{"gene":"BAIAP2L2","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2011,"finding":"Pinkbar (BAIAP2L2) is an I-BAR subfamily member whose BAR domain does not induce membrane tubulation but instead promotes the formation of planar membrane sheets. Structural and mutagenesis analyses reveal that the BAR domain has a relatively flat lipid-binding interface and assembles into sheet-like oligomers in crystals and in solution, explaining its unique membrane-deforming activity.","method":"Crystal structure determination, mutagenesis, in vitro membrane-deformation assays, biochemical oligomerization analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro membrane assays in a single rigorous study","pmids":["21743456"],"is_preprint":false},{"year":2011,"finding":"In intestinal epithelial cells, Pinkbar (BAIAP2L2) localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions.","method":"Immunofluorescence/co-localization with Rab13 marker in intestinal epithelial cells","journal":"Nature structural & molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-localization imaging in a single study with functional context but no direct functional consequence tested for the vesicle localization","pmids":["21743456"],"is_preprint":false},{"year":2020,"finding":"BAIAP2L2 localizes to the tips of shorter (row 2/3) transducing stereocilia in cochlear hair cells, and its loss causes progressive degeneration of the second and third rows of stereocilia, loss of mechanoelectrical transducer (MET) current, and deafness by 8 months. BAIAP2L2 localization to stereocilia tips depends on the motor protein MYO15A and its cargo EPS8. BAIAP2L2 interacts with stereociliary proteins CDC42, RAC1, EPS8, and ESPNL.","method":"Immunohistochemistry, Baiap2l2 knockout mouse model, electrophysiology (MET current recording), co-immunoprecipitation/interaction assays","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined electrophysiological phenotype, co-IP interactions, localization dependency shown, replicated across multiple labs","pmids":["33151556"],"is_preprint":false},{"year":2021,"finding":"BAIAP2L2 is a component of the row 2 stereociliary tip complex and binds to known row 2 complex components EPS8L2, TWF2, and CAPZB2. The stereociliary tip localization of CAPZB2 depends on functional BAIAP2L2. BAIAP2L2 also binds to MET complex component CIB2, and BAIAP2L2 tip localization is abolished in Cib2 knockout mice.","method":"Baiap2l2 knockout mouse, co-immunoprecipitation/pulldown with EPS8L2, TWF2, CAPZB2, CIB2; immunohistochemistry; FM 1-43FX dye uptake; electrophysiology","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP binding partners, KO mice with defined phenotype, epistatic dependency of CAPZB2 localization on BAIAP2L2, and CIB2 KO epistasis; replicated across labs","pmids":["34346063"],"is_preprint":false},{"year":2022,"finding":"BAIAP2L2 is transported to stereocilia tips by a MYO15A–EPS8 complex; a tripartite complex of BAIAP2L2, EPS8, and MYO15A forms efficiently in vitro and robustly targets to filopodia tips when coexpressed in cultured cells. Ca2+ entry through open mechanotransduction channels retains BAIAP2L2 at row 2 stereocilia tips: mice lacking functional transduction channels or cochlear explants with channels blocked by tubocurarine no longer concentrate BAIAP2L2 at row 2 tips, and reduction of intracellular Ca2+ with BAPTA-AM leads to loss of BAIAP2L2 at tips. Membrane localization of BAIAP2L2 is enhanced in the presence of Ca2+.","method":"In vitro complex reconstitution, filopodia-targeting assay in cultured cells, Baiap2l2/MYO15A/EPS8 mutant mice, channel blockers (tubocurarine), BAPTA-AM Ca2+ chelation, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of tripartite complex combined with multiple genetic and pharmacological epistasis experiments establishing Ca2+-dependent retention mechanism","pmids":["35044843"],"is_preprint":false},{"year":2022,"finding":"BAIAP2L2 inactivation does not affect stereocilia development, maintenance, MET function, or CAPZB2 tip localization in vestibular hair cells, despite BAIAP2L2 being present at shorter-row stereocilia tips in vestibular hair cells.","method":"Baiap2l2 knockout mouse, confocal microscopy, MET electrophysiology, vestibular function tests, immunohistochemistry of CAPZB2","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple functional readouts; single lab; negative result in vestibular vs. positive in cochlear hair cells is mechanistically informative","pmids":["35242013"],"is_preprint":false},{"year":2023,"finding":"HNF1β directly activates the BAIAP2L2 promoter (validated by reporter luciferase assay). BAIAP2L2 binds to other I-BAR domain-containing family members BAIAP2 and BAIAP2L1 (by mass spectrometry). However, Baiap2l2 knockout mice and kidney epithelial cells lacking BAIAP2L2 display normal F-actin distribution, normal