{"gene":"PBX2","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":1991,"finding":"PBX2 encodes a TALE homeodomain protein with 92% identity to PBX1 over 266 amino acids within and flanking the homeodomain; unlike PBX1 and PBX3, PBX2 is not alternatively spliced. PBX2 maps to chromosome 3q22-23 and is widely expressed in fetal and adult tissues, suggesting a generalized role.","method":"cDNA cloning, sequence analysis, chromosome in situ hybridization, Northern blotting","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — foundational cloning paper with multiple orthogonal methods, widely replicated","pmids":["1682799"],"is_preprint":false},{"year":1995,"finding":"PBX1 and PBX2 bind cooperatively to DNA with HOX proteins (Hoxb-7 and Hoxb-8), and E2A-PBX1 retains this ability; the hexapeptide (LFPWMR) and its position relative to the homeodomain in Hoxb-8 are required for cooperative DNA binding with PBX1 and PBX2.","method":"EMSA (electrophoretic mobility shift assay), deletion and point mutagenesis of the hexapeptide","journal":"Mechanisms of development; Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 — in vitro DNA binding reconstitution with mutagenesis, confirmed by two independent papers","pmids":["7577680","7568094"],"is_preprint":false},{"year":1999,"finding":"In myeloid cells, PBX2 forms trimeric complexes with HOXA9 and MEIS1; MEIS1 enhances HOXA9-PBX2 complex formation in the absence of DNA, and immunoprecipitation of HOXA9 co-precipitates PBX2 and MEIS1. HOXA9, PBX2, and MEIS1 co-localize in nuclear speckles.","method":"EMSA, co-immunoprecipitation, nuclear fractionation, immunofluorescence co-localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus EMSA and localization, moderate evidence from single lab with multiple orthogonal methods","pmids":["10082572"],"is_preprint":false},{"year":2002,"finding":"A PBX2-PREP1 heterodimer binds to the Pbx site in the UGT2B17 promoter and interferes with HNF1α binding to its adjacent site, resulting in down-regulation of HNF1α-mediated transcriptional activation of UGT2B17.","method":"EMSA (gel shift assay), promoter-reporter functional assays, competition binding assays","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA plus functional reporter assays in a single lab study","pmids":["12065766"],"is_preprint":false},{"year":2002,"finding":"A PBX2-containing complex (including PREP1) binds a novel regulatory element (PRE-1048) in the HOX11 promoter and activates HOX11 transcription in K562 cells, representing the first report of a homeobox gene regulated specifically by PBX2.","method":"EMSA, promoter-reporter transcription assays, supershift assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA plus functional reporter assays; single lab, single study","pmids":["12054735"],"is_preprint":false},{"year":2003,"finding":"PREP-1 overexpression stabilizes PBX-2 protein by preventing its proteasomal degradation; dimerization of PBX-2 with PREP-1 reduces proteasome-dependent decay of PBX-2, increasing nuclear DNA-binding activity of PREP-PBX complexes.","method":"Cycloheximide chase, proteasome inhibitor (MG132) treatment, EMSA, immunoblotting in stably transfected F9 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — pharmacological and genetic perturbation with multiple orthogonal readouts in a single rigorous study","pmids":["12871956"],"is_preprint":false},{"year":2004,"finding":"Retinoic acid (RA) treatment increases PBX2 mRNA as a primary transcriptional response (not requiring new protein synthesis) and extends PBX2 protein half-life post-translationally, partly through RA-induced increased MEIS protein levels that stabilize PBX proteins against proteasomal degradation.","method":"Cycloheximide chase, RT-PCR, immunoblotting, mRNA stability assays in P19 cells with RAR antagonists","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple approaches in a single lab; consistent with independent stabilization mechanism findings","pmids":["15095411"],"is_preprint":false},{"year":2004,"finding":"Pbx2-null mice are viable with no detectable developmental or hematopoietic phenotype, indicating functional redundancy with other Pbx proteins; Pbx2 protein is expressed at considerably lower levels than Pbx1/Pbx3 in embryonic tissues but is the predominant high-MW Pbx isoform in postnatal bone marrow and thymus.","method":"Knockout mouse generation, developmental analysis, immunoblotting, flow cytometry","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean germline KO with comprehensive phenotypic analysis across multiple tissues and life stages","pmids":["15169896"],"is_preprint":false},{"year":2006,"finding":"Pbx1/Pbx2 compound loss-of-function in mice causes severe distal limb defects and complete limb absence in Pbx1−/−;Pbx2−/− embryos; the mechanism involves hierarchical control of Hox gene spatial distribution in the posterior limb and regulation of Shh expression in the ZPA.","method":"Compound knockout mouse model, in situ hybridization, skeletal analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with clean compound KO, multiple molecular readouts, Strong evidence for pathway position","pmids":["16672333"],"is_preprint":false},{"year":2008,"finding":"Pbx1/Pbx2 govern axial skeletal patterning by controlling Polycomb and Hox expression/spatial distribution in paraxial mesoderm, and Pax1/Pax9 expression in sclerotome; compound Pbx1/Pbx2 mutants show homogeneous vertebral column, loss of vertebral identity, rudimentary ribs, and rostral hindlimb shifts.","method":"Compound knockout mouse model, in situ hybridization, skeletal staining, gene expression analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with defined molecular pathway placements and multiple readouts","pmids":["18691704"],"is_preprint":false},{"year":2008,"finding":"Prep1/Pbx2 complexes