{"gene":"BMP2K","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2020,"finding":"BMP2K (BIKE) is required for dengue virus (DENV) infection, mediating both early (post-internalization) and late (assembly/egress) stages of the DENV life cycle; this function is mediated in part through phosphorylation of threonine 156 (T156) in the μ subunit of the AP-2 adaptor protein complex.","method":"Pharmacological inhibition (5Z-7-oxozeaenol and selective BIKE inhibitors), BIKE overexpression rescue experiments, in vitro and ex vivo antiviral assays","journal":"Antiviral research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional inhibition, overexpression rescue, and identification of a specific phosphorylation substrate in a single focused study with multiple orthogonal methods","pmids":["33137362"],"is_preprint":false},{"year":2021,"finding":"BMP2K phosphorylates the AP-2 adaptor protein complex both in vitro and in vivo; functional impairment of BMP2K impedes AP-2 phosphorylation, disrupts clathrin-coated pit (CCP) morphology, and inhibits cargo internalization. BMP2K interacts with AP-2 via its extended C-terminus, and this interaction is required for BMP2K's CCP localization and function. Additionally, endogenous BMP2K levels decline upon AP-2 functional impairment, indicating AP-2-dependent BMP2K stabilization.","method":"In vitro kinase assay, loss-of-function (BMP2K impairment), Co-IP/interaction mapping (C-terminus domain), live imaging of CCP morphology, cargo internalization assays, zebrafish loss-of-function (gastrulation phenotype)","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay plus in vivo phosphorylation, domain mapping, cellular phenotype, and in vivo vertebrate validation in a single focused study","pmids":["34480404"],"is_preprint":false},{"year":2020,"finding":"BMP2K has two splicing variants (BMP2K-L and BMP2K-S) that constitute a regulatory system in erythroid cells: both isoforms interact with SEC16A and can localize to the juxtanuclear secretory compartment; BMP2K-L promotes autophagic degradation and erythroid differentiation while BMP2K-S restricts them. Both variants differentially regulate distribution of SEC16A and SEC24B and abundance of SEC31A at COPII assemblies, revealing a novel role in COPII-dependent secretory trafficking distinct from AP-2/endocytosis.","method":"Splicing variant-specific depletion, Co-IP (SEC16A interaction), subcellular localization (juxtanuclear compartment fractionation/imaging), autophagy assays, erythroid differentiation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — isoform-specific knockdown, reciprocal interaction validation, localization experiments, and functional differentiation assays with multiple orthogonal methods in one study","pmids":["32795391"],"is_preprint":false},{"year":2020,"finding":"BMP2K splicing variants BMP2K-L and BMP2K-S play opposing roles in autophagic degradation in erythroid cells, potentially via differential regulation of SEC16A-dependent COPII assembly; SEC24B, a SEC16A interactor implicated in autophagy, is differentially affected by the two isoforms.","method":"Isoform-specific depletion, autophagy assays, COPII assembly analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab confirmatory study summarizing findings from the eLife paper; adds mechanistic detail but same group, largely overlapping methods","pmids":["33025853"],"is_preprint":false},{"year":2022,"finding":"BIKE (BMP2K) phosphorylates threonine 294 of the cargo adapter protein CLINT1 both in vitro and in cell culture. CLINT1 phosphorylation by BIKE mediates CLINT1 binding to the DENV nonstructural 3 (NS3) protein, thereby promoting DENV assembly and egress. Live-cell imaging showed CLINT1 co-traffics with DENV particles, establishing CLINT1 as a downstream substrate through which BIKE controls a late stage of the DENV life cycle.","method":"Barcode fusion genetics-yeast two-hybrid screen, affinity-purification mass spectrometry, mammalian cell-based protein-protein interaction assays (19 of 47 putative interactors validated), in vitro and in-cell kinase assay (T294 phosphorylation), live-cell imaging, DENV assembly/egress assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro and in-cell phosphorylation