polarized spheroid formation, normal kidney and colon morphology, and normal electrolyte homeostasis.","method":"ChIP-seq/RNA-seq bioinformatics, luciferase reporter assay, mass spectrometry pulldown, Baiap2l2 knockout mouse and knockout cell model, histology, electrolyte measurement","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter for transcriptional activation, MS-confirmed binding partners; negative kidney phenotype is a single-lab study","pmids":["36520027"],"is_preprint":false},{"year":2024,"finding":"BAIAP2L2 interacts with GABPB1 and inhibits its ubiquitin-mediated degradation, promoting GABPB1 nuclear translocation. This interaction suppresses reactive oxygen species (ROS) levels in hepatocellular carcinoma cells. NFκB1 stimulates BAIAP2L2 transcription by directly binding to its promoter region.","method":"Co-immunoprecipitation, ubiquitination assay, nuclear fractionation, ROS measurement, ChIP/promoter binding assay, western blot","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP binding and ubiquitination assay, promoter binding, single lab with multiple orthogonal methods but cancer cell line context","pmids":["39496939"],"is_preprint":false},{"year":2025,"finding":"BAIAP2L2 co-localizes and physically interacts with JAK1 in hepatocellular carcinoma cells, enhancing activation of the JAK1/STAT3 signaling pathway. JAK1 inhibition with Ruxolitinib reverses BAIAP2L2-induced proliferation, migration, invasion, and PD-L1 upregulation.","method":"Co-localization imaging, co-immunoprecipitation, JAK1 inhibitor rescue experiment (Ruxolitinib), western blot for STAT3 pathway activation, in vitro and in vivo functional assays","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP interaction and pharmacological epistasis in cancer cells; single lab, no structural validation","pmids":["40097840"],"is_preprint":false},{"year":2025,"finding":"YTHDF1 facilitates the translation of BAIAP2L2 through m6A modifications (validated by RIP-qPCR), and BAIAP2L2 promotes the transfer of chemotherapy resistance from resistant to sensitive gastric cancer cells through extracellular vesicle proteins including ANXA4.","method":"RIP-qPCR with YTHDF1-specific antibody, extracellular vesicle isolation/characterization (TEM, NTA, western blot), TMT proteomics, subcutaneous tumor model","journal":"Journal of translational medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, RIP-qPCR for m6A reader interaction, indirect mechanistic chain for EV transfer; no reconstitution or structural validation","pmids":["40082986"],"is_preprint":false},{"year":2024,"finding":"BAIAP2L1 (a paralog) localizes to tallest-row stereocilia tips in a calcium-independent manner, in contrast to BAIAP2L2 whose stereocilia-tip localization requires calcium. This demonstrates that the two I-BAR paralogs regulate different stereociliary rows by distinct mechanisms.","method":"Immunofluorescence in hair cells, Baiap2l1 and Baiap2l2 knockout mice, calcium-dependency assays, auditory and balance function testing","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct comparative KO study with functional readouts establishing mechanistic distinction between BAIAP2L2 and its paralog regarding calcium dependency; single lab","pmids":["39093051"],"is_preprint":false}],"current_model":"BAIAP2L2 (Pinkbar) is an I-BAR domain protein with a uniquely flat lipid-binding interface that generates planar membrane sheets rather than tubules; in cochlear hair cells it is transported to the tips of shorter transducing stereocilia by a MYO15A–EPS8 motor complex and is retained there by Ca2+ entry through open mechanotransduction channels, where it forms part of the 'row 2 tip complex' by binding EPS8L2, TWF2, CAPZB2, CIB2, CDC42, RAC1, and ESPNL, and its loss causes progressive degeneration of transducing stereocilia and deafness; additionally, BAIAP2L2 transcription is activated by HNF1β and NFκB1, its translation is enhanced by YTHDF1-mediated m6A modification, and in cancer contexts it interacts with JAK1 to activate JAK1/STAT3 signaling and with GABPB1 to suppress ROS."},"narrative":{"mechanistic_narrative":"BAIAP2L2 (Pinkbar) is an I-BAR subfamily protein that, unlike tubule-forming BAR proteins, possesses a relatively flat lipid-binding interface and assembles into sheet-like oligomers to generate planar membrane sheets [PMID:21743456]. Its principal characterized role is in cochlear hair-cell mechanotransduction: BAIAP2L2 localizes to the tips of the shorter (row 2/3) transducing stereocilia, where its loss causes progressive degeneration of these rows, loss of mechanoelectrical transducer current, and deafness [PMID:33151556]. It is a constituent of the row 2 tip complex, binding EPS8L2, TWF2, CAPZB2, and the MET-complex component CIB2, with CAPZB2 tip localization and BAIAP2L2's own localization being mutually dependent