bind the -2578 G allele of the CCL2 promoter (a polymorphism that creates a consensus Prep1 binding site) and suppress basal CCL2 transcription in astrocytes; upon IL-1β stimulation, Prep1/Pbx2 remains bound but no longer represses transcription, enabling hyper-responsive induction.","method":"EMSA, promoter-reporter assays, allele-specific binding experiments","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 2 — EMSA plus functional reporter assays, single lab","pmids":["18480829"],"is_preprint":false},{"year":2013,"finding":"The HOXB7/PBX2 dimer acts as a positive transcriptional regulator of miR-221 and miR-222 in melanoma; disruption of HOXB7/PBX2 dimerization (using peptide HXR9) reduces miR-221/222 transcription, elevates c-FOS expression, and induces apoptosis.","method":"HOX/PBX dimerization antagonist (HXR9), miRNA expression analysis, reporter assays, apoptosis assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological disruption of the dimer with functional readouts; mechanism inferred but direct ChIP not shown for PBX2","pmids":["23400877"],"is_preprint":false},{"year":2021,"finding":"PBX2 acts as a transcriptional activator of circTLK1 in glioma cells; circTLK1 in turn activates JAK/STAT signaling via a circTLK1/miR-452-5p/SSR1 axis to promote glioma progression.","method":"ChIP, luciferase reporter assay, AGO2-RIP, RNA pulldown, knockdown experiments","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and luciferase reporter demonstrate direct transcriptional regulation; single lab study","pmids":["34721518"],"is_preprint":false},{"year":2021,"finding":"HOXA6 physically interacts with and stabilizes PBX2 in gastric cancer cells; HOXA6-PBX2 co-expression promotes cell migration, invasion, and metastasis in vitro and in vivo.","method":"Co-immunoprecipitation, siRNA knockdown, orthotopic implantation in vivo, transwell migration/invasion assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus functional KD with defined cellular phenotype; single lab","pmids":["33535170"],"is_preprint":false},{"year":2023,"finding":"HOXB9 interacts with PBX2 to form a heterodimer that transcriptionally upregulates CDK6, driving G1-phase cell cycle progression in gastric cancer; E2F1 upregulates HOXB9 upstream, constituting an E2F1-HOXB9/PBX2-CDK6 oncogenic axis.","method":"Co-immunoprecipitation, ChIP, reporter assays, siRNA knockdown, cell cycle analysis","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ChIP, and functional knockdown with cell cycle readout; single lab","pmids":["37272544"],"is_preprint":false},{"year":2023,"finding":"PBX2 is phosphorylated by GSK3 and dephosphorylated by PP1; mTORC1 activity promotes dephosphorylation of PBX2 (but not other PBX family members) via PP1, establishing PBX2 as a novel downstream target of mTORC1 signaling.","method":"Large-scale phosphoproteomics re-analysis, pharmacological inhibition (rapamycin, GSK3 inhibitors), siRNA knockdown of GSK3/PP1, immunoblotting with phospho-specific analysis","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — phosphoproteomics plus pharmacological and genetic perturbations; single lab, moderate evidence","pmids":["36477205"],"is_preprint":false}],"current_model":"PBX2 is a TALE homeodomain transcription factor that forms heterodimeric complexes with PREP1/MEIS proteins (which protect it from proteasomal degradation) and cooperative DNA-binding complexes with HOX proteins (via the HOX hexapeptide), functioning as a context-dependent transcriptional activator or repressor at composite HOX-PBX binding sites; it also participates in trimeric complexes with HOXA9 and MEIS1 in myeloid cells, is required with PBX1 for limb and axial skeletal patterning via hierarchical control of Hox/Polycomb/Pax gene expression, and its activity is regulated post-translationally by mTORC1-dependent phosphorylation status determined by the antagonistic actions of GSK3 and PP1."},"narrative":{"teleology":[{"year":1991,"claim":"Identification of PBX2 as a new TALE homeodomain protein closely related to PBX1 established the existence of a multigene PBX family with potential functional overlap, and its ubiquitous expression pattern distinguished it from more tissue-restricted paralogs.","evidence":"cDNA cloning, sequence analysis, chromosomal mapping, and Northern blotting across fetal and adult tissues","pmids":["1682799"],"confidence":"High","gaps":["Transcriptional targets and in vivo functions of PBX2 were unknown","Whether PBX2 was functionally redundant with PBX1/PBX3 was untested"]},{"year":1995,"claim":"Demonstration that PBX2 cooperatively binds DNA with HOX proteins (Hoxb-7, Hoxb-8) through the hexapeptide motif established the molecular basis for HOX–PBX heterodimer formation and composite DNA recognition, a paradigm for TALE homeodomain partnerships.","evidence":"EMSA with deletion and point mutagenesis of the HOX hexapeptide","pmids":["7577680","7568094"],"confidence":"High","gaps":["Whether HOX–PBX2 complexes regulate specific endogenous target genes was unknown","The structural basis of the hexapeptide–PBX interaction awaited crystallographic analysis"]},{"year":1999,"claim":"Discovery of trimeric HOXA9–PBX2–MEIS1 complexes in myeloid cells, with MEIS1 enhancing HOXA9–PBX2 complex formation even without DNA, revealed a higher-order combinatorial logic for TALE–HOX transcription factor assemblies and their subnuclear organization.","evidence":"Co-immunoprecipitation, EMSA, and immunofluorescence co-localization in nuclear speckles in myeloid cells","pmids":["10082572"],"confidence":"High","gaps":["Specific genomic targets of the trimeric complex were not identified","Functional significance of nuclear speckle localization was not determined"]},{"year":2002,"claim":"Identification of PBX2–PREP1 as both a transcriptional repressor (at the UGT2B17 