assays, live-cell imaging, and multiple orthogonal interaction screens converging on CLINT1 as a BIKE substrate in a single focused study","pmids":["35452674"],"is_preprint":false},{"year":2020,"finding":"BMP2K upregulation suppresses megakaryocyte polyploidization and differentiation; mechanistically, CDK2 interacts with BMP2K and partially mediates its function. BMP2K overexpression reduced the G2/M cell-cycle fraction and increased G1 phase in megakaryoblastic leukemia cells challenged with MLN8237 or nocodazole, suggesting BMP2K promotes mitosis at the expense of endomitosis/polyploidization.","method":"Co-IP (CDK2-BMP2K interaction), BMP2K overexpression and knockdown, cell-cycle analysis (flow cytometry), megakaryocyte differentiation assays, drug sensitivity assays","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — single lab, Co-IP for CDK2 interaction, functional overexpression/KD with cell-cycle phenotype but limited mechanistic depth","pmids":["32322386"],"is_preprint":false},{"year":2023,"finding":"BMP2K subcellular distribution is regulated by two mechanisms: (1) liquid-liquid phase separation (LLPS) driven by a glutamine-rich region, with droplet formation controlled by hyperosmolarity; (2) cytoplasmic retention enforced by phosphorylation of Ser-1010 (which inhibits its nuclear localization signal) and by a newly identified cytoplasmic localization region that antagonizes the NLS, explaining why BMP2K localizes to the cytoplasm despite possessing an NLS.","method":"Domain deletion/mutation analysis, phosphorylation-mimetic and phospho-dead mutants, live-cell imaging of droplet formation, osmolarity perturbation experiments, NLS mutagenesis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, multiple mutagenesis and imaging approaches but no independent replication; mechanistic conclusions about LLPS and NLS regulation are internally consistent","pmids":["36739695"],"is_preprint":false},{"year":2025,"finding":"An in-frame BMP2K::PDGFRA fusion gene was detected in a patient with myeloid/lymphoid neoplasm with eosinophilia, establishing BMP2K as a novel fusion partner for PDGFRA in this disease context.","method":"RNA sequencing (Archer Fusion Plex Pan Solid Tumor Panel), DNA NGS","journal":"Journal of hematopathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single clinical case with RNA-seq detection only; no functional mechanistic characterization of the fusion protein","pmids":["41131416"],"is_preprint":false}],"current_model":"BMP2K (BIKE) is a serine-threonine kinase of the Numb-associated kinase (NAK) family that phosphorylates the AP-2 adaptor complex (μ subunit T156) to regulate clathrin-mediated endocytosis and clathrin-coated pit morphology; it also phosphorylates the cargo adapter CLINT1 (T294) to promote DENV assembly/egress; its two splicing isoforms (BMP2K-L and BMP2K-S) differentially regulate SEC16A/COPII assembly abundance and autophagy to fine-tune erythroid differentiation; BMP2K interacts with CDK2 to promote mitosis over polyploidization in megakaryopoiesis; and its cytoplasmic localization is controlled by Ser-1010 phosphorylation (suppressing its NLS) and a glutamine-rich region that drives liquid-liquid phase separation."},"narrative":{"mechanistic_narrative":"BMP2K (BIKE) is a serine-threonine kinase that controls clathrin- and COPII-dependent membrane trafficking and links these functions to viral infection, hematopoietic differentiation, and cell-cycle decisions [PMID:34480404, PMID:32795391]. Its core endocytic activity is to phosphorylate the μ subunit of the AP-2 adaptor complex (T156); loss of this activity disrupts clathrin-coated pit morphology and impairs cargo internalization, and BMP2K is recruited to coated pits through an extended C-terminal interaction with AP-2 that also stabilizes the kinase [PMID:34480404]. Through AP-2 phosphorylation and through phosphorylation of the cargo adapter CLINT1 (T294), which enables CLINT1 binding to the dengue virus NS3 protein, BMP2K supports both early (post-internalization) and late (assembly/egress) stages of the dengue virus life cycle [PMID:33137362, PMID:35452674]. Two splicing isoforms, BMP2K-L and BMP2K-S, both bind SEC16A and act antagonistically on COPII assembly (distribution of SEC16A/SEC24B and abundance of SEC31A), autophagic degradation, and erythroid differentiation [PMID:32795391, PMID:33025853]. BMP2K also interacts with CDK2 and, when upregulated, suppresses megakaryocyte polyploidization in favor of mitosis [PMID:32322386]. Its predominantly cytoplasmic distribution is enforced by Ser-1010 phosphorylation that suppresses an NLS and by a glutamine-rich region that drives liquid-liquid phase separation [PMID:36739695].","teleology":[{"year":2020,"claim":"Established BMP2K as a host kinase required for dengue virus infection and identified AP-2 μ-subunit T156 phosphorylation as a contributing mechanism, connecting the kinase to a defined endocytic substrate.","evidence":"Pharmacological inhibition, BIKE overexpression rescue, and antiviral assays in cell and ex vivo systems","pmids":["33137362"],"confidence":"High","gaps":["Did not separate the kinase's direct catalytic contribution from scaffolding at each viral life-cycle stage","Late-stage (assembly/egress) substrate not yet identified in this study"]},{"year":2020,"claim":"Revealed a non-endocytic role by showing the two BMP2K splicing isoforms differentially control SEC16A/COPII secretory assembly, autophagy, and erythroid differentiation, expanding the kinase beyond AP-2/endocytosis.","evidence":"Isoform-specific depletion, SEC16A Co-IP, juxtanuclear localization, and autophagy/differentiation assays in erythroid cells","pmids":["32795391"],"confidence":"High","gaps":["COPII components were not shown to be direct kinase substrates","Mechanism by which L and S isoforms exert opposite effects unresolved"]},{"year":2020,"claim":"Linked BMP2K to megakaryocyte cell-fate decisions, showing it interacts with CDK2 and biases cells toward mitosis over polyploidization when upregulated.","evidence":"CDK2 Co-IP, overexpression/knockdown, and cell-cycle/differentiation assays in megakaryoblastic leukemia cells","pmids":["32322386"],"confidence":"Medium","gaps":["CDK2 not shown to be a phosphorylation substrate","Single Co-IP without structural or reciprocal mapping","Catalytic dependence of the cell-cycle phenotype untested"]},{"year":2020,"claim":"Reinforced the isoform-specific autophagy mechanism by tying opposing L/S effects to differential SEC16A-dependent COPII assembly and SEC24B regulation.","evidence":"Isoform-specific depletion, autophagy assays, and COPII assembly analysis (confirmatory same-group study)","pmids":["33025853"],"confidence":"Medium","gaps":["Largely overlapping methods and same group as the primary study","Direct causal chain from COPII to autophagy not established"]},{"year":2021,"claim":"Defined the endocytic mechanism in detail: BMP2K phosphorylates AP-2 in vitro and in vivo, is recruited to coated pits via a C-terminal AP-2 interaction required for its localization and function, and is itself stabilized by AP-2.","evidence":"In vitro kinase assay, loss-of-function, Co-IP/domain mapping, live CCP imaging, cargo internalization, and zebrafish gastrulation phenotype","pmids":["34480404"],"confidence":"High","gaps":["Structural basis of the C-terminus/AP-2 interaction not resolved","Mechanism of AP-2-dependent BMP2K stabilization unknown"]},{"year":2022,"claim":"Identified CLINT1 T294 as a BMP2K substrate whose phosphorylation drives CLINT1 binding to dengue NS3, explaining how the kinase controls a late (assembly/egress) stage of the viral life cycle.","evidence":"Y2H and AP-MS interaction screens, in vitro and in-cell kinase assays, live-cell imaging of co-trafficking, and DENV assembly/egress assays","pmids":["35452674"],"confidence":"High","gaps":["Endogenous host (non-viral) function of CLINT1 phosphorylation not defined","Whether CLINT1 phosphorylation intersects the COPII/AP-2 roles untested"]},{"year":2023,"claim":"Explained BMP2K's cytoplasmic distribution by identifying Ser-1010 phosphorylation that suppresses its NLS and a glutamine-rich region driving osmolarity-sensitive liquid-liquid phase separation.","evidence":"Domain deletion, phospho-mimetic/phospho-dead and NLS mutants, live-cell droplet imaging, and osmolarity perturbation","pmids":["36739695"],"confidence":"Medium","gaps":["Functional consequence of phase separation for kinase activity or