on these partners [PMID:34346063]. Targeting to stereocilia tips is achieved by a tripartite MYO15A–EPS8 motor cargo complex that BAIAP2L2 reconstitutes in vitro, and retention there requires Ca2+ entry through open mechanotransduction channels [PMID:35044843], a calcium-dependence that mechanistically distinguishes it from its paralog BAIAP2L1, which marks the tallest row independently of calcium [PMID:39093051]. BAIAP2L2 transcription is directly activated through promoter binding by HNF1β [PMID:36520027] and NFκB1 [PMID:39496939]. In hepatocellular carcinoma it interacts with JAK1 to enhance JAK1/STAT3 signaling and PD-L1 upregulation [PMID:40097840] and binds GABPB1 to block its ubiquitin-mediated degradation and suppress reactive oxygen species [PMID:39496939].","teleology":[{"year":2011,"claim":"Established why BAIAP2L2 behaves unlike other BAR proteins, defining a structural basis for planar membrane sheet generation rather than tubulation.","evidence":"Crystal structure with mutagenesis and in vitro membrane-deformation and oligomerization assays","pmids":["21743456"],"confidence":"High","gaps":["Did not establish a physiological membrane substrate in vivo","Vesicle/junctional localization in epithelial cells shown by co-localization only, no functional consequence tested"]},{"year":2020,"claim":"Identified BAIAP2L2's first defined physiological function by linking its row 2/3 stereocilia-tip localization to transducer current maintenance and hearing.","evidence":"Baiap2l2 knockout mouse, immunohistochemistry, MET current electrophysiology, co-IP with CDC42/RAC1/EPS8/ESPNL","pmids":["33151556"],"confidence":"High","gaps":["Did not resolve how the flat I-BAR activity contributes mechanically to stereocilia maintenance","Direct vs. indirect nature of some interactions not all distinguished"]},{"year":2021,"claim":"Placed BAIAP2L2 within the row 2 tip complex and established epistatic dependencies that order it relative to CAPZB2 and CIB2.","evidence":"Reciprocal co-IP/pulldown with EPS8L2, TWF2, CAPZB2, CIB2; knockout mice; CIB2 KO epistasis; FM 1-43FX uptake","pmids":["34346063"],"confidence":"High","gaps":["Stoichiometry and architecture of the tip complex unresolved","Whether BAIAP2L2 membrane-shaping activity is required for complex assembly untested"]},{"year":2022,"claim":"Resolved both the delivery and retention mechanisms for BAIAP2L2 at stereocilia tips: motor-driven transport plus Ca2+-dependent anchoring.","evidence":"In vitro reconstitution of BAIAP2L2–EPS8–MYO15A tripartite complex, filopodia-targeting assay, mutant mice, tubocurarine channel block, BAPTA-AM chelation","pmids":["35044843"],"confidence":"High","gaps":["Molecular sensor for Ca2+-dependent retention not identified","Quantitative dynamics of delivery vs. turnover unresolved"]},{"year":2022,"claim":"Demonstrated cell-type specificity of BAIAP2L2 function, showing it is dispensable in vestibular hair cells despite being present there.","evidence":"Baiap2l2 knockout mouse, confocal imaging, MET electrophysiology, vestibular function tests, CAPZB2 immunohistochemistry","pmids":["35242013"],"confidence":"Medium","gaps":["Basis for cochlear vs. vestibular requirement difference unknown","Single-lab negative result"]},{"year":2023,"claim":"Identified an upstream transcriptional activator (HNF1β) and intra-family binding partners, while showing BAIAP2L2 is dispensable in kidney/colon epithelia.","evidence":"Luciferase reporter, mass spectrometry pulldown with BAIAP2 and BAIAP2L1, knockout mouse and cell histology, electrolyte measurement","pmids":["36520027"],"confidence":"Medium","gaps":["Functional consequence of BAIAP2/BAIAP2L1 binding not established","Negative epithelial phenotype single-lab only"]},{"year":2024,"claim":"Contrasted BAIAP2L2 with its paralog BAIAP2L1, establishing that the two I-BAR proteins govern different stereociliary rows through distinct calcium dependencies.","evidence":"Comparative Baiap2l1/Baiap2l2 knockout mice, immunofluorescence, calcium-dependency assays, auditory/balance testing","pmids":["39093051"],"confidence":"Medium","gaps":["Molecular determinant of differential calcium dependence not mapped","Single lab"]},{"year":2024,"claim":"Extended BAIAP2L2 biology to cancer by showing it stabilizes GABPB1 against ubiquitin-mediated degradation to suppress ROS, with NFκB1 driving its transcription.","evidence":"Co-IP, ubiquitination assay, nuclear fractionation, ROS measurement, ChIP/promoter binding in hepatocellular carcinoma cells","pmids":["39496939"],"confidence":"Medium","gaps":["Mechanism by which BAIAP2L2 blocks GABPB1 ubiquitination unresolved","Cancer cell-line context not validated in primary tissue"]},{"year":2025,"claim":"Implicated BAIAP2L2 as an activator of JAK1/STAT3 signaling promoting tumor aggressiveness and immune-checkpoint expression.","evidence":"Co-localization, co-IP