promoter, interfering with HNF1α) and an activator (at the HOX11 promoter) established PBX2 as a context-dependent transcriptional regulator whose output depends on the promoter architecture.","evidence":"EMSA, supershift assays, and promoter-reporter assays in K562 and other cell lines","pmids":["12065766","12054735"],"confidence":"Medium","gaps":["Direct ChIP evidence for PBX2 occupancy at these endogenous promoters was not provided","Mechanism switching between activation and repression was not characterized"]},{"year":2003,"claim":"Demonstrating that PREP1 dimerization stabilizes PBX2 by preventing its proteasomal degradation defined a key post-translational regulatory axis in which PBX2 protein levels are controlled by the availability of TALE cofactors.","evidence":"Cycloheximide chase, MG132 proteasome inhibition, EMSA, and immunoblotting in stably transfected F9 cells","pmids":["12871956"],"confidence":"High","gaps":["The ubiquitin ligase responsible for PBX2 degradation was not identified","Whether MEIS proteins stabilize PBX2 through the same mechanism was not formally tested"]},{"year":2004,"claim":"Retinoic acid was shown to increase PBX2 both transcriptionally (as a primary response) and post-translationally via MEIS-mediated stabilization, linking signaling pathways to PBX2 protein accumulation; meanwhile, Pbx2-null mice proved viable, revealing that Pbx2 is functionally redundant with other Pbx members despite being the predominant isoform in postnatal bone marrow and thymus.","evidence":"RT-PCR and cycloheximide chase in P19 cells; germline Pbx2 knockout mouse with developmental, hematopoietic, and expression analysis","pmids":["15095411","15169896"],"confidence":"High","gaps":["Which Pbx paralog(s) compensate for Pbx2 loss in specific tissues was not resolved","Direct RA-responsive elements in the PBX2 promoter were not mapped"]},{"year":2006,"claim":"Compound Pbx1/Pbx2 knockout mice revealed that PBX2 cooperates with PBX1 to pattern the limb skeleton by hierarchically controlling Hox gene domains and Shh expression in the zone of polarizing activity, establishing redundant but essential roles for Pbx factors in appendicular development.","evidence":"Compound knockout mouse with skeletal analysis and in situ hybridization of Hox, Shh targets","pmids":["16672333"],"confidence":"High","gaps":["Direct PBX2 binding at limb enhancers was not shown","Whether PBX3 further compensates was not fully addressed"]},{"year":2008,"claim":"Extension of compound Pbx1/Pbx2 analysis to axial skeleton demonstrated hierarchical control of Polycomb group genes, Hox gene spatial domains, and Pax1/Pax9 in sclerotome, explaining the complete loss of vertebral identity; separately, Prep1/Pbx2 was shown to mediate allele-specific repression of CCL2 in astrocytes, illustrating how genetic variation creates PBX2-dependent regulatory switches.","evidence":"Compound knockout mouse skeletal and molecular analysis; EMSA and reporter assays on CCL2 promoter polymorphism in astrocytes","pmids":["18691704","18480829"],"confidence":"High","gaps":["Genome-wide binding profiles of PBX2 in paraxial mesoderm were not generated","The mechanism by which IL-1β relieves Prep1/Pbx2 repression at CCL2 was not defined"]},{"year":2013,"claim":"The HOXB7–PBX2 dimer was identified as a positive transcriptional regulator of miR-221/222 in melanoma, with dimer disruption inducing apoptosis, providing direct evidence that HOX–PBX2 complexes control non-coding RNA targets relevant to cancer cell survival.","evidence":"HOX/PBX dimerization antagonist HXR9, miRNA expression analysis, apoptosis assays in melanoma cells","pmids":["23400877"],"confidence":"Medium","gaps":["Direct PBX2 ChIP at the miR-221/222 locus was not performed","Whether the apoptotic effect is PBX2-specific or general to all PBX members was not tested"]},{"year":2021,"claim":"PBX2 was shown to directly activate circTLK1 transcription in glioma and to interact with HOXA6 to promote gastric cancer metastasis, broadening the repertoire of HOX–PBX2 target genes in oncogenic contexts and demonstrating that HOXA6 stabilizes PBX2 protein.","evidence":"ChIP, luciferase reporter, AGO2-RIP, RNA pulldown in glioma cells; Co-IP, siRNA knockdown, orthotopic implantation in gastric cancer models","pmids":["34721518","33535170"],"confidence":"Medium","gaps":["Whether PBX2 contributes to tumorigenesis in vivo beyond xenograft models is unknown","Global target gene repertoire of PBX2 in cancer cells has not been defined by genome-wide approaches"]},{"year":2023,"claim":"Two studies identified HOXB9–PBX2 as a transcriptional activator of CDK6 promoting cell cycle progression in gastric cancer, and demonstrated that PBX2 is uniquely regulated among PBX family members by mTORC1-dependent dephosphorylation via PP1 opposing GSK3-mediated phosphorylation, linking PBX2 activity to growth factor signaling.","evidence":"Co-IP, ChIP, reporter and cell cycle assays for HOXB9–PBX2–CDK6 axis; phosphoproteomics, rapamycin treatment, GSK3/PP1 siRNA knockdown for mTORC1 regulation","pmids":["37272544","36477205"],"confidence":"Medium","gaps":["The phosphorylation sites on PBX2 targeted by GSK3/PP1 were not mapped to individual residues","Functional consequences of PBX2 phosphorylation on DNA binding or target gene selection were not determined","Whether mTORC1-dependent PBX2 regulation operates in non-cancer contexts is untested"]},{"year":null,"claim":"Key unresolved questions include the genome-wide binding landscape of PBX2, the identity of the E3 ubiquitin ligase mediating its proteasomal degradation, and the specific phosphorylation sites and their functional impact on PBX2 transcriptional output.