trafficking roles untested","Kinase responsible for Ser-1010 phosphorylation unknown","No independent replication"]},{"year":2025,"claim":"Reported a BMP2K::PDGFRA fusion in a myeloid/lymphoid neoplasm with eosinophilia, nominating BMP2K as a fusion partner in this disease context.","evidence":"RNA-seq fusion detection and DNA NGS in a single clinical case","pmids":["41131416"],"confidence":"Low","gaps":["No functional characterization of the fusion protein","Single case without mechanistic validation","Contribution of BMP2K sequence to fusion oncogenicity unknown"]},{"year":null,"claim":"How BMP2K's distinct activities — AP-2/endocytosis, isoform-specific COPII/autophagy, CDK2/cell-cycle, and phase separation — are integrated and selectively engaged in different cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking the endocytic and secretory/autophagy functions","Whether the catalytic activity is required for all reported roles is untested","In vivo physiological substrate repertoire beyond AP-2 and CLINT1 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["AP2M1","CLINT1","SEC16A","CDK2","SEC24B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NSY1","full_name":"BMP-2-inducible protein kinase","aliases":[],"length_aa":1161,"mass_kda":129.2,"function":"May be involved in osteoblast differentiation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NSY1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BMP2K","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"AP2B1","stoichiometry":0.2},{"gene":"AP2S1","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"NECAP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/BMP2K","total_profiled":1310},"omim":[{"mim_id":"617648","title":"BMP2-INDUCIBLE KINASE; BMP2K","url":"https://www.omim.org/entry/617648"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BMP2K"},"hgnc":{"alias_symbol":["DKFZp434K0614","BIKe"],"prev_symbol":[]},"alphafold":{"accession":"Q9NSY1","domains":[{"cath_id":"3.30.200.20","chopping":"42-133","consensus_level":"medium","plddt":95.1949,"start":42,"end":133},{"cath_id":"1.10.510.10","chopping":"136-348","consensus_level":"medium","plddt":97.2559,"start":136,"end":348}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSY1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSY1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NSY1-F1-predicted_aligned_error_v6.png","plddt_mean":55.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BMP2K","jax_strain_url":"https://www.jax.org/strain/search?query=BMP2K"},"sequence":{"accession":"Q9NSY1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NSY1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NSY1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NSY1"}},"corpus_meta":[{"pmid":"24652987","id":"PMC_24652987","title":"CD16xCD33 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\"Pharmacological inhibition (5Z-7-oxozeaenol and selective BIKE inhibitors), BIKE overexpression rescue experiments, in vitro and ex vivo antiviral assays\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional inhibition, overexpression rescue, and identification of a specific phosphorylation substrate in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"33137362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BMP2K phosphorylates the AP-2 adaptor protein complex both in vitro and in vivo; functional impairment of BMP2K impedes AP-2 phosphorylation, disrupts clathrin-coated pit (CCP) morphology, and inhibits cargo internalization. BMP2K interacts with AP-2 via its extended C-terminus, and this interaction is required for BMP2K's CCP localization and function. Additionally, endogenous BMP2K levels decline upon AP-2 functional impairment, indicating AP-2-dependent BMP2K stabilization.