with JAK1, Ruxolitinib rescue, STAT3 pathway western blots, in vitro and in vivo assays in hepatocellular carcinoma","pmids":["40097840"],"confidence":"Medium","gaps":["Direct vs. scaffold-mediated nature of JAK1 interaction not resolved structurally","Single lab, one cancer context"]},{"year":2025,"claim":"Linked BAIAP2L2 translational regulation to m6A reading and to extracellular-vesicle transfer of chemoresistance.","evidence":"RIP-qPCR with YTHDF1 antibody, EV isolation/characterization, TMT proteomics, subcutaneous tumor model in gastric cancer","pmids":["40082986"],"confidence":"Low","gaps":["Indirect mechanistic chain for EV-mediated resistance transfer; no reconstitution","m6A site on BAIAP2L2 transcript not mapped"]},{"year":null,"claim":"How BAIAP2L2's flat I-BAR membrane-sheet activity mechanically supports stereocilia tips, and whether its cancer signaling roles depend on the same membrane-shaping function, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model connecting membrane deformation to stereocilia maintenance","No demonstration that I-BAR activity is required for JAK1/GABPB1 functions"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,7]}],"complexes":["row 2 stereociliary tip complex","MYO15A–EPS8 motor cargo complex"],"partners":["EPS8","MYO15A","EPS8L2","TWF2","CAPZB2","CIB2","JAK1","GABPB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UXY1","full_name":"BAR/IMD domain-containing adapter protein 2-like 2","aliases":["Brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 2","BAI1-associated protein 2-like protein 2","Planar intestinal- and kidney-specific BAR domain protein","Pinkbar"],"length_aa":529,"mass_kda":59.0,"function":"Phosphoinositides-binding protein that induces the formation of planar or gently curved membrane structures. Binds to phosphoinositides, including to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) headgroups. There seems to be no clear preference for a specific phosphoinositide (By similarity)","subcellular_location":"Cell membrane; Cell junction; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q6UXY1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BAIAP2L2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BAIAP2L2","total_profiled":1310},"omim":[{"mim_id":"617536","title":"BAI1-ASSOCIATED PROTEIN 2-LIKE 2; BAIAP2L2","url":"https://www.omim.org/entry/617536"},{"mim_id":"611877","title":"BAI1-ASSOCIATED PROTEIN 2-LIKE 1; BAIAP2L1","url":"https://www.omim.org/entry/611877"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":92.8},{"tissue":"kidney","ntpm":36.3}],"url":"https://www.proteinatlas.org/search/BAIAP2L2"},"hgnc":{"alias_symbol":["FLJ22582","pinkbar"],"prev_symbol":[]},"alphafold":{"accession":"Q6UXY1","domains":[{"cath_id":"1.20.1270.60","chopping":"4-224","consensus_level":"high","plddt":95.6672,"start":4,"end":224},{"cath_id":"2.30.30.40","chopping":"329-385","consensus_level":"high","plddt":87.9779,"start":329,"end":385}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXY1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXY1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXY1-F1-predicted_aligned_error_v6.png","plddt_mean":69.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BAIAP2L2","jax_strain_url":"https://www.jax.org/strain/search?query=BAIAP2L2"},"sequence":{"accession":"Q6UXY1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UXY1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UXY1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXY1"}},"corpus_meta":[{"pmid":"21743456","id":"PMC_21743456","title":"Pinkbar is an epithelial-specific BAR domain protein that generates planar membrane structures.","date":"2011","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21743456","citation_count":82,"is_preprint":false},{"pmid":"33151556","id":"PMC_33151556","title":"Loss of Baiap2l2 destabilizes the transducing stereocilia of cochlear hair cells and leads to deafness.","date":"2020","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33151556","citation_count":42,"is_preprint":false},{"pmid":"34346063","id":"PMC_34346063","title":"BAIAP2L2 is required for the maintenance of mechanotransducing stereocilia of cochlear hair cells.","date":"2021","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34346063","citation_count":23,"is_preprint":false},{"pmid":"32570120","id":"PMC_32570120","title":"BAIAP2L2 promotes the progression of gastric cancer via AKT/mTOR and Wnt3a/β-catenin signaling pathways.","date":"2020","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/32570120","citation_count":18,"is_preprint":false},{"pmid":"33646530","id":"PMC_33646530","title":"BAIAP2L2 facilitates the malignancy of prostate cancer (PCa) via VEGF and apoptosis signaling pathways.","date":"2021","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33646530","citation_count":14,"is_preprint":false},{"pmid":"35044843","id":"PMC_35044843","title":"Ca2+ entry through mechanotransduction channels localizes BAIAP2L2 to stereocilia tips.","date":"2022","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/35044843","citation_count":13,"is_preprint":false},{"pmid":"34695828","id":"PMC_34695828","title":"Downregulation of Pinkbar/pAKT and MMP2/MMP9 Expression in MDA-MB-231 Breast Cancer Cells as Potential Targets in Cancer Therapy by hAMSCs Secretome.","date":"2021","source":"Cells, tissues, organs","url":"https://pubmed.ncbi.nlm.nih.gov/34695828","citation_count":12,"is_preprint":false},{"pmid":"34786330","id":"PMC_34786330","title":"BAIAP2L2 promotes the proliferation, migration and invasion of osteosarcoma associated with the Wnt/β-catenin pathway.","date":"2021","source":"Journal of bone oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34786330","citation_count":11,"is_preprint":false},{"pmid":"40082986","id":"PMC_40082986","title":"N6-methyladenosine RNA modified BAIAP2L2 facilitates extracellular vesicles-mediated chemoresistance transmission in gastric cancer.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40082986","citation_count":6,"is_preprint":false},{"pmid":"39093051","id":"PMC_39093051","title":"BAIAP2L1 and BAIAP2L2 differently regulate hair cell stereocilia morphology.","date":"2024","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/39093051","citation_count":3,"is_preprint":false},{"pmid":"35242013","id":"PMC_35242013","title":"BAIAP2L2 Inactivation Does Not Affect Stereocilia Development or Maintenance in Vestibular Hair Cells.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35242013","citation_count":3,"is_preprint":false},{"pmid":"40097840","id":"PMC_40097840","title":"BAIAP2L2 facilitates hepatocellular carcinoma progression and immune evasion of via targeting JAK1-mediated pathway and PD-L1 expression.","date":"2025","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40097840","citation_count":2,"is_preprint":false},{"pmid":"39496939","id":"PMC_39496939","title":"BAIAP2L2 promotes the malignancy of hepatocellular carcinoma via GABPB1-mediated reactive oxygen species imbalance.","date":"2024","source":"Cancer gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39496939","citation_count":2,"is_preprint":false},{"pmid":"36520027","id":"PMC_36520027","title":"HNF1β-associated cyst development and electrolyte disturbances are not explained by BAIAP2L2 expression.","date":"2023","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36520027","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9444,"output_tokens":3179,"usd":0.038009,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10600,"output_tokens":3507,"usd":0.070337,"stage2_stop_reason":"end_turn"},"total_usd":0.108346,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"Pinkbar (BAIAP2L2) is an I-BAR subfamily member whose BAR domain does not induce membrane tubulation but instead promotes the formation of planar membrane sheets. Structural and mutagenesis analyses reveal that the BAR domain has a relatively flat lipid-binding interface and assembles into sheet-like oligomers in crystals and in solution, explaining its unique membrane-deforming activity.\",\n      \"method\": \"Crystal structure determination, mutagenesis, in vitro membrane-deformation assays, biochemical oligomerization analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro membrane assays in a single rigorous study\",\n      \"pmids\": [\"21743456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In intestinal epithelial cells, Pinkbar (BAIAP2L2) localizes to Rab13-positive vesicles and to the plasma membrane at intercellular junctions.\",\n      \"method\": \"Immunofluorescence/co-localization with Rab13 marker in intestinal epithelial cells\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-localization imaging in a single study with functional context but no direct functional consequence tested for the vesicle localization\",\n      \"pmids\": [\"21743456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BAIAP2L2 localizes to the tips of shorter (row 2/3) transducing stereocilia in cochlear hair cells, and its loss causes progressive degeneration of the second and third rows of stereocilia, loss of mechanoelectrical transducer (MET) current, and deafness by 8 months. BAIAP2L2 localization to stereocilia tips depends on the motor protein MYO15A and its cargo EPS8. BAIAP2L2 interacts with stereociliary proteins CDC42, RAC1, EPS8, and ESPNL.