistasis in Sordaria macrospora\",\n      \"pmids\": [\"25527523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Nuclear envelope targeting mechanism not mapped to specific STRIPAK subunit\",\n        \"Whether mammalian SLMAP nuclear-envelope localization is similarly STRIPAK-dependent not tested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Biochemical reconstitution and SLMAP CRISPR knockout demonstrated that SLMAP-STRIPAK dephosphorylates the MST2 activation loop after binding MST2's autophosphorylated linker, while SAV1 protects MST2 by directly inhibiting STRIPAK phosphatase activity — resolving the antagonistic SAV1/STRIPAK toggle that controls Hippo kinase output.\",\n      \"evidence\": \"Crystal structure of SAV1-MST2 SARAH domain, in vitro reconstituted phosphatase assays, SLMAP CRISPR KO in human cells, co-IP, mutagenesis\",\n      \"pmids\": [\"29063833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution structure of FHA–MST2 linker interaction still lacking\",\n        \"How membrane anchoring of SLMAP spatially constrains STRIPAK-MST2 interaction in vivo unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SLMAP-3 overexpression in cardiomyocytes increased calcium transients and beating rate while knockdown blunted adrenergic responsiveness, linking SLMAP-striatin signaling to the adrenergic regulation of cardiac contractility.\",\n      \"evidence\": \"AAV-mediated overexpression and shRNA knockdown in cardiomyocytes, confocal live calcium imaging, isoproterenol challenge, proteomics\",\n      \"pmids\": [\"30856349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; adrenergic signaling mechanism downstream of SLMAP-striatin not defined\",\n        \"No in vivo cardiac-specific loss-of-function data at this stage\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SLMAP localizes to the nuclear envelope in neural progenitors, and overexpression prolongs mitosis and alters asymmetric division, neuronal migration, and cortical layer formation, expanding SLMAP's roles to brain development.\",\n      \"evidence\": \"In utero electroporation (OE and Cas9-KD) in developing mouse cortex, live imaging of mitosis, cortical layer analysis, behavioral testing\",\n      \"pmids\": [\"38466184\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Nuclear-envelope isoform identity needs clarification relative to known splice variants\",\n        \"Whether mitosis-lengthening effect is STRIPAK-dependent not tested\",\n        \"Single study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Conditional deletion of Slmap in gut mesenchyme revealed that SLMAP activates YAP by restraining MST3 kinase, driving intestinal elongation; genetic epistasis with Mst3 deletion confirmed SLMAP acts upstream of MST3 in this tissue.\",\n      \"evidence\": \"Mesenchyme-specific conditional KO mice, Slmap/Mst3 double KO rescue, scRNA-seq, YAP activity and proliferation assays\",\n      \"pmids\": [\"40521668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SLMAP–MST3 interaction operates through canonical STRIPAK or a distinct complex is unresolved\",\n        \"Whether intestinal phenotype extends to adult gut homeostasis or tumorigenesis not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution structure of the SLMAP FHA domain bound to MST kinase phospho-peptides, how membrane-anchored SLMAP spatially organizes STRIPAK signaling at distinct organelles, whether cardiac-specific SLMAP knockout recapitulates loss-of-function phenotypes, and the relative contributions of STRIPAK-dependent versus -independent functions across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of FHA–MST interaction\",\n        \"No cardiac-specific conditional knockout model reported\",\n        \"Relative contribution of STRIPAK-dependent vs. independent SLMAP functions unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 3, 4]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [6, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"complexes\": [\n      \"STRIPAK\"\n    ],\n    \"partners\": [\n      \"MST1\",\n      \"MST2\",\n      \"MST3\",\n      \"STRN\",\n      \"PPP2CA\",\n      \"SAV1\",\n      \"STRIP1\",\n      \"MOB4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}