\",\n      \"method\": \"In vitro kinase assay, loss-of-function (BMP2K impairment), Co-IP/interaction mapping (C-terminus domain), live imaging of CCP morphology, cargo internalization assays, zebrafish loss-of-function (gastrulation phenotype)\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay plus in vivo phosphorylation, domain mapping, cellular phenotype, and in vivo vertebrate validation in a single focused study\",\n      \"pmids\": [\"34480404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BMP2K has two splicing variants (BMP2K-L and BMP2K-S) that constitute a regulatory system in erythroid cells: both isoforms interact with SEC16A and can localize to the juxtanuclear secretory compartment; BMP2K-L promotes autophagic degradation and erythroid differentiation while BMP2K-S restricts them. Both variants differentially regulate distribution of SEC16A and SEC24B and abundance of SEC31A at COPII assemblies, revealing a novel role in COPII-dependent secretory trafficking distinct from AP-2/endocytosis.\",\n      \"method\": \"Splicing variant-specific depletion, Co-IP (SEC16A interaction), subcellular localization (juxtanuclear compartment fractionation/imaging), autophagy assays, erythroid differentiation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific knockdown, reciprocal interaction validation, localization experiments, and functional differentiation assays with multiple orthogonal methods in one study\",\n      \"pmids\": [\"32795391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BMP2K splicing variants BMP2K-L and BMP2K-S play opposing roles in autophagic degradation in erythroid cells, potentially via differential regulation of SEC16A-dependent COPII assembly; SEC24B, a SEC16A interactor implicated in autophagy, is differentially affected by the two isoforms.\",\n      \"method\": \"Isoform-specific depletion, autophagy assays, COPII assembly analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab confirmatory study summarizing findings from the eLife paper; adds mechanistic detail but same group, largely overlapping methods\",\n      \"pmids\": [\"33025853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BIKE (BMP2K) phosphorylates threonine 294 of the cargo adapter protein CLINT1 both in vitro and in cell culture. CLINT1 phosphorylation by BIKE mediates CLINT1 binding to the DENV nonstructural 3 (NS3) protein, thereby promoting DENV assembly and egress. Live-cell imaging showed CLINT1 co-traffics with DENV particles, establishing CLINT1 as a downstream substrate through which BIKE controls a late stage of the DENV life cycle.\",\n      \"method\": \"Barcode fusion genetics-yeast two-hybrid screen, affinity-purification mass spectrometry, mammalian cell-based protein-protein interaction assays (19 of 47 putative interactors validated), in vitro and in-cell kinase assay (T294 phosphorylation), live-cell imaging, DENV assembly/egress assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro and in-cell phosphorylation assays, live-cell imaging, and multiple orthogonal interaction screens converging on CLINT1 as a BIKE substrate in a single focused study\",\n      \"pmids\": [\"35452674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BMP2K upregulation suppresses megakaryocyte polyploidization and differentiation; mechanistically, CDK2 interacts with BMP2K and partially mediates its function. BMP2K overexpression reduced the G2/M cell-cycle fraction and increased G1 phase in megakaryoblastic leukemia cells challenged with MLN8237 or nocodazole, suggesting BMP2K promotes mitosis at the expense of endomitosis/polyploidization.\",\n      \"method\": \"Co-IP (CDK2-BMP2K interaction), BMP2K overexpression and knockdown, cell-cycle analysis (flow cytometry), megakaryocyte differentiation assays, drug sensitivity assays\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — single lab, Co-IP for CDK2 interaction, functional overexpression/KD with cell-cycle phenotype but limited mechanistic depth\",\n      \"pmids\": [\"32322386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BMP2K subcellular distribution is regulated by two mechanisms: (1) liquid-liquid phase separation (LLPS) driven by a glutamine-rich region, with droplet formation controlled by hyperosmolarity; (2) cytoplasmic retention enforced by phosphorylation of Ser-1010 (which inhibits its nuclear localization signal) and by a newly identified cytoplasmic localization region that antagonizes the NLS, explaining why BMP2K localizes to the cytoplasm despite possessing an NLS.