\",\n      \"method\": \"Immunohistochemistry, Baiap2l2 knockout mouse model, electrophysiology (MET current recording), co-immunoprecipitation/interaction assays\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined electrophysiological phenotype, co-IP interactions, localization dependency shown, replicated across multiple labs\",\n      \"pmids\": [\"33151556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAIAP2L2 is a component of the row 2 stereociliary tip complex and binds to known row 2 complex components EPS8L2, TWF2, and CAPZB2. The stereociliary tip localization of CAPZB2 depends on functional BAIAP2L2. BAIAP2L2 also binds to MET complex component CIB2, and BAIAP2L2 tip localization is abolished in Cib2 knockout mice.\",\n      \"method\": \"Baiap2l2 knockout mouse, co-immunoprecipitation/pulldown with EPS8L2, TWF2, CAPZB2, CIB2; immunohistochemistry; FM 1-43FX dye uptake; electrophysiology\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP binding partners, KO mice with defined phenotype, epistatic dependency of CAPZB2 localization on BAIAP2L2, and CIB2 KO epistasis; replicated across labs\",\n      \"pmids\": [\"34346063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BAIAP2L2 is transported to stereocilia tips by a MYO15A–EPS8 complex; a tripartite complex of BAIAP2L2, EPS8, and MYO15A forms efficiently in vitro and robustly targets to filopodia tips when coexpressed in cultured cells. Ca2+ entry through open mechanotransduction channels retains BAIAP2L2 at row 2 stereocilia tips: mice lacking functional transduction channels or cochlear explants with channels blocked by tubocurarine no longer concentrate BAIAP2L2 at row 2 tips, and reduction of intracellular Ca2+ with BAPTA-AM leads to loss of BAIAP2L2 at tips. Membrane localization of BAIAP2L2 is enhanced in the presence of Ca2+.\",\n      \"method\": \"In vitro complex reconstitution, filopodia-targeting assay in cultured cells, Baiap2l2/MYO15A/EPS8 mutant mice, channel blockers (tubocurarine), BAPTA-AM Ca2+ chelation, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of tripartite complex combined with multiple genetic and pharmacological epistasis experiments establishing Ca2+-dependent retention mechanism\",\n      \"pmids\": [\"35044843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BAIAP2L2 inactivation does not affect stereocilia development, maintenance, MET function, or CAPZB2 tip localization in vestibular hair cells, despite BAIAP2L2 being present at shorter-row stereocilia tips in vestibular hair cells.\",\n      \"method\": \"Baiap2l2 knockout mouse, confocal microscopy, MET electrophysiology, vestibular function tests, immunohistochemistry of CAPZB2\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple functional readouts; single lab; negative result in vestibular vs. positive in cochlear hair cells is mechanistically informative\",\n      \"pmids\": [\"35242013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HNF1β directly activates the BAIAP2L2 promoter (validated by reporter luciferase assay). BAIAP2L2 binds to other I-BAR domain-containing family members BAIAP2 and BAIAP2L1 (by mass spectrometry). However, Baiap2l2 knockout mice and kidney epithelial cells lacking BAIAP2L2 display normal F-actin distribution, normal polarized spheroid formation, normal kidney and colon morphology, and normal electrolyte homeostasis.\",\n      \"method\": \"ChIP-seq/RNA-seq bioinformatics, luciferase reporter assay, mass spectrometry pulldown, Baiap2l2 knockout mouse and knockout cell model, histology, electrolyte measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter for transcriptional activation, MS-confirmed binding partners; negative kidney phenotype is a single-lab study\",\n      \"pmids\": [\"36520027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAIAP2L2 interacts with GABPB1 and inhibits its ubiquitin-mediated degradation, promoting GABPB1 nuclear translocation. This interaction suppresses reactive oxygen species (ROS) levels in hepatocellular carcinoma cells. NFκB1 stimulates BAIAP2L2 transcription by directly binding to its promoter region.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, nuclear fractionation, ROS measurement, ChIP/promoter binding assay, western blot\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP binding and ubiquitination assay, promoter binding, single lab with multiple orthogonal methods but cancer cell line context\",\n      \"pmids\": [\"39496939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BAIAP2L2 co-localizes and physically interacts with JAK1 in hepatocellular carcinoma cells, enhancing activation of the JAK1/STAT3 signaling pathway. JAK1 inhibition with Ruxolitinib reverses BAIAP2L2-induced proliferation, migration, invasion, and PD-L1 upregulation.\",\n      \"method\": \"Co-localization imaging, co-immunoprecipitation, JAK1 inhibitor rescue experiment (Ruxolitinib), western blot for STAT3 pathway activation, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP interaction and pharmacological epistasis in cancer cells; single lab, no structural validation\",\n      \"pmids\": [\"40097840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YTHDF1 facilitates the translation of BAIAP2L2 through m6A modifications (validated by RIP-qPCR), and BAIAP2L2 promotes the transfer of chemotherapy resistance from resistant to sensitive gastric cancer cells through extracellular vesicle proteins including ANXA4.