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No genome-wide ChIP-seq or CUT&RUN data for PBX2 have been reported","E3 ligase targeting PBX2 for degradation is unidentified","Functional consequence of mTORC1-regulated phosphorylation on specific PBX2 target genes is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,2,3,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,4,11,12,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,5]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15]}],"complexes":[],"partners":["PREP1","MEIS1","HOXA9","HOXB7","HOXB9","HOXA6","PBX1"],"other_free_text":[]},"mechanistic_narrative":"PBX2 is a TALE-class homeodomain transcription factor that functions as a context-dependent transcriptional activator or repressor by forming heterodimeric complexes with HOX proteins (via the HOX hexapeptide motif) and with PREP1/MEIS family members, which also protect PBX2 from proteasomal degradation [PMID:7577680, PMID:12871956, PMID:10082572]. In myeloid cells PBX2 participates in trimeric HOXA9–PBX2–MEIS1 complexes that co-localize in nuclear speckles, while in various cell types HOX–PBX2 dimers regulate targets including miR-221/222, CDK6, circTLK1, and HOX11 [PMID:10082572, PMID:23400877, PMID:37272544, PMID:12054735]. Although Pbx2-null mice are viable owing to functional redundancy with Pbx1 and Pbx3, compound Pbx1/Pbx2 loss-of-function reveals essential roles in limb morphogenesis and axial skeletal patterning through hierarchical control of Hox, Polycomb, Shh, and Pax gene expression [PMID:15169896, PMID:16672333, PMID:18691704]. PBX2 activity is post-translationally regulated by mTORC1-dependent dephosphorylation via PP1, opposing GSK3-mediated phosphorylation, establishing PBX2 as a unique mTORC1 effector among PBX family members [PMID:36477205]."},"prefetch_data":{"uniprot":{"accession":"P40425","full_name":"Pre-B-cell leukemia transcription factor 2","aliases":["Homeobox protein PBX2","Protein G17"],"length_aa":430,"mass_kda":45.9,"function":"Transcriptional activator that binds the sequence 5'-ATCAATCAA-3'. Activates transcription of PF4 in complex with MEIS1","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P40425/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PBX2","classification":"Not Classified","n_dependent_lines":105,"n_total_lines":1208,"dependency_fraction":0.0869205298013245},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PBX2","total_profiled":1310},"omim":[{"mim_id":"618774","title":"CEBALID SYNDROME; CEBALID","url":"https://www.omim.org/entry/618774"},{"mim_id":"603099","title":"1-@ACYLGLYCEROL-3-PHOSPHATE O-ACYLTRANSFERASE 1; AGPAT1","url":"https://www.omim.org/entry/603099"},{"mim_id":"602100","title":"PBX/KNOTTED 1 HOMEOBOX 1; PKNOX1","url":"https://www.omim.org/entry/602100"},{"mim_id":"600214","title":"ADVANCED GLYCOSYLATION END PRODUCT-SPECIFIC RECEPTOR; AGER","url":"https://www.omim.org/entry/600214"},{"mim_id":"176312","title":"PRE-B-CELL LEUKEMIA TRANSCRIPTION FACTOR 3; PBX3","url":"https://www.omim.org/entry/176312"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PBX2"},"hgnc":{"alias_symbol":["G17","HOX12","PBX2MHC"],"prev_symbol":[]},"alphafold":{"accession":"P40425","domains":[{"cath_id":"-","chopping":"65-99","consensus_level":"medium","plddt":85.7274,"start":65,"end":99},{"cath_id":"-","chopping":"112-129_153-245","consensus_level":"high","plddt":89.6593,"start":112,"end":245},{"cath_id":"1.10.10.60","chopping":"252-323","consensus_level":"high","plddt":93.0199,"start":252,"end":323}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P40425","model_url":"https://alphafold.ebi.ac.uk/files/AF-P40425-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P40425-F1-predicted_aligned_error_v6.png","plddt_mean":69.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PBX2","jax_strain_url":"https://www.jax.org/strain/search?query=PBX2"},"sequence":{"accession":"P40425","fasta_url":"https://rest.uniprot.org/uniprotkb/P40425.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P40425/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P40425"}},"corpus_meta":[{"pmid":"1682799","id":"PMC_1682799","title":"PBX2 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33905146","citation_count":11,"is_preprint":false},{"pmid":"37632087","id":"PMC_37632087","title":"First Identification and Pathogenicity Evaluation of an EV-G17 Strain Carrying a Torovirus Papain-like Cysteine Protease (PLCP) Gene in China.","date":"2023","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/37632087","citation_count":10,"is_preprint":false},{"pmid":"12054735","id":"PMC_12054735","title":"A complex containing PBX2 contributes to activation of the proto-oncogene HOX11.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12054735","citation_count":10,"is_preprint":false},{"pmid":"34721518","id":"PMC_34721518","title":"PBX2-Mediated circTLK1 Activates JAK/STAT Signaling to Promote Gliomagenesis via miR-452-5p/SSR1 Axis.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34721518","citation_count":10,"is_preprint":false},{"pmid":"9762332","id":"PMC_9762332","title":"[Gastrin-17 and G17-gly induce proliferation of LoVo cells through the CCK B/gastrin receptor].","date":"1998","source":"Gastroenterologie clinique et biologique","url":"https://pubmed.ncbi.nlm.nih.gov/9762332","citation_count":9,"is_preprint":false},{"pmid":"4082298","id":"PMC_4082298","title":"Light and electron microscope localization of G-17- and G-34-like immunoreactivities of human gastrinomas.","date":"1985","source":"Ultrastructural pathology","url":"https://pubmed.ncbi.nlm.nih.gov/4082298","citation_count":7,"is_preprint":false},{"pmid":"26852910","id":"PMC_26852910","title":"Variant of PBX2 gene in the 6p21.3 asthma susceptibility locus is associated with allergic rhinitis in Chinese subjects.","date":"2016","source":"International forum of allergy & rhinology","url":"https://pubmed.ncbi.nlm.nih.gov/26852910","citation_count":6,"is_preprint":false},{"pmid":"19900509","id":"PMC_19900509","title":"A