\",\n      \"method\": \"Domain deletion/mutation analysis, phosphorylation-mimetic and phospho-dead mutants, live-cell imaging of droplet formation, osmolarity perturbation experiments, NLS mutagenesis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, multiple mutagenesis and imaging approaches but no independent replication; mechanistic conclusions about LLPS and NLS regulation are internally consistent\",\n      \"pmids\": [\"36739695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"An in-frame BMP2K::PDGFRA fusion gene was detected in a patient with myeloid/lymphoid neoplasm with eosinophilia, establishing BMP2K as a novel fusion partner for PDGFRA in this disease context.\",\n      \"method\": \"RNA sequencing (Archer Fusion Plex Pan Solid Tumor Panel), DNA NGS\",\n      \"journal\": \"Journal of hematopathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single clinical case with RNA-seq detection only; no functional mechanistic characterization of the fusion protein\",\n      \"pmids\": [\"41131416\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BMP2K (BIKE) is a serine-threonine kinase of the Numb-associated kinase (NAK) family that phosphorylates the AP-2 adaptor complex (μ subunit T156) to regulate clathrin-mediated endocytosis and clathrin-coated pit morphology; it also phosphorylates the cargo adapter CLINT1 (T294) to promote DENV assembly/egress; its two splicing isoforms (BMP2K-L and BMP2K-S) differentially regulate SEC16A/COPII assembly abundance and autophagy to fine-tune erythroid differentiation; BMP2K interacts with CDK2 to promote mitosis over polyploidization in megakaryopoiesis; and its cytoplasmic localization is controlled by Ser-1010 phosphorylation (suppressing its NLS) and a glutamine-rich region that drives liquid-liquid phase separation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BMP2K (BIKE) is a serine-threonine kinase that controls clathrin- and COPII-dependent membrane trafficking and links these functions to viral infection, hematopoietic differentiation, and cell-cycle decisions [#1, #2]. Its core endocytic activity is to phosphorylate the μ subunit of the AP-2 adaptor complex (T156); loss of this activity disrupts clathrin-coated pit morphology and impairs cargo internalization, and BMP2K is recruited to coated pits through an extended C-terminal interaction with AP-2 that also stabilizes the kinase [#1]. Through AP-2 phosphorylation and through phosphorylation of the cargo adapter CLINT1 (T294), which enables CLINT1 binding to the dengue virus NS3 protein, BMP2K supports both early (post-internalization) and late (assembly/egress) stages of the dengue virus life cycle [#0, #4]. Two splicing isoforms, BMP2K-L and BMP2K-S, both bind SEC16A and act antagonistically on COPII assembly (distribution of SEC16A/SEC24B and abundance of SEC31A), autophagic degradation, and erythroid differentiation [#2, #3]. BMP2K also interacts with CDK2 and, when upregulated, suppresses megakaryocyte polyploidization in favor of mitosis [#5]. Its predominantly cytoplasmic distribution is enforced by Ser-1010 phosphorylation that suppresses an NLS and by a glutamine-rich region that drives liquid-liquid phase separation [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established BMP2K as a host kinase required for dengue virus infection and identified AP-2 μ-subunit T156 phosphorylation as a contributing mechanism, connecting the kinase to a defined endocytic substrate.\",\n      \"evidence\": \"Pharmacological inhibition, BIKE overexpression rescue, and antiviral assays in cell and ex vivo systems\",\n      \"pmids\": [\"33137362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate the kinase's direct catalytic contribution from scaffolding at each viral life-cycle stage\", \"Late-stage (assembly/egress) substrate not yet identified in this study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a non-endocytic role by showing the two BMP2K splicing isoforms differentially control SEC16A/COPII secretory assembly, autophagy, and erythroid differentiation, expanding the kinase beyond AP-2/endocytosis.\",\n      \"evidence\": \"Isoform-specific depletion, SEC16A Co-IP, juxtanuclear localization, and autophagy/differentiation assays in erythroid cells\",\n      \"pmids\": [\"32795391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"COPII components were not shown to be direct kinase substrates\", \"Mechanism by which L and S isoforms exert opposite effects unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked BMP2K to megakaryocyte cell-fate decisions, showing it interacts with CDK2 and biases cells toward mitosis over polyploidization when upregulated.