\",\n      \"method\": \"RIP-qPCR with YTHDF1-specific antibody, extracellular vesicle isolation/characterization (TEM, NTA, western blot), TMT proteomics, subcutaneous tumor model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, RIP-qPCR for m6A reader interaction, indirect mechanistic chain for EV transfer; no reconstitution or structural validation\",\n      \"pmids\": [\"40082986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BAIAP2L1 (a paralog) localizes to tallest-row stereocilia tips in a calcium-independent manner, in contrast to BAIAP2L2 whose stereocilia-tip localization requires calcium. This demonstrates that the two I-BAR paralogs regulate different stereociliary rows by distinct mechanisms.\",\n      \"method\": \"Immunofluorescence in hair cells, Baiap2l1 and Baiap2l2 knockout mice, calcium-dependency assays, auditory and balance function testing\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct comparative KO study with functional readouts establishing mechanistic distinction between BAIAP2L2 and its paralog regarding calcium dependency; single lab\",\n      \"pmids\": [\"39093051\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BAIAP2L2 (Pinkbar) is an I-BAR domain protein with a uniquely flat lipid-binding interface that generates planar membrane sheets rather than tubules; in cochlear hair cells it is transported to the tips of shorter transducing stereocilia by a MYO15A–EPS8 motor complex and is retained there by Ca2+ entry through open mechanotransduction channels, where it forms part of the 'row 2 tip complex' by binding EPS8L2, TWF2, CAPZB2, CIB2, CDC42, RAC1, and ESPNL, and its loss causes progressive degeneration of transducing stereocilia and deafness; additionally, BAIAP2L2 transcription is activated by HNF1β and NFκB1, its translation is enhanced by YTHDF1-mediated m6A modification, and in cancer contexts it interacts with JAK1 to activate JAK1/STAT3 signaling and with GABPB1 to suppress ROS.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BAIAP2L2 (Pinkbar) is an I-BAR subfamily protein that, unlike tubule-forming BAR proteins, possesses a relatively flat lipid-binding interface and assembles into sheet-like oligomers to generate planar membrane sheets [#0]. Its principal characterized role is in cochlear hair-cell mechanotransduction: BAIAP2L2 localizes to the tips of the shorter (row 2/3) transducing stereocilia, where its loss causes progressive degeneration of these rows, loss of mechanoelectrical transducer current, and deafness [#2]. It is a constituent of the row 2 tip complex, binding EPS8L2, TWF2, CAPZB2, and the MET-complex component CIB2, with CAPZB2 tip localization and BAIAP2L2's own localization being mutually dependent on these partners [#3]. Targeting to stereocilia tips is achieved by a tripartite MYO15A–EPS8 motor cargo complex that BAIAP2L2 reconstitutes in vitro, and retention there requires Ca2+ entry through open mechanotransduction channels [#4], a calcium-dependence that mechanistically distinguishes it from its paralog BAIAP2L1, which marks the tallest row independently of calcium [#10]. BAIAP2L2 transcription is directly activated through promoter binding by HNF1\\u03b2 [#6] and NF\\u03baB1 [#7]. In hepatocellular carcinoma it interacts with JAK1 to enhance JAK1/STAT3 signaling and PD-L1 upregulation [#8] and binds GABPB1 to block its ubiquitin-mediated degradation and suppress reactive oxygen species [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established why BAIAP2L2 behaves unlike other BAR proteins, defining a structural basis for planar membrane sheet generation rather than tubulation.\",\n      \"evidence\": \"Crystal structure with mutagenesis and in vitro membrane-deformation and oligomerization assays\",\n      \"pmids\": [\"21743456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish a physiological membrane substrate in vivo\", \"Vesicle/junctional localization in epithelial cells shown by co-localization only, no functional consequence tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified BAIAP2L2's first defined physiological function by linking its row 2/3 stereocilia-tip localization to transducer current maintenance and hearing.\",\n      \"evidence\": \"Baiap2l2 knockout mouse, immunohistochemistry, MET current electrophysiology, co-IP with CDC42/RAC1/EPS8/ESPNL\",\n      \"pmids\": [\"33151556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the flat I-BAR activity contributes mechanically to stereocilia maintenance\", \"Direct vs. indirect nature of some interactions not all distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed BAIAP2L2 within the row 2 tip complex and established epistatic dependencies that order it relative to CAPZB2 and CIB2.