new beta-chain haemoglobin variant with increased oxygen affinity: Hb Roma [beta115(g17)Ala-->Val].","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19900509","citation_count":6,"is_preprint":false},{"pmid":"10870884","id":"PMC_10870884","title":"Hb Madrid [beta115(G17)Ala-->Pro] in a Korean family with chronic hemolytic anemia.","date":"2000","source":"Hemoglobin","url":"https://pubmed.ncbi.nlm.nih.gov/10870884","citation_count":5,"is_preprint":false},{"pmid":"29160311","id":"PMC_29160311","title":"Microstructure variations induced by excess PbX2 or AX within perovskite thin films.","date":"2017","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29160311","citation_count":4,"is_preprint":false},{"pmid":"26100115","id":"PMC_26100115","title":"Description of Three New α Variants and Four New β Variants: Hb Montluel [α110(G17)Ala → Val; HBA1: c.332C > T], Hb Cap d'Agde [α131(H14)Ser → Cys; HBA2: c.395C > G] and Hb Corsica [α100(G7)Leu → Pro; HBA1: 302T > C]; Hb Nîmes [β104(G6)Arg → Gly; HBB: c.313A > G], Hb Saint Marcellin [β112(G14)Cys → Gly; HBB: c.337T > G], Hb Saint Chamond [β80(EF4)Asn → 0; HBB: c.241_243delAAC] and Hb Dompierre [β29(B11)Gly → Arg; HBB: c.88G > C].","date":"2015","source":"Hemoglobin","url":"https://pubmed.ncbi.nlm.nih.gov/26100115","citation_count":4,"is_preprint":false},{"pmid":"39110041","id":"PMC_39110041","title":"Effect of Gastrin G-17 Combined with Pepsinogen PGI and PGII on the Early Screening of Gastric Cancer in the Department of Gastroenterology.","date":"2024","source":"Alternative therapies in health and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39110041","citation_count":3,"is_preprint":false},{"pmid":"8184583","id":"PMC_8184583","title":"[Dominant beta-thalassemia alleles in the Czech and Slovak population (beta-thalassemia mutations in 112(T-A) and 121(G-T) codons and the unstable Hradec Králové hemoglobin or alpha 2 beta 2 115 (G17) Ala-Asp)].","date":"1994","source":"Vnitrni lekarstvi","url":"https://pubmed.ncbi.nlm.nih.gov/8184583","citation_count":2,"is_preprint":false},{"pmid":"36477205","id":"PMC_36477205","title":"Phosphorylation of PBX2, a novel downstream target of mTORC1, is determined by GSK3 and PP1.","date":"2023","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36477205","citation_count":1,"is_preprint":false},{"pmid":"24145822","id":"PMC_24145822","title":"G17-modified hammerhead ribozymes are active in vitro and in vivo.","date":"2013","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/24145822","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.02.25319933","title":"Identifying Potential Drug Targets for Prostate Cancer from a Genetic Perspective: A Mendelian Randomization Study","date":"2025-01-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.02.25319933","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20790,"output_tokens":3606,"usd":0.05823},"stage2":{"model":"claude-opus-4-6","input_tokens":7050,"output_tokens":3305,"usd":0.176813},"total_usd":0.235043,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"PBX2 encodes a TALE homeodomain protein with 92% identity to PBX1 over 266 amino acids within and flanking the homeodomain; unlike PBX1 and PBX3, PBX2 is not alternatively spliced. PBX2 maps to chromosome 3q22-23 and is widely expressed in fetal and adult tissues, suggesting a generalized role.\",\n      \"method\": \"cDNA cloning, sequence analysis, chromosome in situ hybridization, Northern blotting\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — foundational cloning paper with multiple orthogonal methods, widely replicated\",\n      \"pmids\": [\"1682799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"PBX1 and PBX2 bind cooperatively to DNA with HOX proteins (Hoxb-7 and Hoxb-8), and E2A-PBX1 retains this ability; the hexapeptide (LFPWMR) and its position relative to the homeodomain in Hoxb-8 are required for cooperative DNA binding with PBX1 and PBX2.\",\n      \"method\": \"EMSA (electrophoretic mobility shift assay), deletion and point mutagenesis of the hexapeptide\",\n      \"journal\": \"Mechanisms of development; Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro DNA binding reconstitution with mutagenesis, confirmed by two independent papers\",\n      \"pmids\": [\"7577680\", \"7568094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In myeloid cells, PBX2 forms trimeric complexes with HOXA9 and MEIS1; MEIS1 enhances HOXA9-PBX2 complex formation in the absence of DNA, and immunoprecipitation of HOXA9 co-precipitates PBX2 and MEIS1. HOXA9, PBX2, and MEIS1 co-localize in nuclear speckles.\",\n      \"method\": \"EMSA, co-immunoprecipitation, nuclear fractionation, immunofluorescence co-localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus EMSA and localization, moderate evidence from single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10082572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A PBX2-PREP1 heterodimer binds to the Pbx site in the UGT2B17 promoter and interferes with HNF1α binding to its adjacent site, resulting in down-regulation of HNF1α-mediated transcriptional activation of UGT2B17.\",\n      \"method\": \"EMSA (gel shift assay), promoter-reporter functional assays, competition binding assays\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA plus functional reporter assays in a single lab study\",\n      \"pmids\": [\"12065766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A PBX2-containing complex (including PREP1) binds a novel regulatory element (PRE-1048) in the HOX11 promoter and activates HOX11 transcription in K562 cells, representing the first report of a homeobox gene regulated specifically by PBX2.