\",\n      \"evidence\": \"CDK2 Co-IP, overexpression/knockdown, and cell-cycle/differentiation assays in megakaryoblastic leukemia cells\",\n      \"pmids\": [\"32322386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CDK2 not shown to be a phosphorylation substrate\", \"Single Co-IP without structural or reciprocal mapping\", \"Catalytic dependence of the cell-cycle phenotype untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reinforced the isoform-specific autophagy mechanism by tying opposing L/S effects to differential SEC16A-dependent COPII assembly and SEC24B regulation.\",\n      \"evidence\": \"Isoform-specific depletion, autophagy assays, and COPII assembly analysis (confirmatory same-group study)\",\n      \"pmids\": [\"33025853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Largely overlapping methods and same group as the primary study\", \"Direct causal chain from COPII to autophagy not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the endocytic mechanism in detail: BMP2K phosphorylates AP-2 in vitro and in vivo, is recruited to coated pits via a C-terminal AP-2 interaction required for its localization and function, and is itself stabilized by AP-2.\",\n      \"evidence\": \"In vitro kinase assay, loss-of-function, Co-IP/domain mapping, live CCP imaging, cargo internalization, and zebrafish gastrulation phenotype\",\n      \"pmids\": [\"34480404\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the C-terminus/AP-2 interaction not resolved\", \"Mechanism of AP-2-dependent BMP2K stabilization unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified CLINT1 T294 as a BMP2K substrate whose phosphorylation drives CLINT1 binding to dengue NS3, explaining how the kinase controls a late (assembly/egress) stage of the viral life cycle.\",\n      \"evidence\": \"Y2H and AP-MS interaction screens, in vitro and in-cell kinase assays, live-cell imaging of co-trafficking, and DENV assembly/egress assays\",\n      \"pmids\": [\"35452674\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous host (non-viral) function of CLINT1 phosphorylation not defined\", \"Whether CLINT1 phosphorylation intersects the COPII/AP-2 roles untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Explained BMP2K's cytoplasmic distribution by identifying Ser-1010 phosphorylation that suppresses its NLS and a glutamine-rich region driving osmolarity-sensitive liquid-liquid phase separation.\",\n      \"evidence\": \"Domain deletion, phospho-mimetic/phospho-dead and NLS mutants, live-cell droplet imaging, and osmolarity perturbation\",\n      \"pmids\": [\"36739695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of phase separation for kinase activity or trafficking roles untested\", \"Kinase responsible for Ser-1010 phosphorylation unknown\", \"No independent replication\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported a BMP2K::PDGFRA fusion in a myeloid/lymphoid neoplasm with eosinophilia, nominating BMP2K as a fusion partner in this disease context.\",\n      \"evidence\": \"RNA-seq fusion detection and DNA NGS in a single clinical case\",\n      \"pmids\": [\"41131416\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional characterization of the fusion protein\", \"Single case without mechanistic validation\", \"Contribution of BMP2K sequence to fusion oncogenicity unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BMP2K's distinct activities — AP-2/endocytosis, isoform-specific COPII/autophagy, CDK2/cell-cycle, and phase separation — are integrated and selectively engaged in different cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking the endocytic and secretory/autophagy functions\", \"Whether the catalytic activity is required for all reported roles is untested\", \"In vivo physiological substrate repertoire beyond AP-2 and CLINT1 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AP2M1\", \"CLINT1\", \"SEC16A\", \"CDK2\", \"SEC24B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}