\",\n      \"evidence\": \"Reciprocal co-IP/pulldown with EPS8L2, TWF2, CAPZB2, CIB2; knockout mice; CIB2 KO epistasis; FM 1-43FX uptake\",\n      \"pmids\": [\"34346063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and architecture of the tip complex unresolved\", \"Whether BAIAP2L2 membrane-shaping activity is required for complex assembly untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved both the delivery and retention mechanisms for BAIAP2L2 at stereocilia tips: motor-driven transport plus Ca2+-dependent anchoring.\",\n      \"evidence\": \"In vitro reconstitution of BAIAP2L2\\u2013EPS8\\u2013MYO15A tripartite complex, filopodia-targeting assay, mutant mice, tubocurarine channel block, BAPTA-AM chelation\",\n      \"pmids\": [\"35044843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor for Ca2+-dependent retention not identified\", \"Quantitative dynamics of delivery vs. turnover unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated cell-type specificity of BAIAP2L2 function, showing it is dispensable in vestibular hair cells despite being present there.\",\n      \"evidence\": \"Baiap2l2 knockout mouse, confocal imaging, MET electrophysiology, vestibular function tests, CAPZB2 immunohistochemistry\",\n      \"pmids\": [\"35242013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for cochlear vs. vestibular requirement difference unknown\", \"Single-lab negative result\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an upstream transcriptional activator (HNF1\\u03b2) and intra-family binding partners, while showing BAIAP2L2 is dispensable in kidney/colon epithelia.\",\n      \"evidence\": \"Luciferase reporter, mass spectrometry pulldown with BAIAP2 and BAIAP2L1, knockout mouse and cell histology, electrolyte measurement\",\n      \"pmids\": [\"36520027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of BAIAP2/BAIAP2L1 binding not established\", \"Negative epithelial phenotype single-lab only\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Contrasted BAIAP2L2 with its paralog BAIAP2L1, establishing that the two I-BAR proteins govern different stereociliary rows through distinct calcium dependencies.\",\n      \"evidence\": \"Comparative Baiap2l1/Baiap2l2 knockout mice, immunofluorescence, calcium-dependency assays, auditory/balance testing\",\n      \"pmids\": [\"39093051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular determinant of differential calcium dependence not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended BAIAP2L2 biology to cancer by showing it stabilizes GABPB1 against ubiquitin-mediated degradation to suppress ROS, with NF\\u03baB1 driving its transcription.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, nuclear fractionation, ROS measurement, ChIP/promoter binding in hepatocellular carcinoma cells\",\n      \"pmids\": [\"39496939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which BAIAP2L2 blocks GABPB1 ubiquitination unresolved\", \"Cancer cell-line context not validated in primary tissue\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated BAIAP2L2 as an activator of JAK1/STAT3 signaling promoting tumor aggressiveness and immune-checkpoint expression.\",\n      \"evidence\": \"Co-localization, co-IP with JAK1, Ruxolitinib rescue, STAT3 pathway western blots, in vitro and in vivo assays in hepatocellular carcinoma\",\n      \"pmids\": [\"40097840\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. scaffold-mediated nature of JAK1 interaction not resolved structurally\", \"Single lab, one cancer context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked BAIAP2L2 translational regulation to m6A reading and to extracellular-vesicle transfer of chemoresistance.\",\n      \"evidence\": \"RIP-qPCR with YTHDF1 antibody, EV isolation/characterization, TMT proteomics, subcutaneous tumor model in gastric cancer\",\n      \"pmids\": [\"40082986\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Indirect mechanistic chain for EV-mediated resistance transfer; no reconstitution\", \"m6A site on BAIAP2L2 transcript not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BAIAP2L2's flat I-BAR membrane-sheet activity mechanically supports stereocilia tips, and whether its cancer signaling roles depend on the same membrane-shaping function, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model connecting membrane deformation to stereocilia maintenance\", \"No demonstration that I-BAR activity is required for JAK1/GABPB1 functions\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\"row 2 stereociliary tip complex\", \"MYO15A–EPS8 motor cargo complex\"],\n    \"partners\": [\"EPS8\", \"MYO15A\", \"EPS8L2\", \"TWF2\", \"CAPZB2\", \"CIB2\", \"JAK1\", \"GABPB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}