\",\n      \"method\": \"EMSA, promoter-reporter transcription assays, supershift assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA plus functional reporter assays; single lab, single study\",\n      \"pmids\": [\"12054735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PREP-1 overexpression stabilizes PBX-2 protein by preventing its proteasomal degradation; dimerization of PBX-2 with PREP-1 reduces proteasome-dependent decay of PBX-2, increasing nuclear DNA-binding activity of PREP-PBX complexes.\",\n      \"method\": \"Cycloheximide chase, proteasome inhibitor (MG132) treatment, EMSA, immunoblotting in stably transfected F9 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — pharmacological and genetic perturbation with multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"12871956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Retinoic acid (RA) treatment increases PBX2 mRNA as a primary transcriptional response (not requiring new protein synthesis) and extends PBX2 protein half-life post-translationally, partly through RA-induced increased MEIS protein levels that stabilize PBX proteins against proteasomal degradation.\",\n      \"method\": \"Cycloheximide chase, RT-PCR, immunoblotting, mRNA stability assays in P19 cells with RAR antagonists\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple approaches in a single lab; consistent with independent stabilization mechanism findings\",\n      \"pmids\": [\"15095411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Pbx2-null mice are viable with no detectable developmental or hematopoietic phenotype, indicating functional redundancy with other Pbx proteins; Pbx2 protein is expressed at considerably lower levels than Pbx1/Pbx3 in embryonic tissues but is the predominant high-MW Pbx isoform in postnatal bone marrow and thymus.\",\n      \"method\": \"Knockout mouse generation, developmental analysis, immunoblotting, flow cytometry\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean germline KO with comprehensive phenotypic analysis across multiple tissues and life stages\",\n      \"pmids\": [\"15169896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Pbx1/Pbx2 compound loss-of-function in mice causes severe distal limb defects and complete limb absence in Pbx1−/−;Pbx2−/− embryos; the mechanism involves hierarchical control of Hox gene spatial distribution in the posterior limb and regulation of Shh expression in the ZPA.\",\n      \"method\": \"Compound knockout mouse model, in situ hybridization, skeletal analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with clean compound KO, multiple molecular readouts, Strong evidence for pathway position\",\n      \"pmids\": [\"16672333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Pbx1/Pbx2 govern axial skeletal patterning by controlling Polycomb and Hox expression/spatial distribution in paraxial mesoderm, and Pax1/Pax9 expression in sclerotome; compound Pbx1/Pbx2 mutants show homogeneous vertebral column, loss of vertebral identity, rudimentary ribs, and rostral hindlimb shifts.\",\n      \"method\": \"Compound knockout mouse model, in situ hybridization, skeletal staining, gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined molecular pathway placements and multiple readouts\",\n      \"pmids\": [\"18691704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Prep1/Pbx2 complexes bind the -2578 G allele of the CCL2 promoter (a polymorphism that creates a consensus Prep1 binding site) and suppress basal CCL2 transcription in astrocytes; upon IL-1β stimulation, Prep1/Pbx2 remains bound but no longer represses transcription, enabling hyper-responsive induction.\",\n      \"method\": \"EMSA, promoter-reporter assays, allele-specific binding experiments\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EMSA plus functional reporter assays, single lab\",\n      \"pmids\": [\"18480829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The HOXB7/PBX2 dimer acts as a positive transcriptional regulator of miR-221 and miR-222 in melanoma; disruption of HOXB7/PBX2 dimerization (using peptide HXR9) reduces miR-221/222 transcription, elevates c-FOS expression, and induces apoptosis.\",\n      \"method\": \"HOX/PBX dimerization antagonist (HXR9), miRNA expression analysis, reporter assays, apoptosis assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological disruption of the dimer with functional readouts; mechanism inferred but direct ChIP not shown for PBX2\",\n      \"pmids\": [\"23400877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PBX2 acts as a transcriptional activator of circTLK1 in glioma cells; circTLK1 in turn activates JAK/STAT signaling via a circTLK1/miR-452-5p/SSR1 axis to promote glioma progression.\",\n      \"method\": \"ChIP, luciferase reporter assay, AGO2-RIP, RNA pulldown, knockdown experiments\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and luciferase reporter demonstrate direct transcriptional regulation; single lab study\",\n      \"pmids\": [\"34721518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOXA6 physically interacts with and stabilizes PBX2 in gastric cancer cells; HOXA6-PBX2 co-expression promotes cell migration, invasion, and metastasis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, orthotopic implantation in vivo, transwell migration/invasion assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional KD with defined cellular phenotype; single lab\",\n      \"pmids\": [\"33535170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HOXB9 interacts with PBX2 to form a heterodimer that transcriptionally upregulates CDK6, driving G1-phase cell cycle progression in gastric cancer; E2F1 upregulates HOXB9 upstream, constituting an E2F1-HOXB9/PBX2-CDK6 oncogenic axis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, reporter assays, siRNA knockdown, cell cycle analysis\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, and functional knockdown with cell cycle readout; single lab\",\n      \"pmids\": [\"37272544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PBX2 is phosphorylated by GSK3 and dephosphorylated by PP1; mTORC1 activity promotes dephosphorylation of PBX2 (but not other PBX family members) via PP1, establishing PBX2 as a novel downstream target of mTORC1 signaling.\",\n      \"method\": \"Large-scale phosphoproteomics re-analysis, pharmacological inhibition (rapamycin, GSK3 inhibitors), siRNA knockdown of GSK3/PP1, immunoblotting with phospho-specific analysis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphoproteomics plus pharmacological and genetic perturbations; single lab, moderate evidence\",\n      \"pmids\": [\"36477205\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PBX2 is a TALE homeodomain transcription factor that forms heterodimeric complexes with PREP1/MEIS proteins (which protect it from proteasomal degradation) and cooperative DNA-binding complexes with HOX proteins (via the HOX hexapeptide), functioning as a context-dependent transcriptional activator or repressor at composite HOX-PBX binding sites; it also participates in trimeric complexes with HOXA9 and MEIS1 in myeloid cells, is required with PBX1 for limb and axial skeletal patterning via hierarchical control of Hox/Polycomb/Pax gene expression, and its activity is regulated post-translationally by mTORC1-dependent phosphorylation status determined by the antagonistic actions of GSK3 and PP1.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PBX2 is a TALE-class homeodomain transcription factor that functions as a context-dependent transcriptional activator or repressor by forming heterodimeric complexes with HOX proteins (via the HOX hexapeptide motif) and with PREP1/MEIS family members, which also protect PBX2 from proteasomal degradation [PMID:7577680, PMID:12871956, PMID:10082572]. In myeloid cells PBX2 participates in trimeric HOXA9–PBX2–MEIS1 complexes that co-localize in nuclear speckles, while in various cell types HOX–PBX2 dimers regulate targets including miR-221/222, CDK6, circTLK1, and HOX11 [PMID:10082572, PMID:23400877, PMID:37272544, PMID:12054735]. Although Pbx2-null mice are viable owing to functional redundancy with Pbx1 and Pbx3, compound Pbx1/Pbx2 loss-of-function reveals essential roles in limb morphogenesis and axial skeletal patterning through hierarchical control of Hox, Polycomb, Shh, and Pax gene expression [PMID:15169896, PMID:16672333, PMID:18691704]. PBX2 activity is post-translationally regulated by mTORC1-dependent dephosphorylation via PP1, opposing GSK3-mediated phosphorylation, establishing PBX2 as a unique mTORC1 effector among PBX family members [PMID:36477205].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Identification of PBX2 as a new TALE homeodomain protein closely related to PBX1 established the existence of a multigene PBX family with potential functional overlap, and its ubiquitous expression pattern distinguished it from more tissue-restricted paralogs.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, chromosomal mapping, and Northern blotting across fetal and adult tissues\",\n      \"pmids\": [\"1682799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional targets and in vivo functions of PBX2 were unknown\", \"Whether PBX2 was functionally redundant with PBX1/PBX3 was untested\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Demonstration that PBX2 cooperatively binds DNA with HOX proteins (Hoxb-7, Hoxb-8) through the hexapeptide motif established the molecular basis for HOX–PBX heterodimer formation and composite DNA recognition, a paradigm for TALE homeodomain partnerships.\",\n      \"evidence\": \"EMSA with deletion and point mutagenesis of the HOX hexapeptide\",\n      \"pmids\": [\"7577680\", \"7568094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HOX–PBX2 complexes regulate specific endogenous target genes was unknown\", \"The structural basis of the hexapeptide–PBX interaction awaited crystallographic analysis\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Discovery of trimeric HOXA9–PBX2–MEIS1 complexes in myeloid cells, with MEIS1 enhancing HOXA9–PBX2 complex formation even without DNA, revealed a higher-order combinatorial logic for TALE–HOX transcription factor assemblies and their subnuclear organization.\",\n      \"evidence\": \"Co-immunoprecipitation, EMSA, and immunofluorescence co-localization in nuclear speckles in myeloid cells\",\n      \"pmids\": [\"10082572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific genomic targets of the trimeric complex were not identified\", \"Functional significance of nuclear speckle localization was not determined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of PBX2–PREP1 as both a transcriptional repressor (at the UGT2B17 promoter, interfering with HNF1α) and an activator (at the HOX11 promoter) established PBX2 as a context-dependent transcriptional regulator whose output depends on the promoter architecture.\",\n      \"evidence\": \"EMSA, supershift assays, and promoter-reporter assays in K562 and other cell lines\",\n      \"pmids\": [\"12065766\", \"12054735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ChIP evidence for PBX2 occupancy at these endogenous promoters was not provided\", \"Mechanism switching between activation and repression was not characterized\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that PREP1 dimerization stabilizes PBX2 by preventing its proteasomal degradation defined a key post-translational regulatory axis in which PBX2 protein levels are controlled by the availability of TALE cofactors.\",\n      \"evidence\": \"Cycloheximide chase, MG132 proteasome inhibition, EMSA, and immunoblotting in stably transfected F9 cells\",\n      \"pmids\": [\"12871956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The ubiquitin ligase responsible for PBX2 degradation was not identified\", \"Whether MEIS proteins stabilize PBX2 through the same mechanism was not formally tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Retinoic acid was shown to increase PBX2 both transcriptionally (as a primary response) and post-translationally via MEIS-mediated stabilization, linking signaling pathways to PBX2 protein accumulation; meanwhile, Pbx2-null mice proved viable, revealing that Pbx2 is functionally redundant with other Pbx members despite being the predominant isoform in postnatal bone marrow and thymus.\",\n      \"evidence\": \"RT-PCR and cycloheximide chase in P19 cells; germline Pbx2 knockout mouse with developmental, hematopoietic, and expression analysis\",\n      \"pmids\": [\"15095411\", \"15169896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which Pbx paralog(s) compensate for Pbx2 loss in specific tissues was not resolved\", \"Direct RA-responsive elements in the PBX2 promoter were not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Compound Pbx1/Pbx2 knockout mice revealed that PBX2 cooperates with PBX1 to pattern the limb skeleton by hierarchically controlling Hox gene domains and Shh expression in the zone of polarizing activity, establishing redundant but essential roles for Pbx factors in appendicular development.\",\n      \"evidence\": \"Compound knockout mouse with skeletal analysis and in situ hybridization of Hox, Shh targets\",\n      \"pmids\": [\"16672333\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PBX2 binding at limb enhancers was not shown\", \"Whether PBX3 further compensates was not fully addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extension of compound Pbx1/Pbx2 analysis to axial skeleton demonstrated hierarchical control of Polycomb group genes, Hox gene spatial domains, and Pax1/Pax9 in sclerotome, explaining the complete loss of vertebral identity; separately, Prep1/Pbx2 was shown to mediate allele-specific repression of CCL2 in astrocytes, illustrating how genetic variation creates PBX2-dependent regulatory switches.\",\n      \"evidence\": \"Compound knockout mouse skeletal and molecular analysis; EMSA and reporter assays on CCL2 promoter polymorphism in astrocytes\",\n      \"pmids\": [\"18691704\", \"18480829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide binding profiles of PBX2 in paraxial mesoderm were not generated\", \"The mechanism by which IL-1β relieves Prep1/Pbx2 repression at CCL2 was not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The HOXB7–PBX2 dimer was identified as a positive transcriptional regulator of miR-221/222 in melanoma, with dimer disruption inducing apoptosis, providing direct evidence that HOX–PBX2 complexes control non-coding RNA targets relevant to cancer cell survival.\",\n      \"evidence\": \"HOX/PBX dimerization antagonist HXR9, miRNA expression analysis, apoptosis assays in melanoma cells\",\n      \"pmids\": [\"23400877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PBX2 ChIP at the miR-221/222 locus was not performed\", \"Whether the apoptotic effect is PBX2-specific or general to all PBX members was not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PBX2 was shown to directly activate circTLK1 transcription in glioma and to interact with HOXA6 to promote gastric cancer metastasis, broadening the repertoire of HOX–PBX2 target genes in oncogenic contexts and demonstrating that HOXA6 stabilizes PBX2 protein.\",\n      \"evidence\": \"ChIP, luciferase reporter, AGO2-RIP, RNA pulldown in glioma cells; Co-IP, siRNA knockdown, orthotopic implantation in gastric cancer models\",\n      \"pmids\": [\"34721518\", \"33535170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PBX2 contributes to tumorigenesis in vivo beyond xenograft models is unknown\", \"Global target gene repertoire of PBX2 in cancer cells has not been defined by genome-wide approaches\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies identified HOXB9–PBX2 as a transcriptional activator of CDK6 promoting cell cycle progression in gastric cancer, and demonstrated that PBX2 is uniquely regulated among PBX family members by mTORC1-dependent dephosphorylation via PP1 opposing GSK3-mediated phosphorylation, linking PBX2 activity to growth factor signaling.\",\n      \"evidence\": \"Co-IP, ChIP, reporter and cell cycle assays for HOXB9–PBX2–CDK6 axis; phosphoproteomics, rapamycin treatment, GSK3/PP1 siRNA knockdown for mTORC1 regulation\",\n      \"pmids\": [\"37272544\", \"36477205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The phosphorylation sites on PBX2 targeted by GSK3/PP1 were not mapped to individual residues\", \"Functional consequences of PBX2 phosphorylation on DNA binding or target gene selection were not determined\", \"Whether mTORC1-dependent PBX2 regulation operates in non-cancer contexts is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the genome-wide binding landscape of PBX2, the identity of the E3 ubiquitin ligase mediating its proteasomal degradation, and the specific phosphorylation sites and their functional impact on PBX2 transcriptional output.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide ChIP-seq or CUT&RUN data for PBX2 have been reported\", \"E3 ligase targeting PBX2 for degradation is unidentified\", \"Functional consequence of mTORC1-regulated phosphorylation on specific PBX2 target genes is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 4, 11, 12, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0074160\", \"supporting_discovery_ids\": [3, 4, 11, 12, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"PREP1\",\n      \"MEIS1\",\n      \"HOXA9\",\n      \"HOXB7\",\n      \"HOXB9\",\n      \"HOXA6\",\n      \"PBX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}